Download Identification of Anticancer Peptides from Bovine Milk Proteins and

Identification of Anticancer Peptides from Bovine
Milk Proteins and Their Potential Roles in
Management of Cancer: A Critical Review
B. N. P. Sah, T. Vasiljevic, S. McKechnie, and O. N. Donkor
Abstract: Cancer is the most widely recognized reason for human deaths globally. Conventional anticancer therapies,
including chemotherapy and radiation, are very costly and induce severe side effects on the individual. The discovery of
natural anticancer compounds like peptides may thus be a better alternative for cancer prevention and management. The
anticancer peptides also exist in the amino acid chain of milk proteins and can be generated during proteolytic activities
such as gastrointestinal digestion or food processing including fermentation. This paper presents an exhaustive overview
of the contemporary literature on antitumor activities of peptides released from milk proteins. In addition, caseins and
whey proteins have been evaluated for anticancer potential using the AntiCP database, a web-based prediction server.
Proline and lysine, respectively, dominate at various positions in anticancer peptides obtained from caseins and whey
proteins. The remarkable number of potential anticancer peptides revealed milk proteins as favorable candidates for the
development of anticancer agents or milk and milk products for reduction of cancer risks. Moreover, anticancer peptides
liberated from milk proteins can be identified from fermented dairy products. Although current findings of correlation
between dairy food intakes and cancer risks lack consistency, dairy-derived peptides show promise as candidates for cancer
therapy. This critical review supports the notion that milk proteins are not only a nutritious part of a normal daily diet
but also have potential for prevention and/or management of cancer.
Keywords: anticancer activity, bioactive peptides, caseins, whey proteins
Introduction
Exponential rate of urbanization, mechanization, and industrialization has led to dramatic changes in life cycle and dietary
patterns of population, which in turn has been accompanied by an
increase in the occurrence of chronic noncommunicable disease
such as cancers. Cancers represent about one-eighth of all deaths
worldwide and have become a leading cause of mortality (Matsuo
and others 2010). Lung (12.7%), breast (10.9%), and colorectal
(9.7%) cancers were the most commonly diagnosed cancers worldwide in 2008. The common causes of death due to cancers in
2008 were lung (18.2%), stomach (9.7%), and liver (9.2%) cancers
(Ferlay and others 2010). New cases of cancers are reported every
day and mortality rates continue to rise (Jemal and others 2011).
Cancer is a term for a class of diseases identified by uncontrolled
growth and spread of abnormal cells, which may be induced by external environmental factors (radiation, chemicals, and infectious
MS 20141563 Submitted 18/9/2014, Accepted 3/12/2014. Authors Sah, Vasiljevic, and Donkor are with College of Health and Biomedicine, Victoria Univ.,
Werribee Campus, PO Box 14428, Melbourne, Victoria 8001, Australia Author
McKechnie is with College of Engineering and Science, Victoria Univ., Werribee
Campus, PO Box 14428, Melbourne, Victoria 8001, Australia. Direct inquiries to
author Donkor (E-mail: [email protected]).
C 2015 Institute of Food Technologists®
doi: 10.1111/1541-4337.12126
organisms) or internal factors (mutations, hormones, and altered
immunity; Tanaka 1997). The carcinogenesis process includes
multiple stages of molecular biochemical alterations in the cells of
the tissue where cancer develops (Tanaka 2009). The 3 main stages
in carcinogenesis are: (i) initiation, in which free radicals induce
genetic changes; (ii) promotion, which is a relatively slower stage
of carcinogenesis and involves selective and sustained preneoplasia,
causing specific expansion of initiated cells to a benign tumor;
and (iii) tumor progression, in which a high degree of genetic
instability prompts chromosomal alterations (Tanaka 1997).
Fortunately, rapid progress in treatment has switched some fatal cancers to survivable chronic diseases because of development
of anticancer drugs such as hormone agonists/antagonists, antimetabolites, and DNA-alkylating agents (Pérez-Tomás 2006).
An example of this is the study carried out by Oeffinger and
others (2006) and Sant and others (2009) in which anthracyclines
exhibited the furtherance of survival in breast cancer and childhood cancer. Unfortunately, this advancement has been associated
with several cardiotoxicities (Curigliano and others 2010). Furthermore, it is difficult to deliver the precise dose of a drug to
malignant cells without adversely influencing normal cells, with
common problems such as drug resistance and biotransformation
(Kakde and others 2011). The questions raised about safety inherent in existing chemotherapeutic medications have encouraged
Vol. 14, 2015 r Comprehensive Reviews in Food Science and Food Safety 123
Advanced food systems research unit . . .
the quest for new anticancer agents including peptide vaccines
with increased therapeutic index and reduced toxicity.
Peptide-based drug therapies have drawn attention nowadays
for their interesting promising applications in drug design owing
to their possession of various key benefits, including low cytotoxicity, strong specificity, tumor-penetrating ability, small size,
and easy modification (Barras and Widmann 2011). Recently, researchers have shown an increased interest in the generation of
biologically active peptides encrypted within various proteins/and
protein sources, with a perspective to using such peptides as functional components as well (Ryan and others 2011). The functional
attributes of these proteins can be enhanced by hydrolysis under
specific conditions (Jumeri and Kim 2011). About 60 approved
peptide drugs are now commercially available with annual sales of
more than $13 billion (Thayer 2011). Many natural or synthetic
cationic peptides have been accounted for exhibiting antitumor
activities, with interesting features including high specificity towards cancer cells (Hoskin and Ramamoorthy 2008). Anticancer
peptides have been reported to display activities against cancer cells
mainly through cytoplasmic membrane disruption through pore
formation or micellization, and apoptosis induction (Papo and
Shai 2005). The evidence from several structure/activity studies
on both natural and synthetic anticancer peptides thus far supports
the idea that a number of factors are responsible for this activity,
including amphipathicity, hydrophobicity, net charge, secondary
structure in membrane, and oligomerization ability (Hoskin and
Ramamoorthy 2008; Maher and McClean 2008). Moreover,
Huang and others (2011) found that hydrophobicity of peptides
played a critical role during activities against malignant cells because of the hydrophobic environments of cell membrane. These
bioactive peptides are obtainable from various food proteins.
Milk proteins not only deliver excellent nutrients to the suckling
baby but can also display several physiological and biological activities. A variety of bioactive peptides can be generated upon suitable
hydrolysis of caseins (α S1 , α S2 , β, and κ) which account for about
80% of total milk protein, and whey proteins (β-lactoglobulin
[β-Lg], α-lactalbumin [α-LA], bovine lactoferrin, bovine serum
albumin (BSA), lactoperoxidase, and immunoglobulins) representing the remaining 20% of milk proteins (Jakubowicz and Froy
2013). Milk protein hydrolysates may have a remarkable role in
cancer therapy, and are widely abundant in various dairy foods.
Dairy foods are important items of modern menu, but their
relationship with the risks of malignancies is controversial. Therefore, various studies (Park and others 2008; Davoodi and others 2013) have elucidated the role of dairy food consumption in
the development of various malignancies. An increased consumption of dairy foods and calcium has been linked with increased
prostate cancer risks (Gao and others 2005). Larsson and others
(2004) also reported that high intakes of dairy products, particularly milk, are associated with increased risk of serous ovarian cancer. Likewise, Qin and others (2007), from analyzing published
cohort studies with meta-analysis, concluded a positive correlation between high milk and dairy products intakes and increased
prostate cancer risks, and postulated that fat, hormones, and calcium may be responsible for this association as milk is rich in these
nutrients. Duarte-Salles and others (2014) reported a linkage of
increased dairy food consumptions, especially milk and cheese,
with increased risks of hepatocellular carcinoma amidst Western
Europeans. Conversely, higher consumption of dairy foods was observed in association with a reduced risk of bladder cancer (Larsson
and others 2008), breast cancer (Dong and others 2011), and colorectal cancer (Aune and others 2012). Furthermore, the level of
estrogen (a form of endogenous estrogen) in daily dairy product
intake is about 0.25% of the FAO/WHO upper acceptable daily
intake of estradiol (Parodi 2012). Therefore, estrogen-enhanced
tumor growth may not be due to consumption of dairy products
as endogenous hormones such as estrogens involved in cancer development at various hormone-responsive sites including breast,
ovary, prostate, and endometrium (Qin and others 2004; Lukanova
and Kaaks 2005) are below the upper acceptable daily intake.
In this context, the objective of this review was to present a
scientific prediction of anticancer peptides that could be potentially
acquired from milk proteins and explore the available related work
with milk and milk products.
Casein-Derived Antitumor Peptides
β-Casomorphins (β-CMs) are opioid-like peptides purified
from hydrolysates of β-casein and were initially separated from
enzymatically digested casein (Henschen and others 1979). It was
noted that β-CMs could reach a notable level in the stomach
due to high resistance to proteolytic activities attributed to the
presence of proline in its sequence (Sun and others 2003). Casomorphins have been purified from peptic hydrolysate of α-casein,
whose structures vary extensively from those of β-CMs. The active fractions mainly contained 2 peptides derived from α s1 -casein
(fractions 90 to 95 [Arg-Tyr-Leu-Gly-Tyr-Leu] and 90 to 96
[Arg-Tyr-Leu-Gly-Tyr-Leu-Glu]). Different casomorphins were
reported to induce anticancer activities as presented in Table 1.
The tryptic hydrolysis residues of bovine β-casein showed antitumor effect in an animal model as well as in vitro antiproliferative
activity (Table 1). Similarly, κ-casecidin derived from κ-casein
displays antitumor activity (Table 1). In addition to the apoptotic
mechanisms, it has been proposed that peptides liberated from
casein may exert their anticancer activities by a process partly involving opioid receptors (Sienkiewicz-Szlapka and others 2009).
Many casomorphin peptides obtained from both α- and β-caseins
diminish the proliferation of prostate carcinoma cell lines by this
process (Table 1).
Caseinphosphopeptides (CPPs) are an alternate group of bioactive peptides liberated during the digestion of casein. This name
has been given because of the high number of phosphorylated
sites, which are attributed to bind and solubilize calcium (Berrocal
and others 1989). This attribute is accountable for their antitumor
activities against intestinal malignant cells (HT-29), through
regulating the proliferation and apoptosis of cells. The activation
of voltage-activated L-type calcium channels in malignant colon
cells (HT-29 and AZ-97) is found associated with apoptosis,
and their blockade might elevate the growth of malignant colon
cells (Zawadzki and others 2008). Perego and others (2012)
have reported that CPPs preserve differentiated intestinal cells
from toxicity due to calcium overload, counteract apoptosis, and
support proliferation, in the meantime inducing apoptosis in
undifferentiated malignant cells. This impact is prone to be the
outcome of the binding of CPPs with extracellular calcium in a
specific dose–response relationship, bringing on a decrease in the
rate of cell proliferation and apoptosis. Actually, the antagonists
of calcium channels nullify the responses to CPPs or decrease
both percentages of responsive cells and the rise of intracellular
calcium concentrations. More recently, it has become possible to
predict anticancer peptides scientifically from different proteins
using AntiCP, a web-based prediction server for anticancer
peptides (http://crdd.osdd.net/raghava/anticp/submit_prot.php;
Tyagi and others 2013). Amino acid sequences of the caseins of bovine milk were obtained from BIOPEP database
124 Comprehensive Reviews in Food Science and Food Safety r Vol. 14, 2015
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Advanced food systems research unit . . .
Table 1–Examples of antitumor peptides.
