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Activities of Thymoquinone and Thymohydroquinone against Breast and
Colorectal Cancer
Ayesha Siddique Butt*1 and Numrah Nisar2
1.
PhD scholar, Department of Environmental Science Lahore College For Women University, Lahore.
Email:[email protected]
2.
Assistant Professor, Department of Environmental Science Lahore College For Women University , Lahore.
Email:[email protected]
*Corresponding Author
Ayesha Siddique Butt
PhD Research Scholar
Department of Environmental Science Lahore College For Women University, Jail
Road, Lahore.
Email:[email protected]
ABSTRACT
Thymoquinone (TQ) and Thymohydroquinone (THQ) are considered to be very
important phyto-chemical components for their therapeutic properties from the Nigella
sativa and Thymus vulgaris. Different studies on TQ and THQ using as drugs have
shown the effective treatment against different types of cancer. Many research studies
have revealed TQ as promising anti-cancer agent against in vitro and in vivo disease
models by their anti-inflammatory, anti-proliferative and apoptotic effects on abnormal
cells. The present knowledge about antitumor activity of THQ is very limited and till
today there is no data about antitumor activity of THQ in vivo and in vitro. The present
review highlights the activities of both quinones (TQ and THQ) as drugs against most
predominant cancers i.e. breast and colorectal cancer. The increasing incidents of both
these cancer in the last decades have shifted researchers to the production and
improvement of anti-cancer drugs and their chemotherapies approaches by the
scientific investigation of vast pool of synthetic, biological and natural products. TQ and
THQ considered being the ideal compounds for the cancer therapy as they are
economically and environmental friendly and have less toxicity level to the survival and
diseased model up to increased dosage level. Further studies are also being carrying
out by loading these compounds on different drug carriers like PLGA which enhances
their cytotoxic activities. This review will lead to the introduction and importance of
natural drugs to the cancer world for its