Peptide
Pro-Gly-Pro-Ile-Pro-Asn (f63–68 of β-casein)
Ile-Asn-Lys-Lys-Ile (f41–45 of β-casein)
Tyr-Val-Pro-Phe-Pro (α s1 -casomorphin; f158–162 of
α s1 -casein)
Arg-Pro-Lys, Leu-Lys-Lys, and Tyr-Lys (α-casecidins;
f1–3 , f101–103 , f104–105 of α S1 -casein)
A partially purified peptide subfraction from buffalo
cheese acid whey, called f3
Phe-Phe-Ser-Asp-Lys (κ-casecidin; f17–21 of bovine
κ-casein)
Phe-Lys-Cys-Arg-Arg-Trp-Gln-Trp-Arg-Met-Lys-LysLeu-Gly-Ala-Pro-Ser-Ile-Thr-Cys-Val-Arg (f17–38 of
bovine lactoferrin)
Phe-Lys-Cys-Arg-Arg-Trp-Gln-Trp-Arg-Met-Lys-LysLeu-Gly-Ala-Pro-Ser-Ile-Thr-Cys-Val-Arg-Arg-AlaPhe (f17–41 of bovine
lactoferrin)
Phe-Lys-Cys-Arg-Arg-Trp-Gln-Trp-Arg-Met-Lys-LysLeu-Gly-Ala-Pro-Ser-Ile-Thr-Cys-Val-Arg (synthetic
bovine lactoferricin)
Bovine lactoferricin (pepsin digestion of bovine
lactoferrin)
Phe-Lys-Cys-Arg-Arg-Trp-Gln-Trp-Arg-Met-Lys-LysLeu-Gly-Ala-Pro-Ser-Ile-Thr-Cys-Val-Arg (synthetic
bovine lactoferricin)
Phe-Lys-Cys-Arg-Arg-Trp-Gln-Trp-Arg-Met-Lys-LysLeu-Gly-Ala-Pro-Ser-Ile-Thr-Cys-Val-Arg (synthetic
bovine lactoferricin)
Val-Leu-Ser-Leu-Ser-Gln-Ser-Lys-Val-Leu-Pro-Val-ProGln-Lys (f162–176 of β-casein)
Val-Leu-Ser-Leu-Ser-Gln-Ser-Lys-Val-Leu-Pro-Val-ProGln-Lys-Ala-Val-Pro-Tyr-Pro-Gln-Arg-Asp-Met-ProIle-Gln-Ala (f162–189 of
β-casein)
Ile-Pro-Ile-Gln-Tyr (f26–30 of κ-casein)
Gln-Gln-Pro-Val-Leu-Gly-Pro-Val-Arg-Gly-Pro-PhePro-Ile-Ile-Val (f194–209 of β-casein)
Gly-Val-Arg-Gly-Pro-Phe-Pro-Ile-Ile (f200–208 of
β-casein)
Ala-Arg-His-Pro-His-Pro-His-Leu-Ser-Phe-Met
(f96–106 of κ-casein)
Crude water soluble peptide extract prepared by
high-speed centrifugation of yogurt
Pepsin-hydrolysed casein
Freeze-dried powder prepared from isoelectric
extraction (pH 4.6) of kefir
Peptides released from milk proteins, mainly caseins,
of fermented milk
Hydrolysed casein
Leu-Leu-Tyr-Gln-Glu-Pro-Val-Leu-Gly-Pro-Val-ArgGly-Pro-Phe-Pro-Ile-Ile-Val (C-terminal sequence
f191–209 of β-casein)
Antitumor activities
Inhibited proliferation of SKOV3 human ovarian
cancer cells partially through promoting apoptosis
by hindering BCL2 pathway
Induced cytotoxicity to B16F10 melanoma cells
Inhibited proliferation of T47D human breast cancer
cells
Induced necrosis of leukemic T- and B-cell lines
(Azevedo and others 2012)
(Kampa and others 1996)
(Otani and Suzuki 2003)
Reduced the proliferation of human epithelial colon
cancer (Caco-2) cells by modulating cell cycle
Displayed cytotoxic activity toward some
mammalian cells, including human leukemic cell
lines.
Induced cell proliferation inhibition activity in HL-60
cells due to induction of apoptosis
(De Simone and others 2009)
Exerted cytotoxic activity against fibrosarcoma
(Meth A), melanoma, and colon carcinoma cell
lines in vitro
(Eliassen and others 2002)
Induced apoptosis in MDA-MB-435 breast cancer
cell cultures
(Furlong and others 2006)
Showed cytotoxic activity in vitro and in vivo against
neuroblastoma cell lines Kelly, SK-N-DZ and
IMR-32 through the induction of cleavage of
caspase-6, caspase-7, and caspase-9 followed by
cell death
Showed capacity of inhibiting angiogenesis in vitro
and in vivo
(Eliassen and others 2006)
Induced apoptosis in Jurkat T-leukemia cells by the
mitochondrial pathway
(Mader and others 2007)
Antioxidant
(Chang and others 2013)
Antioxidant
(Chang and others 2013)
Antioxidant
Antioxidant
(Farvin and others 2010)
(Farvin and others 2010)
Antioxidant
(Farvin and others 2010)
Antioxidant
(Kudoh and others 2001)
Antioxidant and antimutagenic
(Sah and others 2014)
Antimutagenic activity against
4-nitroquinoline-N -oxide
Antimutagenic activity against
N-methyl-N’-nitro-N-nitrosoguanidine and
4-nitroquinoline-N - oxide
Antimutagenic activity
(van Boekel and others 1993)
β-Glucuronidase inhibitory activity
Immunomodulatory
(Gourley and others 1997)
(Bonomi and others 2011)
(http://www.uwm.edu.pl/biochemia/index.php/pl/biopep)
(Minkiewicz and others 2008) and employed for the scientific
prediction of anticancer peptides in support vector machine
(SVM) threshold range of −1 to +1 using AntiCP webserver.
Based on this service, the caseins contain many potential anticancer peptides as presented in Table 2.1–2.6. In this regard, the
primary structure plays an important role. For example, due to
mutation at position 67 in the amino acid sequence, β-casein gen.
var. A1 has a few more anticancer peptides (PGPIP, LVYPFPGPIP,
VYPFPGPIPN, YPFPGPIPNS) in addition to that of β-casein
gen. var. A2 (Table 2.1 and 2.2). In silico studies demonstrated
that proline, leucine, glutamine, valine, lysine, phenylalanine,
C 2015 Institute of Food Technologists®
Reference
(Wang and others 2013)
(Matin and Otani 2002)
(Roy and others 2002)
(Mader and others 2006)
(Liu and others 2005)
(Matar and others 1997)
and histidine dominated various positions in anticancer peptides
derived from caseins (α S1 -casein gen. var. A, B, C, β-casein gen.
var. A1, A2, A3, B, C, E, F, κ-casein gen. var. A, precursor;
Figure 1).
Whey Protein-Derived Antitumor Peptides
α-LA has a molecular weight of 14175 Da and contains 123
amino acid residues with an isoelectric point between 4.2 and 4.5
(Brew and others 1970). The multimeric form of α-LA was found
to accelerate apoptotic processes in transformed and juvenile cells,
but to protect mature epithelial cells. Elevation of calcium level
Vol. 14, 2015 r Comprehensive Reviews in Food Science and Food Safety 125
Advanced food systems research unit . . .
Table 2.1–Predicted anticancer peptides of β-casein gen. var. A1 of Bos taurus (amino acid residues = 209; formula weight = 23622.4 Da) using
AntiCP, a web-based prediction server for anticancer peptides (http://crdd.osdd.net/raghava/anticp/submit_prot.php)
of β-casein gen. var. A1 of Bos taurus
1 RELEELNVPG EIVESLSSSE ESITRINKKI EKFQSEEQQQ TEDELQDKIH PFAQTQSLVY
61 PFPGPIHNSL PQNIPPLTQT PVVVPPFLQP EVMGVSKVKE AMAPKHKEMP FPKYPVQPFT
121 ESQSLTLTDV ENLHLPPLLL QSWMHQPHQP LPPTVMFPPQ SVLSLSQSKV LPVPEKAVPY
181 PQRDMPIQAF LLYQQPVLGP VRGPFPIIV
a Amino acid sequence
Predicted anticancer peptides
f(2–6), f(3–7), f(15–19), f(17–21), f(18–22), f(23–27), f(24–28), f(25–29), f(26–30), f(28–32), f(29–33), f(30–34), f(36–40), f(37–41), f(38–42),
f(45–49), f(46–50), f(48–52), f(49–53), f(50–54), f(59–63), f(60–64), f(61–65), f(62–66), f(63–67), f(75–79), f(76–80), f(77–81), f(80–84),
f(81–85), f(82–86), f(83–87), f(84–88), f(85–89), f(86–90), f(87–91), f(91–95), f(92–96), f(93–97), f(94–98), f(95–99), f(97–101), f(101–105),
f(102–106), f(103–107), f(108–112), f(109–113), f(110–114), f(111–115), f(112–116), f(114–118), f(115–119), f(124–128), f(125–129),
f(131–135), f(132–136), f(133–137), f(134–138), f(135–139), f(136–140), f(137–141), f(138–142), f(139–143), f(143–147), f(144–148),
f(145–149), f(146–150), f(147–151), f(148–152), f(149–153), f(150–154), f(152–156), f(155–159), f(156–160), f(157–161), f(158–162),
f(160–164), f(161–165), f(168–172), f(169–173), f(170–174), f(171–175), f(172–176), f(176–180), f(177–181), f(178–182), f(179–183),
f(180–184), f(187–191), f(196–200), f(197–201), f(198–202), f(199–203), f(200–204), f(201–205), f(202–206), f(203–207), f(205–209),
f(25–34), f(56–65), f(57–66), f(58–67), f(59–68), f(60–69), f(81–90), f(92–101), f(94–103), f(97–106), f(98–107), f(103–112), f(106–115),
f(107–116), f(108–117), f(109–118), f(110–119), f(111–120), f(130–139), f(131–140), f(132–141), f(133–142), f(134–143), f(135–144),
f(136–145), f(137–146), f(138–147), f(139–148), f(143–152), f(144–153), f(145–154), f(146–155), f(147–156), f(149–158), f(150–159),
f(151–160), f(152–161), f(162–171), f(169–178), f(170–179), f(171–180), f(172–181), f(173–182), f(174–183), f(177–186), f(179–188),
f(195–204), f(196–205), f(197–206), f(198–207), f(200–209), f(199–208), f(92–106), f(101–115), f(104–118), f(131–145), f(132–146),
f(133–147), f(134–148), f(135–149), f(136–150), f(137–151), f(138–152), f(139–153), f(144–158), f(145–159), f(146–160), f(147–161),
f(192–206), f(193–207), f(194–208), f(195–209), f(132–151), f(133–152), f(134–153), and f(135–154).
a The amino acid sequence of β-casein gen. var. A1 of Bos taurus (ID = 1097) was obtained from the BIOPEP database (http://www.uwm.edu.pl/biochemia/index.php/pl/biopep). Amino acid nomenclature:
C, cysteine; H, histidine; I, isoleucine; M, methionine; S, serine; V, valine; A, alanine; G, glycine; L, leucine; P, proline; T, threonine; F, phenylalanine; R, arginine; Y, tyrosine; W, tryptophan; D, aspartic acid; N,
asparagine; E, glutamic acid; Q, glutamine; K, lysine.
Table 2.2–Predicted anticancer peptides of β-casein gen. var. A2 of Bos taurus (amino acid residues = 209; formula weight = 23582.4 Da) using
AntiCP, a web-based prediction server for anticancer peptides (http://crdd.osdd.net/raghava/anticp/submit_prot.php).
of β-casein gen. var. A2 of Bos taurus
1 RELEELNVPG EIVESLSSSE ESITRINKKI EKFQSEEQQQ TEDELQDKIH PFAQTQSLVY
61 PFPGPIPNSL PQNIPPLTQT PVVVPPFLQP EVMGVSKVKE AMAPKHKEMP FPKYPVQPFT
121 ESQSLTLTDV ENLHLPPLLL QSWMHQPHQP LPPTVMFPPQ SVLSLSQSKV LPVPEKAVPY
181 PQRDMPIQAF LLYQQPVLGP VRGPFPIIV
a Amino acid sequence
Predicted anticancer peptides
f(2–6), f(3–7), f(15–19), f(17–21), f(18–22), f(23–27), f(24–28), f(25–29), f(26–30), f(28–32), f(29–33), f(30–34), f(36–40), f(37–41), f(38–42),
f(45–49), f(46–50), f(48–52), f(49–53), f(50–54), f(59–63), f(60–64), f(61–65), f(62–66), f(63–67), f(75–79), f(76–80), f(77–81), f(80–84),
f(81–85), f(82–86), f(83–87), f(84–88), f(85–89), f(86–90), f(87–91), f(91–95), f(92–96), f(93–97), f(94–98), f(95–99), f(97–101), f(101–105),
f(102–106), f(103–107), f(108–112), f(109–113), f(110–114), f(111–115), f(112–116), f(114–118), f(115–119), f(124–128), f(125–129),
f(131–135), f(132–136), f(133–137), f(134–138), f(135–139), f(136–140), f(137–141), f(138–142), f(139–143), f(143–147), f(144–148),
f(145–149), f(146–150), f(147–151), f(148–152), f(149–153), f(150–154), f(152–156), f(155–159), f(156–160), f(157–161), f(158–162),
f(160–164), f(161–165), f(168–172), f(169–173), f(170–174), f(171–175), f(172–176), f(176–180), f(177–181), f(178–182), f(179–183),
f(180–184), f(187–191), f(196–200), f(197–201), f(198–202), f(199–203), f(200–204), f(201–205), f(202–206), f(203–207), f(205–209),
f(25–34), f(56–65), f(57–66), f(58–67), f(59–68), f(60–69), f(81–90), f(92–101), f(94–103), f(97–106), f(98–107), f(103–112), f(106–115),
f(107–116), f(108–117), f(109–118), f(110–119), f(111–120), f(130–139), f(131–140), f(132–141), f(133–142), f(134–143), f(135–144),
f(136–145), f(137–146), f(138–147), f(139–148), f(143–152), f(144–153), f(145–154), f(146–155), f(147–156), f(149–158), f(150–159),
f(151–160), f(152–161), f(162–171), f(169–178), f(170–179), f(171–180), f(172–181), f(173–182), f(174–183), f(177–186), f(179–188),
f(195–204), f(196–205), f(197–206), f(198–207), f(200–209), f(199–208), f(92–106), f(101–115), f(104–118), f(131–145), f(132–146),
f(133–147), f(134–148), f(135–149), f(136–150), f(137–151), f(138–152), f(139–153), f(144–158), f(145–159), f(146–160), f(147–161),
f(192–206), f(193–207), f(194–208), f(195–209), f(132–151), f(133–152), f(134–153), and f(135–154).
a The amino acid sequence of β-casein gen. var. A1 of Bos taurus (ID = 1098) was obtained from the BIOPEP database (http://www.uwm.edu.pl/biochemia/index.php/pl/biopep). Amino acid nomenclature:
C, cysteine; H, histidine; I, isoleucine; M, methionine; S, serine; V, valine; A, alanine; G, glycine; L, leucine; P, proline; T, threonine; F, phenylalanine; R, arginine; Y, tyrosine; W, tryptophan; D, aspartic acid; N,
asparagine; E, glutamic acid; Q, glutamine; K, lysine.
during this process indicates an association between calcium levels
and apoptosis. Most likely, interaction of α-LA with cell surface
modulators alters cell growth rate, calcium transport rates, and
intracellular calcium. Furthermore, this protein possesses antiproliferative properties, which may have an effect on colon cancer
cells (Caco-2 or HT-29 monolayers).
β-Lg has been found to provide protection against cancer development in an animal model when administered orally. β-Lg has
also become an ingredient of choice in the formulation of many
recent food products and beverages because of its high dietary and
functional value (Chatterton and others 2006).
BSA prevented the growth of human breast cancer cell
line (MCF-7) in a dose-dependent way (Laursen and others
1990). BSA may influence cell proliferation through regulating the activities of autocrine growth regulatory factors. Additionally, it has been reported to display anti-proliferative effect
on a Chinese hamster epithelial cell line (Bosselaers and others
1994).
Bovine lactoferrin inhibited the growth of MCF-7 breast cancer
cell in a dose-dependent manner by inducing apoptosis (Zhang
and others 2015). Antitumor activities of bovine lactoferrin are
also mediated through the retardation of angiogenesis (a multistep
biological process for growth of new blood vessels from the preexisting vessels) and diminishing of endothelial cell proliferation
(Shimamura and others 2004; Hoskin and Ramamoorthy 2008).
Lactoferricin is a cationic peptide comprised of 25 amino acid
residues generated during the hydrolysis of mammalian lactoferrin using acid pepsin (Tomita and others 1991). Bovine lactoferrin
fragments (Table 1) have been shown to exhibit cytotoxic activities
on various human and rat malignant cell lines, including fibrosarcoma, leukemia, different carcinoma, and neuroblastoma cells. Interestingly, the structural properties of lactoferricin that depict the
126 Comprehensive Reviews in Food Science and Food Safety r Vol. 14, 2015
C 2015 Institute of Food Technologists®
Advanced food systems research unit . . .
Table 2.3–Predicted anticancer peptides of β-casein gen. var. B of Bos taurus (amino acid residues = 209; formula weight = 23652.5 Da) using AntiCP,
a web-based prediction server for anticancer peptides (http://crdd.osdd.net/raghava/anticp/submit_prot.php).
of β-casein gen. var. A2 of Bos taurus
1 RELEELNVPG EIVESLSSSE ESITRINKKI EKFQSEEQQQ TEDELQDKIH PFAQTQSLVY
61 PFPGPIPNSL PQNIPPLTQT PVVVPPFLQP EVMGVSKVKE AMAPKHKEMP FPKYPVEPFT
121 ERQSLTLTDV ENLHLPLPLL QSWMHQPHQP LPPTVMFPPQ SVLSLSQSKV LPVPQKAVPY
181 PQRDMPIQAF LLYQEPVLGP VRGPFPIIV
a Amino acid sequence
Predicted anticancer peptides
f(2–6), f(3–7), f(15–19), f(17–21), f(18–22), f(23–27), f(24–28), f(25–29), f(26–30), f(28–32), f(29–33), f(30–34), f(36–40), f(37–41), f(38–42),
f(45–49), f(46–50), f(48–52), f(49–53), f(50–54), f(59–63), f(60–64), f(61–65), f(62–66), f(63–67), f(75–79), f(76–80), f(77–81), f(80–84),
f(81–85), f(82–86), f(83–87), f(84–88), f(85–89), f(86–90), f(87–91), f(91–95), f(92–96), f(93–97), f(94–98), f(95–99), f(97–101), f(101–105),
f(102–106), f(103–107), f(108–112), f(109–113), f(110–114), f(111–115), f(112–116), f(114–118), f(115–119), f(124–128), f(125–129),
f(131–135), f(132–136), f(133–137), f(134–138), f(135–139), f(136–140), f(137–141), f(138–142), f(139–143), f(143–147), f(144–148),
f(145–149), f(146–150), f(147–151), f(148–152), f(149–153), f(150–154), f(152–156), f(155–159), f(156–160), f(157–161), f(158–162),
f(160–164), f(161–165), f(168–172), f(169–173), f(170–174), f(171–175), f(172–176), f(176–180), f(177–181), f(178–182), f(179–183),
f(180–184), f(187–191), f(196–200), f(197–201), f(198–202), f(199–203), f(200–204), f(201–205), f(202–206), f(203–207), f(205–209),
f(25–34), f(56–65), f(57–66), f(58–67), f(59–68), f(60–69), f(81–90), f(92–101), f(94–103), f(97–106), f(98–107), f(103–112), f(106–115),
f(107–116), f(108–117), f(109–118), f(110–119), f(111–120), f(130–139), f(131–140), f(132–141), f(133–142), f(134–143), f(135–144),
f(136–145), f(137–146), f(138–147), f(139–148), f(143–152), f(144–153), f(145–154), f(146–155), f(147–156), f(149–158), f(150–159),
f(151–160), f(152–161), f(162–171), f(169–178), f(170–179), f(171–180), f(172–181), f(173–182), f(174–183), f(177–186), f(179–188),
f(195–204), f(196–205), f(197–206), f(198–207), f(200–209), f(199–208), f(92–106), f(101–115), f(104–118), f(131–145), f(132–146),
f(133–147), f(134–148), f(135–149), f(136–150), f(137–151), f(138–152), f(139–153), f(144–158), f(145–159), f(146–160), f(147–161),
f(192–206), f(193–207), f(194–208), f(195–209), f(132–151), f(133–152), f(134–153), and f(135–154).
a The amino acid sequence of β-casein gen. var. B of Bos taurus (ID = 1100) was obtained from the BIOPEP database (http://www.uwm.edu.pl/biochemia/index.php/pl/biopep). Amino acid nomenclature:
C, cysteine; H, histidine; I, isoleucine; M, methionine; S, serine; V, valine; A, alanine; G, glycine; L, leucine; P, proline; T, threonine; F, phenylalanine; R, arginine; Y, tyrosine; W, tryptophan; D, aspartic acid; N,
asparagine; E, glutamic acid; Q, glutamine; K, lysine.
Table 2.4–Predicted anticancer peptides of α S1 -casein gen. var. B of Bos taurus (amino acid residues = 199; formula weight = 22973.9 Da) using
AntiCP, a web-based prediction server for anticancer peptides (http://crdd.osdd.net/raghava/anticp/submit_prot.php).
of α S1 -casein gen. var. B of Bos taurus
1 RPKHPIKHQG LPQEVLNENL LRFFVAPFPQ VFGKEKVNEL SKDIGSESTE DQAMEDIKEM
61 EAESISSSEE IVPNSVEQKH IQKEDVPSER YLGYLEQLLR LKKYKVPQLE IVPNSAEERL
121 HSMKQGIHAQ QKEPMIGVNQ ELAYFYPELF RQFYQLDAYP SGAWYYVPLG TQYTDAPSFS
181 DIPNPIGSEN SEKTTMPLW
a Amino acid sequence
Predicted anticancer peptides
f(1–5), f(2–6), f(4–8), f(6–10), f(7–11), f(8–12), f(16–20), f(17–21), f(19–23), f(20–24), f(21–25), f(22–26), f(23–27), f(24–28), f(25–29), f(26–30),
f(27–31), f(28–32), f(29–33), f(30–34), f(31–35), f(32–36), f(33–37), f(39–44), f(40–45), f(41–46), f(44–48), f(59–63), f(63–67), f(64–68),
f(65–69), f(66–70), f(78–82), f(79–83), f(87–91), f(90–94), f(91–95), f(95–99), f(97–101), f(98–102), f(99–103), f(101–105), f(102–106),
f(105–109), f(119–123), f(124–128), f(125–129), f(126–130), f(127–131), f(128–132), f(134–138), f(142–146), f(143–147), f(144–148),
f(145–149), f(146–150), f(147–151), f(148–152), f(149–153), f(150–154), f(151–155), f(158–162), f(159–163), f(160–164), f(161–165),
f(162–166), f(163–167), f(164–168), f(165–169), f(166–170), f(170–174), f(171–175), f(172–176), f(173–177), f(176–180), f(192–196),
f(193–197), f(194–198), f(195–199), f(1–10), f(2–11), f(3–12), f(4–13), f(20–29), f(21–30), f(22–31), f(23–32), f(24–33), f(25–34), f(26–35),
f(27–36), f(28–37), f(97–106), f(98–107), f(120–129), f(123–132), f(124–133), f(141–150), f(142–151), f(143–152), f(144–153), f(145–154),
f(146–155), f(147–156), f(156–165), f(157–166), f(158–167), f(159–168), f(160–169), f(161–170), f(162–171), f(163–172), f(164–173),
f(20–34), f(21–35), f(22–36), f(23–37), f(24–38), f(152–166), f(154–168), f(156–170), f(157–171), f(158–172), f(159–173), f(160–174),
f(158–177), f(142–166), and f(144–168).
a The amino acid sequence of α -casein gen. var. B of Bos taurus (ID = 1087) was obtained from the BIOPEP database (http://www.uwm.edu.pl/biochemia/index.php/pl/biopep). Amino acid nomenclature:
S1
C, cysteine; H, histidine; I, isoleucine; M, methionine; S, serine; V, valine; A, alanine; G, glycine; L, leucine; P, proline; T, threonine; F, phenylalanine; R, arginine; Y, tyrosine; W, tryptophan; D, aspartic acid; N,
asparagine; E, glutamic acid; Q, glutamine; K, lysine.
antitumor impacts are the same as those that exhibit antibacterial activities (Gifford and others 2005). The net negative charges
of the outer membrane of various malignant cells are because of
differential branching and sialic acid contents of N-linked glycan
with transmembrane glycoprotein (Dennis 1991), and increased
expression of anionic molecule including phosphatidylserine
(Dobrzyńska and others 2005). The limit of bovine lactoferricin
to induce apoptotic processes in malignant cells through pathways
mediated by the generation of intracellular reactive oxygen species
(ROS) and initialization of Ca2+ /Mg2+ -dependent endonucleases
was also verified by Mader and others (2007) who reported apoptosis caused by lactoferricin. They additionally showed that bovine
lactoferricin triggered caspase cascades in human T-leukemia cells
prompting cell death by apoptosis. In addition, the induction of
necrotic or apoptotic cell death is subject to the peptide concentration (Eliassen and others 2006; Onishi and others 2008).
Eliassen and others (2006) found that systemic or intratumoral
administration of lactoferricin led to the inhibition of growth
C 2015 Institute of Food Technologists®
and/or metastasis of various tumors in mice. This inhibitory impact of lactoferricin-induced apoptosis is due to the neutralization
of charges of the outer membrane of malignant cells. It has recently been demonstrated that lactoferricin-induced apoptosis in
B-lymphoma cells does not include the caspase cascades but involvement of cathepsin B in apoptosis (Furlong and others 2010).
Amino acid sequences of the whey proteins from bovine milk
were obtained from the BIOPEP database and employed for the
scientific prediction of anticancer peptides in the SVM threshold
range of −1 to +1 using AntiCP webserver. The whey proteins
contain many potential anticancer peptides as shown in Table 3.1–
3.3 Furthermore, in silico studies demonstrated that lysine, leucine,
alanine, cysteine, glycine, and serine dominated at various
positions in anticancer peptides derived from whey proteins
(α-LA, gen. var. B, precursor [142 amino acids; MW = 16381.5],
β-Lg, gen. var. A, precursor [178 amino acids; MW = 20059.4],
serum albumin, precursor [607 amino acids; MW = 69883.7]
and lactoferrin [689 amino acids; MW = 72637.3]; Figure 1).
Vol. 14, 2015 r Comprehensive Reviews in Food Science and Food Safety 127
Advanced food systems research unit . . .
Table 2.5–Predicted anticancer peptides of α S1 -casein gen. var. C of Bos taurus (amino acid residues = 199; formula weight = 22901.9 Da) using
AntiCP, a web-based prediction server for anticancer peptides (http://crdd.osdd.net/raghava/anticp/submit_prot.php).
of α S1 -casein gen. var. C of Bos taurus
1 RPKHPIKHQG LPQEVLNENL LRFFVAPFPQ VFGKEKVNEL SKDIGSESTE DQAMEDIKEM
61 EAESISSSEE IVPNSVEQKH IQKEDVPSER YLGYLEQLLR LKKYKVPQLE IVPNSAEERL
121 HSMKQGIHAQ QKEPMIGVNQ ELAYFYPELF RQFYQLDAYP SGAWYYVPLG TQYTDAPSFS
181 DIPNPIGSEN SGKTTMPLW
a Amino acid sequence
Predicted anticancer peptides
f(1–5), f(2–6), f(4–8), f(6–10), f(7–11), f(8–12), f(16–20), f(17–21), f(19–23), f(20–24), f(21–25), f(22–26), f(23–27), f(24–28), f(25–29), f(26–30),
f(27–31), f(28–32), f(29–33), f(30–34), f(31–35), f(32–36), f(33–37), f(39–44), f(40–45), f(41–46), f(44–48), f(59–63), f(63–67), f(64–68),
f(65–69), f(66–70), f(78–82), f(79–83), f(87–91), f(90–94), f(91–95), f(95–99), f(97–101), f(98–102), f(99–103), f(101–105), f(102–106),
f(105–109), f(119–123), f(124–128), f(125–129), f(126–130), f(127–131), f(128–132), f(134–138), f(142–146), f(143–147), f(144–148),
f(145–149), f(146–150), f(147–151), f(148–152), f(149–153), f(150–154), f(151–155), f(158–162), f(159–163), f(160–164), f(161–165),
f(162–166), f(163–167), f(164–168), f(165–169), f(166–170), f(170–174), f(171–175), f(172–176), f(173–177), f(176–180), f(193–197),
f(194–198), f(195–199), f(1–10), f(2–11), f(3–12), f(4–13), f(20–29), f(21–30), f(22–31), f(23–32), f(24–33), f(25–34), f(26–35), f(27–36),
f(28–37), f(97–106), f(98–107), f(120–129), f(123–132), f(124–133), f(141–150), f(142–151), f(143–152), f(144–153), f(145–154),
f(146–155), f(147–156), f(156–165), f(157–166), f(158–167), f(159–168), f(160–169), f(161–170), f(162–171), f(163–172), f(164–173),
f(20–34), f(21–35), f(22–36), f(23–37), f(24–38), f(152–166), f(154–168), f(156–170), f(157–171), f(158–172), f(159–173), f(160–174),
f(158–177), f(142–166), and f(144–168).
a The amino acid sequence of α -casein gen. var. C of Bos taurus (ID = 1088) was obtained from the BIOPEP database (http://www.uwm.edu.pl/biochemia/index.php/pl/biopep). Amino acid nomenclature:
S1
C, cysteine; H, histidine; I, isoleucine; M, methionine; S, serine; V, valine; A, alanine; G, glycine; L, leucine; P, proline; T, threonine; F, phenylalanine; R, arginine; Y, tyrosine; W, tryptophan; D, aspartic acid; N,
asparagine; E, glutamic acid; Q, glutamine; K, lysine.
Table 2.6–Predicted anticancer peptides of κ-casein gen. var. A, precursor of Bos taurus (amino acid residues = 190; formula weight = 21303.1 Da)
using AntiCP, a web-based prediction server for anticancer peptides (http://crdd.osdd.net/raghava/anticp/submit_prot.php).
of κ-casein gen. var. A, precursor of Bos taurus
1 MMKSFFLVVT ILALTLPFLG AQEQNQEQPI RCEKDERFFS DKIAKYIPIQ YVLSRYPSYG
61 LNYYQQKPVA LINNQFLPYP YYAKPAAVRS PAQILQWQVL SNTVPAKSCQ AQPTTMARHP
121 HPHLSFMAIP PKKNQDKTEI PTINTIASGE PTSTPTTEAV ESTVATLEDS PEVIESPPEI
181 NTVQVTSTAV
a Amino acid sequence
Predicted anticancer peptides
f(3–7), f(5–9), f(10–14), f(11–15), f(12–16), f(13–17), f(14–18), f(15–19), f(16–20), f(17–21), f(22–26), f(24–28), f(28–32), f(29–33), f(30–34),
f(38–42), f(39–43), f(40–44), f(41–45), f(42–46), f(43–47), f(44–48), f(53–57), f(54–58), f(55–59), f(56–60), f(57–61), f(59–63), f(60–64),
f(61–65), f(62–66), f(63–67), f(64–68), f(65–69), f(66–70), f(67–71), f(68–72), f(70–74), f(72–76), f(75–79), f(76–80), f(77–81), f(78–82),
f(79–83), f(80–84), f(81–85), f(82–86), f(83–87), f(84–88), f(93–97), f(94–98), f(103–107), f(104–108), f(105–109), f(106–110), f(107–111),
f(111–115), f(112–116), f(113–117), f(114–118), f(115–119), f(116–120), f(117–121), f(118–122), f(119–123), f(120–124), f(121–125),
f(127–131), f(128–132), f(130–134), f(132–136), f(133–137), f(141–145), f(142–146), f(143–147), f(145–149), f(146–150), f(147–151),
f(151–155), f(152–156), f(153–157), f(154–158), f(155–159), f(156–160), f(162–166), f(175–179), f(182–186), f(185–189), f(186–190),
f(10–19), f(11–20), f(12–21), f(37–46), f(38–47), f(39–48), f(40–49), f(41–50), f(42–51), f(43–52), f(51–60), f(54–63), f(55–64), f(56–65),
f(73–82), f(74–83), f(75–84), f(76–85), f(77–86), f(78–87), f(79–88), f(80–89), f(81–90), f(82–91), f(102–111), f(104–113), f(105–114),
f(106–115), f(112–121), f(113–122), f(114–123), f(115–124), f(116–125), f(117–126), f(118–127), f(119–128), f(138–147), f(37–51),
f(72–86), f(73–87), f(74–88), f(75–89), f(76–90), f(77–91), f(78–92), f(79–93), f(80–94), f(107–121), f(108–122), f(109–123), f(110–124),
f(111–125), f(116–130), f(117–131), f(118–132), f(119–133), f(67–86), f(68–87), f(73–92), f(74–93), f(75–94), f(76–95), f(78–97),
f(104–123), f(105–124), and f(63–87).
a The amino acid sequence of κ-casein gen. var. A, precursor of Bos taurus (ID = 1117) was obtained from the BIOPEP database (http://www.uwm.edu.pl/biochemia/index.php/pl/biopep). Amino acid
nomenclature: C, cysteine; H, histidine; I, isoleucine; M, methionine; S, serine; V, valine; A, alanine; G, glycine; L, leucine; P, proline; T, threonine; F, phenylalanine; R, arginine; Y, tyrosine; W, tryptophan; D, aspartic
acid; N, asparagine; E, glutamic acid; Q, glutamine; K, lysine.
Generation of Peptides with Antitumor Activity
Milk provides various nutrients and displays many biological
activities that have an effect on digestion processes, metabolic response to assimilated nutrients, development, and improvement of
particular organs, and resistances to diseases (Jakubowicz and Froy
2013). These biological activities are mainly because of proteins
and peptides present in milk. However, some biological activities
of milk protein components are latent and are liberated only upon
proteolytic activities. The major mode to generate functional
peptides from precursor milk proteins can be listed as follows:
(a) hydrolysis using digestive enzyme, (b) fermentation using a
proteolytic culture, and (c) proteolysis using plant or microbial
enzyme. Several studies employed a combination of 2 of them
(Korhonen and Pihlanto 2006). Importantly, liberation of bioactive peptides from milk proteins also occurs in the gastrointestinal
tract of consumers by digestive enzymes (Schlimme and Meisel
1995). In addition to this, fermentation is also considered an
effective approach to deliver bioactive peptides (Korhonen and
Pihlanto 2006).
Several peptides previously reported in the isolated fractions
from fermented milk and milk products share similar amino acid
sequences with predicted anticancer peptides using a webserver,
AntiCP (Table 4). It can therefore be concluded that bioactive
peptides with anticancer potential can be isolated from fermented
milk and milk products.
Absorption of Peptides
Proof exists that bioactive peptides derived from proteins may
be absorbed in intact form, enter blood circulation, and cause systemic influences (Grimble 2000; Sienkiewicz-Szlapka and others
2009). Biologically active peptides may be transported intact across
the epithelial cell monolayer by means of carrier-mediated transport or through paracellular diffusion (Shimizu and Son 2007).
According to Satake and others (2002), di- and tripeptides
are transported by means of a particular transporter (protondependent peptide transporter, PepT1), but oligopeptides may be
transported through the paracellular route. The peptide integrity is
maintained during the paracellular pathway, as it is a nondegradative transport route. Therefore, other food substances also facilitate paracellular transport by modulating the junction structures
(Tsukita and others 2001). Moreover, oligopeptides might be carried by vesicle-mediated transcellular transport (Shen and others
1992). Several studies have been conducted on the transport of
biologically active peptides in Caco-2 cells (Foltz and others 2007;
128 Comprehensive Reviews in Food Science and Food Safety r Vol. 14, 2015
C 2015 Institute of Food Technologists®
Advanced food systems research unit . . .
Figure 1–Occurrence frequency of amino acids in the predicted anticancer peptides from caseins (α S1 -casein gen. var. A, B, C, β-casein gen. var. A1,
A2, A3, B, C, E, F, κ-casein gen. var. A precursor) and whey proteins (lactoferrin, α-lactalbumin, gen. var. B precursor, β-lactoglobulin, gen. var. A
precursor, serum albumin precursor) using the AntiCP, a web-based prediction server for anticancer peptides
(http://crdd.osdd.net/raghava/anticp/submit_prot.php); Amino acid sequences of the milk proteins were obtained from the BIOPEP database.
(http://www.uwm.edu.pl/biochemia/index.php/pl/biopep).
Iwan and others 2008). The technique for transport was not just
subject to the size of the peptide but also the hydrogen bonding, charge, hydrophobicity, and molecular weight of the peptide
molecules (Iwan and others 2008; Sienkiewicz-Szlapka and others
2009).
Transport of the Peptide Across Cell Membranes
To exert bioactivity, peptides need to cross the gastrointestinal
lining, reach the circulatory system, and afterward be conveyed
to the target sites in an active structure (Vermeirssen and others 2002). The bioavailability of orally ingested peptides depends
mainly on the resistance to enzymatic degradations and transport
across intestinal cells. Molecular mass, hydrophobicity, and charge
or tendencies to aggregate are some unique factors of a peptide
influencing absorption in intact form through the intestinal epithelium (Aito-Inoue and others 2007).
Cationic peptides have been studied recently as potential anticancer agents. They have the ability to selectively permeabilize
biological membranes of tumor cells, probably due to an interaction with the negatively charged tumor cell surface (Araya and
Lomonte 2007).
Cellular Targets for the Prevention and Treatment of
Cancer
Though surgery, chemotherapy, and radiation therapy are common cancer therapies, many others including targeted therapy, immunotherapy, and hormone therapy are also emerging. Anticancer
substances induce cell death through various mechanisms; some
of them are through influencing the tubulin–microtubule balance, inhibiting angiogenesis, or inducing apoptosis (Reed 2000).
Apoptosis is a naturally happening process that leads to death of
redundant cells (Danial and Korsmeyer 2004). Moreover, its deregulations either by loss of proapoptotic signals or increase of antiapoptotic signals can lead to cancer or result in treatment failures
(Burz and others 2009; Fulda and Pervaiz 2010). The apoptosis
is usually interceded by the activation of various caspase cascades
C 2015 Institute of Food Technologists®
(Oliver and Vallette 2005). In mammalians, there are 2 significant
signaling systems that bring about the stimulation of caspases, such
as the extrinsic death receptor pathway (Thorburn 2004) and the
intrinsic mitochondrial pathway (Gupta and others 2009). As caspases are involved in both pathways, recognition of caspase activators gets to be an alternate approach for revelation of novel
anticancer peptides (Okun and others 2008). The equilibrium between the proapoptotic gene Bax and the prosurvival gene Bcl-2
assumes a key function in keeping up cell viability. In this manner,
induction of Bax or inhibition of Bcl-2 turns into an effective
strategy to accelerate apoptotic processes (Yip and Reed 2008).
Furthermore, apoptosis does not always accelerate immune or inflammatory response; it turns into an ideal method for cancer cell
death during the treatment of cancer. In that capacity, modulation
of pathway and induction of apoptosis are likely be a promising
strategy for cancer therapies (Ziegler and Kung 2008). The majority of promoters of cancer are potent apoptotic inhibitors, and thus
apoptosis-inducing peptides might be considered as probable anticancer agents. Impacts on both immune cell function and viability
can be a way by which biologically active peptide displays protective impacts on cancer advancements (Meisel 2005). The findings
about the cellular and molecular science of tumors have prompted
the identification of numerous physiological methodologies or
molecules that could be therapeutically employed to treat cancer
utilizing the supposed “targeted therapies.” Many have argued that
targeted therapies would not only be more effective but also less
toxic. There are various targeted therapeutics; some of them are
listed below.
Matrix metalloproteinase inhibitors (MMPi)
Matrix metalloproteinases, specifically, MMP-2 (gelatinase A),
MMP-9 (gelatinase B), and MMP-14 (a primary activator of proMMP-2) may represent encouraging targets to develop new potential antitumor medications as they assume a noteworthy role in
tumorigenesis, angiogenesis, and tumor growths at primary and
metastatic locations (Hua and others 2011).
Vol. 14, 2015 r Comprehensive Reviews in Food Science and Food Safety 129
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Table 3.1–Predicted anticancer peptides of α-lactalbumin of Bos taurus (amino acid residues = 142; formula weight = 16381.5 Da) using AntiCP, a
web-based prediction server for anticancer peptides (http://crdd.osdd.net/raghava/anticp/submit_prot.php).
of α-lactalbumin of Bos taurus
1 MMSFVSLLLV GILFHATQAE QLTKCEVFRE LKDLKGYGGV SLPEWVCTTF
61 HTSGYDTQAI VQNNDSTEYG LFQINNKIWC KDDQNPHSSN ICNISCDKFL
121 DDDLTDDIMC VKKILDKVGI NYWLAHKALC SEKLDQWLCE KL
a Amino acid sequence
Predicted anticancer peptides
f(5–9), f(6–10), f(8–12), f(9–13), f(10–14), f(11–15), f(12–16), f(13–17), f(14–18), f(15–19), f(21–25), f(22–26), f(23–27), f(24–28), f(25–29),
f(28–32), f(30–34), f(31–35), f(32–36), f(34–38), f(35–39), f(36–40), f(37–41), f(38–42), f(39–43), f(41–45), f(42–46), f(43–47), f(44–48),
f(45–49), f(46–50), f(47–51), f(48–52), f(49–53), f(51–55), f(55–59), f(63–67), f(70–74), f(72–76), f(73–77), f(74–78), f(75–79), f(76–80),
f(77–81), f(78–82), f(79–83), f(80–84), f(81–85), f(82–86), f(89–93), f(90–94), f(91–95), f(92–96), f(93–97), f(94–98), f(95–99), f(96–100),
f(97–101), f(98–102), f(99–103), f(100–104), f(101–105), f(102–106), f(103–107), f(104–108), f(105–109), f(106–110), f(108–112),
f(109–113), f(110–114), f(111–115), f(112–116), f(113–117), f(114–118), f(115–119), f(116–120), f(117–121), f(119–123), f(120–124),
f(121–125), f(122–126), f(123–127), f(124–128), f(125–129), f(126–130), f(127–131), f(128–132), f(129–133), f(130–134), f(133–137),
f(134–138), f(135–139), f(136–140), f(137–141), f(138–142), f(3–12), f(4–13), f(5–14), f(6–15), f(7–16), f(8–17), f(10–19), f(15–24), f(16–25),
f(31–40), f(32–41), f(33–42), f(34–43), f(35–44), f(36–45), f(38–47), f(42–51), f(43–52), f(44–53), f(45–54), f(46–55), f(47–56), f(70–79),
f(71–80), f(72–81), f(73–82), f(74–83), f(75–84), f(76–85), f(77–86), f(78–87), f(89–98), f(90–99), f(91–100), f(92–101), f(93–102), f(94–103),
f(95–104), f(96–105), f(97–106), f(98–107), f(99–108), f(100–109), f(101–110), f(104–113), f(105–114), f(106–115), f(107–116),
f(108–117), f(109–118), f(110–119), f(111–120), f(112–121), f(113–122), f(116–125), f(117–126), f(118–127), f(119–128), f(120–129),
f(121–130), f(122–131), f(123–132), f(124–133), f(125–134), f(126–135), f(127–136), f(128–137), f(129–138), f(130–139), f(132–141),
f(133–142), f(11–25), f(34–48), f(45–59), f(67–81), f(68–82), f(69–83), f(70–84), f(71–85), f(72–86), f(89–103), f(90–104), f(91–105),
f(92–106), f(93–107), f(94–108), f(95–109), f(96–110), f(97–111), f(98–112), f(99–113), f(100–114), f(101–115), f(102–116), f(103–117),
f(104–118), f(105–119), f(106–120), f(107–121), f(108–122), f(109–123), f(110–124), f(111–125), f(112–126), f(113–127), f(114–128),
f(115–129), f(116–130), f(117–131), f(118–132), f(119–133), f(120–134), f(121–135), f(122–136), f(123–137), f(124–138), f(125–139),
f(126–140), f(127–141), f(128–142), f(88–107), f(89–108), f(90–109), f(91–110), f(92–111), f(93–112), f(94–113), f(95–114), f(96–115),
f(97–116), f(98–117), f(99–118), f(100–119), f(101–120), f(106–125), f(107–126), f(108–127), f(109–128), f(110–129), f(111–130),
f(112–131), f(113–132), f(114–133), f(115–134), f(117–136), f(118–137), f(119–138), f(120–139), f(121–140), f(122–141), f(123–142),
f(89–113), f(90–114), f(91–115), f(92–116), f(93–117), f(94–118), f(95–119), f(96–120), f(97–121), f(104–128), f(105–129), f(106–130),
f(107–131), f(108–132), f(109–133), f(110–134), f(111–135), f(112–136), f(113–137), f(114–138), f(115–139), f(116–140), f(117–141),
f(118–142), f(88–117), f(89–118), f(90–119), f(91–120), f(92–121), f(94–123), f(95–124), f(96–125), f(98–127), f(101–134), f(104–133),
f(105–134), f(106–135), f(107–136), f(108–137), f(109–138), f(110–139), f(111–140), f(112–141), f(113–142), f(90–124), f(91–125),
f(94–128), f(95–129), f(96–130), f(97–131), f(104–138), f(105–139), f(106–140), f(107–141), f(108–142), f(90–129), f(91–130), f(92–131),
f(94–133), f(96–135), f(98–137), f(103–142), f(90–134), f(91–135), f(94–138), f(95–139), f(96–140), f(97–141), f(98–142), f(90–139),
f(91–140), and f(92–141).
a The amino acid sequence of α-lactalbumin of Bos taurus (ID = 1115) was obtained from the BIOPEP database (http://www.uwm.edu.pl/biochemia/index.php/pl/biopep).
Amino acid nomenclature: C, cysteine; H, histidine; I, isoleucine; M, methionine; S, serine; V, valine; A, alanine; G, glycine; L, leucine; P, proline; T, threonine; F, phenylalanine; R, arginine; Y, tyrosine; W, tryptophan;
D, aspartic acid; N, asparagine; E, glutamic acid; Q, glutamine; K, lysine.
Table 3.2–Predicted anticancer peptides of β-lactoglobulin, gen. var. A, precursor of Bos taurus (amino acid residues = 178; formula weight = 20059.4
Da) using AntiCP, a web-based prediction server for anticancer peptides (http://crdd.osdd.net/raghava/anticp/submit_prot.php).
a Amino acid sequence of β-lactoglobulin, gen. var. A, precursor of Bos taurus
1 MKCLLLALAL TCGAQALIVT QTMKGLDIQK VAGTWYSLAM AASDISLLDA QSAPLRVYVE
61 ELKPTPEGDL EILLQKWEND ECAQKKIIAE KTKIPAVFKI DALNENKVLV LDTDYKKYLL
121 FCMENSAEPE QSLACQCLVR TPEVDDEALE KFDKALKALP MHIRLSFNPT QLEEQCHI
Predicted anticancer peptides
f(1–5), f(2–6), f(3–7), f(4–8), f(5–9), f(6–10), f(7–11), f(8–12), f(9–13), f(10–14), f(11–15), f(12–16), f(13–17), f(14–18), f(20–24), f(23–27),
f(24–28), f(26–30), f(27–31), f(28–32), f(29–33), f(30–34), f(31–35), f(32–36), f(33–37), f(34–38), f(35–39), f(37–41), f(38–42), f(39–43),
f(44–48), f(45–49), f(46–50), f(54–58), f(57–61), f(62–66), f(63–67), f(69–73), f(70–74), f(72–76), f(73–77), f(74–78), f(81–85), f(82–86),
f(83–87), f(84–88), f(85–89), f(86–90), f(87–91), f(88–92), f(89–93), f(92–96), f(93–97), f(94–98), f(95–99), f(96–100), f(97–101), f(98–102),
f(99–103), f(100–104), f(102–106), f(107–111), f(111–115), f(112–116), f(114–118), f(115–119), f(116–120), f(117–121), f(118–122),
f(119–123), f(120–124), f(133–137), f(134–138), f(135–139), f(136–140), f(137–141), f(148–152), f(149–153), f(150–154), f(151–155),
f(152–156), f(153–157), f(154–158), f(155–159), f(156–160), f(157–161), f(158–162), f(159–163), f(160–164), f(161–165), f(173–177),
f(174–178), f(1–10), f(2–11), f(3–12), f(4–13), f(5–14), f(9–18), f(11–20), f(23–32), f(24–33), f(25–34), f(26–35), f(27–36), f(28–37), f(29–38),
f(30–39), f(32–41), f(33–42), f(34–43), f(68–77), f(69–78), f(70–79), f(79–88), f(80–89), f(81–90), f(82–91), f(83–92), f(84–93), f(85–94),
f(86–95), f(87–96), f(88–97), f(89–98), f(91–100), f(92–101), f(93–102), f(94–103), f(98–107), f(113–122), f(114–123), f(132–141),
f(133–142), f(134–143), f(135–144), f(148–157), f(149–158), f(150–159), f(151–160), f(152–161), f(153–162), f(154–163), f(155–164),
f(156–165), f(1–15), f(2–16), f(3–17), f(4–18), f(11–25), f(24–38), f(28–42), f(29–43), f(72–86), f(73–87), f(74–88), f(75–89), f(76–90),
f(77–91), f(79–93), f(80–94), f(81–95), f(82–96), f(83–97), f(84–98), f(85–99), f(86–100), f(87–101), f(88–102), f(89–103), f(90–104),
f(91–105), f(93–107), f(148–162), f(149–163), f(151–165), f(1–20), f(2–21), f(24–43), f(70–89), f(72–91), f(73–92), f(74–93), f(75–94),
f(76–95), f(77–96), f(79–98), f(80–99), f(81–100), f(82–101), f(83–102), f(84–103), f(85–104), f(86–105), f(87–106), f(88–107), f(148–167),
f(1–25), f(2–26), f(70–94), f(72–96), f(73–97), f(74–98), f(75–99), f(76–100), f(77–101), f(78–102), f(78–103), f(79–104), f(80–105),
f(81–106), f(82–107), f(83–108), f(84–109), f(85–110), f(1–30), f(2–31), f(70–99), f(71–100), f(72–101), f(73–102), f(74–103), f(75–104),
f(76–105), f(80–109), f(81–110), f(82–111), f(83–112), f(1–35), f(2–36), f(68–102), f(69–103), f(70–104), f(72–106), and f(2–41).
a The amino acid sequence of β-lactoglobulin, gen. var. A, precursor of Bos taurus (ID = 1115) was obtained from the BIOPEP database (http://www.uwm.edu.pl/biochemia/index.php/pl/biopep).
Amino acid nomenclature: C, cysteine; H, histidine; I, isoleucine; M, methionine; S, serine; V, valine; A, alanine; G, glycine; L, leucine; P, proline; T, threonine; F, phenylalanine; R, arginine; Y, tyrosine; W, tryptophan;
D, aspartic acid; N, asparagine; E, glutamic acid; Q, glutamine; K, lysine.
Antiangiogenic therapeutics
The inhibition of angiogenesis (development of new blood vessels) has long been considered an attractive therapeutic target for
treatment of cancers as it is a hallmark of cancer development.
The vascular endothelial growth factor (VEGF), which plays a
core role in angiogenesis, is a signaling molecule and highly expressed in tumors. Hence, clinical studies are concentrated on
developing antiangiogenic therapies by inhibiting VEGF through
intervening the supply of essential nutrients and the removal of
metabolites (Welti and others 2013).
Histone deacetylase (HDAC) inhibitors
The epigenetic silence of tumor suppressor genes plays an important role in tumorigenesis and is induced by overexpression
of HDACs. Thus, the HDAC inhibitors display antiproliferative
activities in carcinogenesis (Qiu and others 2013).
130 Comprehensive Reviews in Food Science and Food Safety r Vol. 14, 2015
C 2015 Institute of Food Technologists®
Advanced food systems research unit . . .
Table 3.3–Predicted anticancer peptides of lactoferrin of Bos taurus (amino acid residues = 689; Formula weight = 72637.3 Da) using AntiCP, a
web-based prediction server for anticancer peptides (http://crdd.osdd.net/raghava/anticp/submit_prot.php).
of lactoferrin of Bos taurus
1 APRKN VRWCT ISQPE WFKCR RWQWR MKKLG APSIT CVRRA FALEC IRAIA EKKAD AVTLD
61 GGMVF EAGRD PYKLR PVAAE IYGTK ESPQT HYYAV AVVKK GSNFQ LDQLQ GRKSC HTGLG
121 RSAGW IIPMG ILRPY LSWTE SLEPL QGAVA KFFSA SCVPC IDRQA YPNLC QLCKG EGENQ
181 CACSS REPYF GYSGA FKCLQ DGAGD VAFVK ETTVF ENLPE KADRD QYELL CLNNS RAPVD
241 AFKEC HLAQV PSHAV VARSV DGKED LIWKL LSKAQ EKFGK NKSRS FQLFG SPPGQ RDLLF
301 KDSAL GFLRI PSKVD SALYL GSRYL TTLKN LRETA EEVKA RYTRV VWCAV GPEEQ KKCQQ
361 WSQQS GQNVT CATAS TTDDC IVLVL KGEAD ALNLD GGYIY TAGKC GLVPV LAENR KSSKH
421 SSLDC VLRPT EGYLA VAVVK KANEG LTWNS LKDKK SCHTA VDRTA GWNIP MGLIV NQTGS
481 CAFDE FFSQS CAPGA DPKSR LCALC AGDDQ GLDKC VPNSK EKYYG YTGAF RCLAE DVGDV
541 AFVKN DTVWE NTNGE STADW AKNLN REDFR LLCLD GTRKP VTEAQ SCHLA VAPNH AVVSR
601 SDRAA HVKQV LLHQQ ALFGK NGKNC PDKFC LFKSE TKNLL FNDNT ECLAK LGGRP TYEEY
661 LGTEY VTAIA NLKKC STSPL LEACA FLTR
a Amino acid sequence
Predicted anticancer peptides
f(4–8), f(5–9), f(6–10), f(7–11), f(8–12), f(9–13), f(13–17), f(14–18), f(15–19), f(16–20), f(17–21), f(18–22), f(19–23), f(20–24), f(21–25),
f(22–26), f(23–27), f(24–28), f(25–29), f(26–30), f(27–31), f(28–32), f(29–33), f(30–34), f(32–36), f(33–37), f(34–38), f(35–39), f(36–40),
f(41–45), f(42–46), f(43–47), f(45–49), f(46–50), f(48–52), f(49–53), f(50–54), f(52–56), f(60–64), f(61–65), f(64–68), f(68–72), f(69–73),
f(71–75), f(72–76), f(73–77), f(78–82), f(79–83), f(81–85), f(88–92), f(89–93), f(90–94), f(91–95), f(92–96), f(93–97), f(94–98), f(95–99),
f(96–100), f(97–101), f(98–102), f(100–104), f(104–108), f(109–113), f(111–115), f(112–116), f(113–117), f(114–118), f(115–119),
f(116–120), f(118–122), f(119–123), f(120–124), f(121–125), f(122–126), f(123–127), f(124–128), f(125–129), f(128–132), f(129–133),
f(130–134), f(131–135), f(132–136), f(133–137), f(134–138), f(135–139), f(136–140), f(138–142), f(146–150), f(147–151), f(148–152),
f(149–153), f(150–154), f(151–155), f(152–156), f(153–157), f(154–158), f(155–159), f(156–160), f(157–161), f(158–162), f(159–163),
f(160–164), f(163–167), f(164–168), f(165–169), f(166–170), f(167–171), f(169–173), f(170–174), f(171–175), f(172–176), f(173–177),
f(179–183), f(180–184), f(181–185), f(182–186), f(183–187), f(185–189), f(186–190), f(187–191), f(188–192), f(189–193), f(190–194),
f(191–195), f(192–196), f(193–197), f(194–198), f(195–199), f(196–200), f(197–201), f(200–204), f(201–205), f(202–206), f(204–208),
f(206–210), f(223–227), f(227–231), f(228–232), f(229–233), f(230–234), f(231–235), f(239–243), f(241–245), f(242–246), f(243–247),
f(244–248), f(245–249), f(246–250), f(250–254), f(251–255), f(252–256), f(253–257), f(255–259), f(256–260), f(259–263), f(264–268),
f(265–269), f(266–270), f(267–271), f(268–272), f(269–273), f(270–274), f(271–275), f(273–277), f(275–279), f(276–280), f(277–281),
f(278–282), f(286–290), f(287–291), f(288–292), f(289–293), f(290–294), f(291–295), f(292–296), f(296–300), f(297–301), f(298–302),
f(299–303), f(300–304), f(301–305), f(303–307), f(304–308), f(305–309), f(306–310), f(307–311), f(317–321), f(318–322), f(319–323),
f(320–324), f(321–325), f(323–327), f(324–328), f(325–329), f(326–330), f(327–331), f(328–332), f(333–337), f(338–342), f(339–343),
f(341–345), f(342–346), f(343–347), f(344–348), f(345–349), f(346–350), f(347–351), f(348–352), f(349–353), f(353–357), f(354–358),
f(355–359), f(356–360), f(357–361), f(359–363), f(360–364), f(363–367), f(367–371), f(368–372), f(369–373), f(370–374), f(371–375),
f(372–376), f(373–377), f(374–378), f(375–379), f(376–380), f(377–381), f(378–382), f(379–383), f(380–384), f(381–385), f(382–386),
f(383–387), f(385–389), f(396–400), f(397–401), f(398–402), f(399–403), f(400–404), f(401–405), f(402–406), f(403–407), f(404–408),
f(405–409), f(406–410), f(407–411), f(408–412), f(421–425), f(424–428), f(425–429), f(432–436), f(434–438), f(435–439), f(436–440),
f(437–441), f(438–442), f(439–443), f(450–454), f(451–455), f(452–456), f(453–457), f(454–458), f(455–459), f(456–460), f(457–461),
f(463–467), f(464–468), f(465–469), f(469–473), f(470–474), f(471–475), f(472–476), f(477–481), f(478–482), f(479–483), f(483–487),
f(488–492), f(489–493), f(490–494), f(491–495), f(493–497), f(498–502), f(499–503), f(500–504), f(501–505), f(502–506), f(503–507),
f(504–508), f(505–509), f(507–511), f(510–514), f(511–515), f(512–516), f(513–517), f(514–518), f(515–519), f(520–524), f(521–525),
f(522–526), f(523–527), f(524–528), f(525–529), f(526–530), f(528–532), f(529–533), f(530–534), f(536–540), f(537–541), f(538–542),
f(540–544), f(541–545), f(542–546), f(549–553), f(556–560), f(557–561), f(558–562), f(559–563), f(560–564), f(561–565), f(562–566),
f(563–567), f(568–572), f(569–573), f(570–574), f(571–575), f(572–576), f(573–577), f(584–588), f(585–589), f(586–590), f(587–591),
f(588–592), f(591–595), f(592–596), f(593–597), f(594–598), f(595–599), f(596–600), f(597–601), f(603–607), f(604–608), f(605–609),
f(606–610), f(607–611), f(609–613), f(610–614), f(611–615), f(612–616), f(613–617), f(616–620), f(617–621), f(618–622), f(619–623),
f(620–624), f(621–625), f(622–626), f(623–627), f(624–628), f(625–629), f(626–630), f(627–631), f(628–632), f(629–633), f(630–634),
f(631–635), f(636–640), f(637–641), f(638–642), f(639–643), f(640–644), f(641–645), f(642–646), f(643–647), f(644–648), f(645–649),
f(646–650), f(647–651), f(648–652), f(649–653), f(650–654), f(651–655), f(653–657), f(654–658), f(655–659), f(656–660), f(657–661),
f(663–667), f(664–668), f(665–669), f(667–671), f(668–672), f(669–673), f(670–674), f(671–675), f(672–676), f(673–677), f(674–678),
f(675–679), f(679–683), f(680–684), f(682–686), f(683–687), f(684–688), f(1–10), f(2–11), f(3–12), f(4–13), f(7–16), f(8–17), f(9–18),
f(10–19), f(11–20), f(12–21), f(13–22), f(14–23), f(15–24), f(16–25), f(17–26), f(18–27), f(19–28), f(20–29), f(21–30), f(22–31), f(23–32),
f(24–33), f(25–34), f(26–35), f(27–36), f(28–37), f(29–38), f(30–39), f(32–41), f(43–52), f(44–53), f(45–54), f(46–55), f(76–85), f(87–96),
f(88–97), f(89–98), f(90–99), f(91–100), f(92–101), f(93–102), f(94–103), f(95–104), f(96–105), f(97–106), f(108–117), f(109–118),
f(110–119), f(111–120), f(112–121), f(113–122), f(114–123), f(115–124), f(116–125), f(117–126), f(118–127), f(119–128), f(120–129),
f(121–130), f(122–131), f(123–132), f(124–133), f(125–134), f(126–135), f(127–136), f(128–137), f(144–153), f(145–154), f(146–155),
f(147–156), f(148–157), f(149–158), f(150–159), f(151–160), f(152–161), f(153–162), f(154–163), f(155–164), f(156–165), f(157–166),
f(159–168), f(164–173), f(165–174), f(166–175), f(167–176), f(168–177), f(173–182), f(174–183), f(177–186), f(179–188), f(180–189),
f(181–190), f(182–191), f(183–192), f(184–193), f(185–194), f(186–195), f(187–196), f(188–197), f(189–198), f(190–199), f(191–200),
f(192–201), f(193–202), f(194–203), f(194–204), f(195–205), f(201–210), f(202–211), f(241–250), f(242–251), f(244–253), f(245–254),
f(246–255), f(247–256), f(248–257), f(249–258), f(250–259), f(251–260), f(253–262), f(260–269), f(261–270), f(262–271), f(263–272),
f(264–273), f(265–274), f(266–275), f(267–276), f(268–277), f(269–278), f(270–279), f(271–280), f(272–281), f(273–282), f(274–283),
f(277–286), f(278–287), f(282–291), f(284–293), f(285–294), f(286–295), f(287–296), f(292–301), f(296–305), f(297–306), f(298–307),
f(299–308), f(300–309), f(301–310), f(303–312), f(304–313), f(305–314), f(325–334), f(339–348), f(340–349), f(341–350), f(342–351),
f(343–352), f(344–353), f(345–354), f(347–356), f(355–364), f(365–374), f(366–375), f(367–376), f(368–377), f(369–378), f(370–379),
f(371–380), f(372–381), f(373–382), f(378–387), f(380–389), f(395–404), f(396–405), f(397–406), f(398–407), f(399–408), f(400–409),
f(401–410), f(402–411), f(403–412), f(404–413), f(431–440), f(432–441), f(433–442), f(434–443), f(436–445), f(437–446), f(445–454),
f(446–455), f(448–457), f(450–459), f(451–460), f(452–461), f(455–464), f(457–466), f(465–474), f(486–495), f(488–497), f(489–498),
f(490–499), f(491–500), f(493–502), f(494–503), f(496–505), f(497–506), f(498–507), f(499–508), f(511–520), f(519–528), f(520–529),
f(521–530), f(522–531), f(523–532), f(524–533), f(525–534), f(569–578), f(570–579), f(571–580), f(584–593), f(586–595), f(587–596),
f(588–597), f(589–598), f(590–599), f(603–312), f(604–613), f(605–614), f(606–615), f(611–620), f(613–622), f(614–623), f(615–624),
f(616–625), f(617–626), f(618–627), f(619–628), f(620–629), f(621–630), f(622–631), f(623–632), f(624–633), f(625–634), f(626–635),
f(627–636), f(628–637), f(629–638), f(630–639), f(636–645), f(638–647), f(641–650), f(642–651), f(644–653), f(646–655), f(647–656),
f(648–657), f(656–665), f(665–674), f(666–675), f(667–676), f(668–677), f(669–678), f(670–679), f(671–680), f(672–681), f(673–682),
f(674–683), f(675–684), f(678–687), f(679–688), f(2–16), f(3–17), f(4–18), f(5–19), f(6–20), f(7–21), f(8–22), f(9–23), f(10–24), f(11–25),
f(12–26), f(13–27), f(14–28), f(15–29), f(16–30), f(17–31), f(18–32), f(19–33), f(20–34), f(21–35), f(22–36), f(23–37), f(24–38), f(26–40),
f(27–41), f(28–42), f(32–46), f(40–54), f(45–59), f(82–96), f(87–101), f(88–102), f(89–103), f(90–104), f(91–105), f(108–122), f(109–123),
f(110–124), f(111–125), f(112–126), f(113–127), f(114–128), f(115–129), f(116–130), f(117–131), f(118–132), f(119–133), f(120–134),
f(121–135), f(122–136), f(123–137), f(124–138), f(143–157), f(144–158), f(145–159), f(146–160), f(148–162), f(149–163), f(150–164),
f(151–165), f(156–170), f(157–171), f(159–173), f(160–174), f(161–175), f(163–177), f(169–183), f(170–184), f(171–185), f(172–186),
(Continued)
C 2015 Institute of Food Technologists®
Vol. 14, 2015 r Comprehensive Reviews in Food Science and Food Safety 131
Advanced food systems research unit . . .
Table 3.3–Continued.
of lactoferrin of Bos taurus
1 APRKN VRWCT ISQPE WFKCR RWQWR MKKLG APSIT CVRRA FALEC IRAIA EKKAD AVTLD
61 GGMVF EAGRD PYKLR PVAAE IYGTK ESPQT HYYAV AVVKK GSNFQ LDQLQ GRKSC HTGLG
121 RSAGW IIPMG ILRPY LSWTE SLEPL QGAVA KFFSA SCVPC IDRQA YPNLC QLCKG EGENQ
181 CACSS REPYF GYSGA FKCLQ DGAGD VAFVK ETTVF ENLPE KADRD QYELL CLNNS RAPVD
241 AFKEC HLAQV PSHAV VARSV DGKED LIWKL LSKAQ EKFGK NKSRS FQLFG SPPGQ RDLLF
301 KDSAL GFLRI PSKVD SALYL GSRYL TTLKN LRETA EEVKA RYTRV VWCAV GPEEQ KKCQQ
361 WSQQS GQNVT CATAS TTDDC IVLVL KGEAD ALNLD GGYIY TAGKC GLVPV LAENR KSSKH
421 SSLDC VLRPT EGYLA VAVVK KANEG LTWNS LKDKK SCHTA VDRTA GWNIP MGLIV NQTGS
481 CAFDE FFSQS CAPGA DPKSR LCALC AGDDQ GLDKC VPNSK EKYYG YTGAF RCLAE DVGDV
541 AFVKN DTVWE NTNGE STADW AKNLN REDFR LLCLD GTRKP VTEAQ SCHLA VAPNH AVVSR
601 SDRAA HVKQV LLHQQ ALFGK NGKNC PDKFC LFKSE TKNLL FNDNT ECLAK LGGRP TYEEY
661 LGTEY VTAIA NLKKC STSPL LEACA FLTR
a Amino acid sequence
f(177–191), f(178–192), f(179–193), f(180–194), f(181–195), f(182–196), f(183–197), f(184–198), f(185–199), f(186–200), f(188–202),
f(189–203), f(190–204), f(191–205), f(192–206), f(193–207), f(194–208), f(196–210), f(241–255), f(242–256), f(243–257), f(244–258),
f(245–259), f(246–260), f(259–273), f(260–274), f(261–275), f(262–276), f(263–277), f(264–278), f(265–279), f(266–280), f(267–281),
f(268–282), f(269–283), f(273–287), f(275–289), f(276–290), f(277–291), f(278–292), f(279–293), f(280–294), f(282–296), f(286–300),
f(287–301), f(288–302), f(294–308), f(296–310), f(297–311), f(298–312), f(299–313), f(300–314), f(337–351), f(338–352), f(339–353),
f(344–358), f(345–359), f(346–360), f(347–361), f(366–380), f(367–381), f(368–382), f(369–383), f(370–384), f(391–405), f(392–406),
f(393–407), f(394–408), f(395–409), f(396–410), f(398–412), f(399–413), f(402–416), f(403–417), f(431–445), f(432–446), f(434–448),
f(445–459), f(446–460), f(447–461), f(453–467), f(454–468), f(455–469), f(486–500), f(488–502), f(489–503), f(490–504), f(491–505),
f(492–506), f(493–507), f(494–508), f(497–511), f(498–512), f(501–515), f(502–516), f(514–528), f(515–529), f(516–530), f(517–531),
f(516–532), f(517–533), f(518–534), f(519–535), f(520–536), f(582–596), f(583–597), f(584–598), f(585–599), f(586–600), f(587–601),
f(603–617), f(604–618), f(605–619), f(606–620), f(608–622), f(609–623), f(611–625), f(612–626), f(614–628), f(615–629), f(616–630),
f(617–631), f(618–632), f(619–633), f(620–634), f(621–635), f(622–636), f(623–637), f(624–638), f(625–639), f(626–640), f(627–641),
f(628–642), f(636–650), f(661–675), f(662–676), f(663–677), f(664–678), f(665–679), f(666–680), f(667–681), f(668–682), f(669–683),
f(670–684), f(671–685), f(672–686), f(673–687), f(674–688), f(675–689), f(1–20), f(2–21), f(3–22), f(4–23), f(5–24), f(6–25), f(7–26), f(8–27),
f(9–28), f(10–29), f(11–30), f(12–31), f(13–32), f(14–33), f(15–34), f(16–35), f(17–36), f(18–37), f(19–38), f(20–39), f(21–40), f(22–41),
f(23–42), f(24–43), f(26–45), f(27–46), f(28–47), f(34–53), f(82–101), f(106–125), f(107–126), f(108–127), f(109–128), f(110–129),
f(111–130), f(112–131), f(113–132), f(114–133), f(115–134), f(116–135), f(117–136), f(118–137), f(119–138), f(120–139), f(141–160),
f(142–161), f(144–163), f(147–166), f(151–170), f(154–173), f(155–174), f(156–175), f(157–176), f(158–177), f(164–183), f(165–184),
f(166–185), f(167–186), f(169–188), f(170–189), f(172–191), f(173–192), f(177–196), f(178–197), f(179–198), f(180–199), f(181–200),
f(182–201), f(183–202), f(185–204), f(188–207), f(189–208), f(190–209), f(191–210), f(241–260), f(259–278), f(260–279), f(261–280),
f(262–281), f(263–282), f(264–283), f(265–284), f(266–285), f(267–286), f(268–287), f(269–288), f(270–289), f(271–290), f(272–291),
f(273–292), f(275–294), f(276–295), f(277–296), f(276–297), f(282–301), f(288–207), f(289–308), f(294–313), f(339–358), f(340–359),
f(342–361), f(386–405), f(391–410), f(393–412), f(396–415), f(396–416), f(401–420), f(402–421), f(403–422), f(441–460), f(448–467),
f(450–469), f(451–470), f(486–505), f(487–506), f(488–507), f(489–508), f(490–509), f(496–515), f(497–516), f(498–517), f(501–520),
f(511–530), f(513–532), f(514–533), f(515–534), f(579–598), f(601–620), f(603–622), f(604–623), f(605–624), f(606–625), f(607–626),
f(610–629), f(611–630), f(612–631), f(613–632), f(614–633), f(615–634), f(616–635), f(617–636), f(618–637), f(619–638), f(620–639),
f(621–640), f(622–641), f(623–642), f(624–643), f(625–644), f(665–684), f(666–685), f(667–686), f(668–687), f(669–688), f(670–689),
f(1–25), f(2–26), f(3–27), f(4–28), f(5–29), f(6–30), f(7–31), f(8–32), f(9–33), f(10–34), f(11–35), f(12–36), f(13–37), f(14–38), f(15–39),
f(16–40), f(17–41), f(18–42), f(19–43), f(20–44), f(21–45), f(22–46), f(23–47), f(24–48), f(25–49), f(26–50), f(77–101), f(78–102), f(96–120),
f(104–128), f(106–130), f(107–131), f(108–132), f(109–133), f(110–134), f(111–135), f(112–136), f(113–137), f(114–138), f(115–139),
f(149–173), f(150–174), f(151–175), f(152–176), f(153–177), f(157–181), f(159–183), f(160–184), f(165–189), f(166–190), f(167–191),
f(168–192), f(169–193), f(170–194), f(171–195), f(172–196), f(173–197), f(174–198), f(175–199), f(179–203), f(180–204), f(181–205),
f(256–280), f(259–283), f(262–286), f(263–287), f(264–288), f(265–289), f(266–290), f(267–291), f(268–292), f(269–293), f(270–294),
f(271–295), f(276–300), f(277–301), f(278–302), f(286–310), f(278–312), f(279–313), f(338–362), f(339–363), f(396–420), f(397–421),
f(402–426), f(403–427), f(434–458), f(445–469), f(481–505), f(491–515), f(498–522), f(510–534), f(602–626), f(603–627), f(604–628),
f(605–629), f(606–630), f(607–631), f(608–632), f(609–633), f(610–634), f(611–635), f(612–636), f(613–637), f(614–638), f(615–639),
f(616–640), f(617–641), f(618–642), f(619–643), f(623–647), f(624–648), f(625–649), f(661–685), f(662–686), f(1–30), f(2–31), f(3–32),
f(4–33), f(5–34), f(6–35), f(7–36), f(8–37), f(9–38), f(10–39), f(11–40), f(12–41), f(13–42), f(14–43), f(15–44), f(16–45), f(17–46), f(18–47),
f(19–48), f(20–49), f(21–50), f(22–51), f(23–52), f(24–53), f(25–54), f(27–56), f(94–124), f(95–125), f(96–126), f(97–127), f(98–128),
f(104–133), f(108–137), f(109–138), f(110–139), f(111–140), f(145–174), f(146–175), f(147–176), f(148–177), f(149–178), f(154–183),
f(155–184), f(156–185), f(157–186), f(163–192), f(165–194), f(166–195), f(167–196), f(168–197), f(169–198), f(170–199), f(171–200),
f(172–201), f(173–202), f(181–210), f(260–289), f(261–290), f(262–291), f(263–292), f(265–294), f(266–295), f(267–296), f(268–297),
f(272–301), f(277–306), f(278–307), f(279–308), f(282–311), f(284–313), f(396–425), f(432–461), f(478–507), f(486–515), f(487–516),
f(488–517), f(490–519), f(491–520), f(502–531), f(503–532), f(505–534), f(601–630), f(602–631), f(603–632), f(604–633), f(605–634),
f(606–635), f(608–637), f(611–640), f(612–641), f(618–647), f(622–651), f(623–652), f(1–35), f(2–36), f(3–37), f(4–38), f(5–39), f(6–40),
f(7–41), f(8–42), f(9–43), f(10–44), f(11–45), f(12–46), f(13–47), f(14–48), f(15–49), f(16–50), f(17–51), f(18–52), f(19–53), f(20–54),
f(21–55), f(22–56), f(91–125), f(92–126), f(93–127), f(94–128), f(96–130), f(97–131), f(98–132), f(99–133), f(147–181), f(149–183),
f(150–184), f(151–185), f(152–186), f(155–189), f(156–190), f(157–191), f(159–193), f(163–197), f(164–198), f(165–199), f(166–200),
f(167–201), f(168–202), f(169–203), f(170–204), f(260–294), f(262–296), f(265–299), f(266–300), f(267–301), f(268–302), f(269–303),
f(273–307), f(274–308), f(276–310), f(277–311), f(278–312), f(279–313), f(486–520), f(491–525), f(498–532), f(500–534), f(599–633),
f(600–634), f(603–637), f(604–638), f(616–650), f(617–651), f(618–652), f(619–653), f(1–40), f(2–41), f(3–42), f(4–43), f(5–44), f(6–45),
f(7–46), f(8–47), f(9–48), f(10–49), f(11–50), f(12–51), f(13–52), f(14–53), f(15–54), f(16–55), f(17–56), f(18–57), f(19–58), f(92–131),
f(93–132), f(94–133), f(95–134), f(99–138), f(144–183), f(145–184), f(146–185), f(147–186), f(150–189), f(151–190), f(152–191),
f(153–192), f(154–193), f(155–194), f(156–195), f(157–196), f(158–197), f(159–198), f(160–199), f(165–204), f(261–301), f(262–302),
f(265–304), f(266–305), f(267–306), f(268–307), f(269–308), f(270–309), f(271–310), f(277–316), f(490–529), f(491–530), f(493–532),
f(616–655), f(1–45), f(2–46), f(3–47), f(4–48), f(5–49), f(6–50), f(7–51), f(8–52), f(9–53), f(10–54), f(11–55), f(12–56), f(13–57), f(14–58),
f(15–59), f(16–60), f(17–61), f(18–62), f(94–138), f(113–157), f(147–191), f(148–192), f(149–193), f(150–194), f(151–195), f(152–196),
f(153–197), f(154–198), f(155–199), f(156–200), f(157–201), f(261–305), f(262–306), f(263–307), f(264–308), f(265–309), f(266–310),
f(267–311), f(268–312), f(269–313), f(270–314), f(277–321), f(486–530), f(488–532), f(489–533), f(490–534), f(1–50), f(2–51), f(3–52),
f(4–53), f(5–54), f(6–55), f(7–56), f(8–57), f(9–58), f(10–59), f(13–62), f(16–65), f(111–160), f(112–161), f(146–195), f(147–196), f(148–197),
f(149–198), f(150–199), f(151–200), f(153–202), f(154–203), f(155–204), f(259–308), f(260–309), f(261–310), f(262–311), f(263–312),
f(264–313), f(265–314), f(266–315), f(267–316), f(268–317), and f(269–318).
a The amino acid sequence of lactoferrin of Bos taurus (ID = 1212) was obtained from the BIOPEP database (http://www.uwm.edu.pl/biochemia/index.php/pl/biopep). Amino acid nomenclature: C, cysteine;
H, histidine; I, isoleucine; M, methionine; S, serine; V, valine; A, alanine; G, glycine; L, leucine; P, proline; T, threonine; F, phenylalanine; R, arginine; Y, tyrosine; W, tryptophan; D, aspartic acid; N, asparagine; E,
glutamic acid; Q, glutamine; K, lysine.
132 Comprehensive Reviews in Food Science and Food Safety r Vol. 14, 2015
C 2015 Institute of Food Technologists®
Predicted anticancer peptides from milk proteins of Bos taurus
f25–29 of β-casein gen. var. A1 (Table 2.1), var. A2 (Table 2.2), var. B (Table 2.3)
f117–121 of κ-casein gen. var. A, precursor (Table 2.6)
f82–86 of κ-casein gen. var. A, precursor (Table 2.6)
f182–186 of κ-casein gen. var. A, precursor (Table 2.6)
f178–182 of β-casein gen. var. A1 (Table 2.1), var. A2 (Table 2.2), var. B (Table 2.3)
f19–23 of α S1 -casein gen. var. B (Table 2.4), var. C (Table 2.5)
f199–208 of β-casein gen. var. A1 (Table 2.1), var. A2 (Table 2.2), var. B (Table 2.3)
f101–105 of β-casein gen. var. A1 (Table 2.1), var. A2 (Table 2.2), var. B (Table 2.3)
f77–82 of β-casein gen. var. A1 (Table 2.1), var. A2 (Table 2.2), var. B (Table 2.3)
f26–30 of β-lactoglobulin, gen. var. A, precursor (Table 3.2)
f195–199 of α S1 -casein gen. var. B (Table 2.4), var. C (Table 2.5)
f62–66 of β-casein gen. var. A1 (Table 2.1), var. A2 (Table 2.2), var. B (Table 2.3)
Peptides purified from fermented milk and milk products
RINKK (f25–29 of β-casein) (Donkor and others 2007)
ARHPH (f96–100 of κ-casein) (Donkor and others 2007)
YAKPA (f61–65 of κ-casein) (Farvin and others 2010)
TVQVT (f161–165 of κ-casein) (Farvin and others 2010; Welderufael and others 2012)
VPYPQ (f178–182 of β-casein) (Farvin and others 2010)
NLLRF (f19–23 of α S1 -casein) (Hernández-Ledesma and others 2005)
GPVRGPFPII (f199–208 of β-casein) (Hernández-Ledesma and others 2005)
AMAPK (f116–120 of β-casein) (Welderufael and others 2012)
LTQTP (f92–96 of β-casein) (Welderufael and others 2012)
LDIQK (f10–14 of β-lactoglobulin) (Welderufael and others 2012)
TMPLW (f195–199 of α S1 -casein) (Hafeez and others 2013)
FPGPI (f62–66 of β-casein) (Hafeez and others 2013)
S.N.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Table 4–Structure homology between peptides identified in fermented milk and milk products and predicted anticancer peptides using AntiCP, a web-based prediction server for anticancer peptides
(http://crdd.osdd.net/raghava/anticp/submit_prot.php).
Advanced food systems research unit . . .
C 2015 Institute of Food Technologists®
Cyclooxygenase-2 inhibitors
The rate-limiting enzyme for the generation of prostaglandins
from arachidonic acid is cyclooxygenase-2. This enzyme activates
and promotes angiogenesis, tumorigenesis, tumor proliferation,
and prevention of apoptosis (Dai and others 2012).
Farnesyltransferase inhibitors
Point mutations in the ras protooncogene bring about permanently active Ras and are, in this manner, oncogenic. The primary
step in the Ras activation is farnesylation employing farnesyl transferase and, hence, inhibitors of this enzyme have antitumor effects
(Agrawal and Somani 2009).
S100P/RAGE interaction inhibitor
S100P is a S100 family of protein and a helpful marker for distinguishing tumor cells from normal cells. S100P can only act through
the receptor for activated glycation end products (RAGE). S100P
has a prominent role during the development and progression
of various malignancies. S100P mediates tumor growth, metastasis, and drug resistance through the RAGE. Therefore, blocking
S100P/RAGE interaction in cancer cells is clinically beneficial
(Arumugam and Logsdon 2011).
p53-MDM2 inhibitor
MDM2 protein negatively regulates transcriptional activity
and stability of p53 tumor suppressor genes through binding.
Therefore, excessive production of MDM2 in tumor cells lead
to impairment of p53 function. Therefore, repairing p53 activity by repressing p53-MDM2 binding indicates an alluring novel
methodology in tumor treatment. Activated p53 is considered to
cause cell cycle arrest, consequently prompting apoptosis. Endeavors are underway to synthesize a variety of chemicals that
could react with the binding sites of Mdm2 for p53 to impair the
p53–MDM2 interaction. Reinstatement of p53 activity by hindering the p53-MDM2 interaction has been viewed as an appealing
approach for malignancy treatment (Wang and Hu 2012).
Hsp90 inhibitors
Heat shock proteins (Hsp’s), in particular Hsp90, play a crucial
role in advancement of tumorigenesis by inhibiting apoptosis in
cancer cells, and enhancing angiogenesis and cell cycle progression.
Additionally, Hsp90 promotes malignant phenotypes by protecting
several oncogenic mutant proteins from degradation. Stabilization
of these oncoproteins results in abnormal signaling cascades and
limitless cellular growth (Franke and others 2013). Therefore, the
compounds that are able to interfere with Hsp90 functions could
be potential anticancer drugs hence, Hsp90 may be considered as
a promising target in cancer therapy.
Proteasome inhibitors
The ubiquitin–proteasome system (UPS) is present in all mammalian cells, where proteins that are no longer needed or have
been misfolded are labeled by ubiquitin, which targets them for
destruction. A cascade of ubiquitination enzymes is involved in
the specific labeling of target proteins with ubiquitin. The labeled
proteins are recognized by chaperone proteins that direct them
to the 26S proteasome. This large multiprotein complex systematically degrades the unneeded/misfolded proteins into smaller
peptide fragments. Cancer cells heavily rely on this pathway to
maintain protein homeostasis, and selective inhibition of UPS enzymes causes a build-up of proteins inducing apoptotic cell death
(Shen and others 2013).
Vol. 14, 2015 r Comprehensive Reviews in Food Science and Food Safety 133
Advanced food systems research unit . . .
Ras and Raf-kinase as a target for cancer therapeutics
The mitogen-activated protein kinase (MARK) signaling pathway exhibits a vital role in relaying proliferative signal of cytoplasmic signaling elements and cell surface receptors to the nucleus.
Few signaling elements of the MARK pathways, especially Ras
and Raf, are encoded by the oncogenes. As the MARK pathway
is mainly dysregulated in human malignancies, several of its aberrant and critical components can be utilized as strategic targets for
cancer therapy (Sridhar and others 2005).
Tyrosine kinase inhibitors (TKIs)
TKIs are currently one of the most important classes of cancer
drugs. Aberrant activation of tyrosine kinase pathways is among the
most dysregulated molecular pathways in human cancers; therefore, a large number of tyrosine kinases may serve as valuable
molecular targets (Natoli and others 2010).
Death receptors (TRAILR1 and TRAILR2)
The intrinsic and extrinsic pathways are 2 main signaling pathways that result into apoptosis in mammalian cells.
As extrinsic-pathway-induced apoptosis complements intrinsicpathway-induced apoptosis in malignant cells, death receptors can
also be taken into consideration as new targets for cancer treatment. The extrinsic pathway is commenced through cascades of
apoptotic signal transductions, which, in turn, are mediated by tumor necrosis factor (TNF) receptor superfamily members. TNFrelated apoptosis-inducing ligand (TRAIL) is a strong stimulator of
apoptosis, and malignant cells are more sensitive towards TRAILinduced apoptosis than normal cells. Therefore, targeting TRAIL
receptors, such as TRAILR1 and TRAILR2, are viewed as a
promising focus for cancer therapy (Wiezorek and others 2010).
Antioxidant
The liberation of excessive free radicals results in oxidative stress.
Oxidative stress is known to be implicated in the development of
cancer and other chronic diseases. Oxidative stress has been a major
predicament of present-day living. It has been the product of imbalance between the processes involved in free radical generation
and their neutralization by enzymatic and non-enzymatic defense
mechanisms. The most common outcome of oxidative stress is
increased damage of lipid, DNA, and proteins that result in the
development of different pathologies. Among these pathologies,
cancer is the most devastating and is linked to multiple mutations
arising due to oxidative DNA and protein damage that ultimately
affect the integrity of the genome.
Antioxidants are chemical compounds that suppress or delay the
oxidative stress by inhibiting oxidative processes (Srinivasan 2014).
Deleterious effects of ROS, such as hydroxyl radicals, superoxide
anion radicals, and hydrogen peroxide molecules, along with reactive nitrogen species such as peroxynitrites and nitrogen oxides,
results in oxidative DNA damage; 8-hydroxyguanine is an oxidized DNA product. This damage is predominantly linked with
the initiation process of carcinogenesis.
Minimizing oxidative damage may be a significant advance in
the prevention or treatment of cancer, since antioxidants are able
to terminate free-radical formation and to prevent oxidizing chain
reactions. These findings have generated great interest in the development of antioxidant-based anticancer drugs (Tekiner-Gulbas
and others 2013; Choudhari and others 2014).
processes in the advancement of cancers. Mutation of the p53
tumor suppressor genes occurs in almost half of all human
malignancies. The p53 protein regulates many cellular functions,
including DNA synthesis and repair, gene transcription, cell cycle
arrest, and apoptosis. Therefore, mutation in the p53 gene leads to
the repudiation of these functions, which in turn results in genetic
instability and progressing of cancers (Hussain and others 2001).
Immunomodulatory agents
Interferon gamma (IFN-γ ) is an immunoregulatory molecule,
which is also involved in the inhibition of angiogenesis and cancer cell proliferation in tumor microenvironments (Ossina and
others 1997; Blankenstein and Qin 2003). Interleukin-2 (IL-2),
IL-6, IL-12, and TNF-α also play a vital role in immunoregulation and antitumor activities. Therefore, these immunoregulatory
molecules are also considered as targets for cancer therapy (Byun
and others 2010).
Bioactive peptides isolated from goat liver inhibited proliferation of human gastric cancer MGC-803 cell line in a dose and
time-dependent fashion (Su and others 2014). Moreover, the
primary purpose of a cancer clinical trial for a new cytotoxic
drug is to identify the maximum tolerated dose, in view of the
supposition that increment of efficacy and toxicity occurs monotonically as the dose increases. However, small toxicity may arise
within the therapeutic dose range for molecularly targeted agents,
and the dose–response curves may not be monotonic. This opposes
the belief that more is better, which is highly believed in conventional chemotherapy. Therefore, continuance of health-related
quality of life for cancer patients has turned into an incredible challenge of conventional chemotherapy. It has become fundamental
to explore the lowest safe dose with the highest efficiency (Bottomley 2002). Thus, anticancer activities of milk peptides should
be studied in various delivery environments including phosphate
buffered saline both at concentration normally circulating in the
human body (biological dose) or above (pharmaceutical dose).
Mode of Application of Peptides as Anticancer Agent
Peptides might be utilized in various ways to prevent or treat
tumors. This includes application of peptides directly as medications, hormones, and immunizations. Out of these possibilities,
peptide medications are now accessible in the business sectors.
They originated from anticancer agents carrying radionuclides
and peptide hormone therapy (Aina and others 2002; Borghouts
and others 2005; Meng and others 2012; Zhang and others 2012).
There are enormous advancements in other areas, for example,
peptide-immunization and angiogenesis inhibitors; some trials are
underway for providing better choices to a large number of tumor
patients.
Direct application of peptides in cancer therapy is gaining wider
use nowadays. Antitumor activity of peptides is attributable to various mechanisms including angiogenesis inhibition, signal transduction pathway, protein–protein interaction, gene expression, or
enzymes (Kakde and others 2011; Rosca and others 2011; Zheng
and others 2011; Li and Cho 2012). An alternate group is peptide antagonists that preferentially bind with a specific receptor
(Cornelio and others 2007; Sotomayor and others 2010). In addition, “proapoptotic” peptides mediate noteworthy induction of
apoptosis in malignant cells (Ellerby and others 1999;Walensky
and others 2004; Smolarczyk and others 2006).
Antimutagenic agents
The anticancer activity of peptides is likely to diminish side efCancer development takes place through multiple stages and fects after conventional tumor treatment. Milk peptides as such or
damage to the genetic material (DNA) is one of the major in combination with antitumor medications or irradiation could
134 Comprehensive Reviews in Food Science and Food Safety r Vol. 14, 2015
C 2015 Institute of Food Technologists®
Advanced food systems research unit . . .
enhance the efficacy and efficiency of cancer therapies. The anti- Aune D, Lau R, Chan DSM, Vieira R, Greenwood DC, Kampman E, Norat
tumor activities of peptides are attributable to various mechanisms, T. 2012. Dairy products and colorectal cancer risk: a systematic review and
meta-analysis of cohort studies. Ann Oncol 23:37–45. DOI:
for example, antioxidant activity (Table 2), antimutagenic activity 10.1093/annonc/mdr269.
(Table 3), immunomodulatory activity (Table 3), antiangiogen- Azevedo RA, Ferreira AK, Auada AVV, Pasqualoto KFM, Marques-Porto R,
esis activity, and β-glucuronidase inhibitory activity (Table 3). Maria DA, Lebrun I. 2012. Antitumor effect of cationic INKKI peptide
Inactivation of carcinogens can occur in the liver by conjugating from bovine β-casein on melanoma B16F10. J Cancer Ther 3:237–44.
with glucuronic acid and excretion with urine or bile. However, DOI: 10.4236/jct.2012.34034.
D, Widmann C. 2011. Promises of apoptosis-inducing peptides in
bacterial β-glucuronidase enzyme may cleave the conjugated car- Barras
cancer therapeutics. Curr Pharm Biotechnol 12:1153–65. DOI:
cinogen in the intestine and the free carcinogen may be recycled. 10.2174/138920111796117337.
Conclusions
Cancer has become the leading reason in developed countries
and the 2nd leading reason in developing countries for mortality.
Effective therapies are surgery, chemotherapy, and radiotherapy,
but these therapies have poor response rates and enormous side
effects (Al-Benna and Steinsträßer 2009). Several peptides liberated
from milk proteins have displayed advantageous impacts on human
wellbeing. Proline, leucine, and glutamine have dominated various positions in predicted anticancer peptides from caseins, while
lysine, leucine, and alanine have dominated at various positions
in predicted anticancer peptides from whey proteins. Moreover,
bioactive peptides with anticancer potential can be isolated from
fermented milk and milk products. Albeit current findings of dairy
food intakes and risks of cancer lack consistency, dairy-derived
peptide exhibits a promising candidate for cancer therapy. The
bioactivities of peptides may also play a vital role in the design
of functional foods that might treat or alleviate the impact of tumors. Biologically active peptides can possibly be utilized in the
design of various functional foods, cosmetics, and drugs. Molecular research is now needed to elucidate the mechanisms of the
anticancer activities of bioactive peptides. Discovery of various
anticancer peptides is expected to advance a “new wave” of more
efficient and effective antitumor medications in the near future,
capturing a big share of the tumor therapeutic markets. Thus, it
additionally is vital to discover new peptides with anticancer activities from fermented dairy products and milk protein-hydrolysates.
This innovation will also contribute toward the advancement of
various functional foods.
Acknowledgments
The authors are thankful to the Australian Government for
offering an Australia Awards Scholarships and Australia Awards
Leadership Program place to B. N. P. Sah.
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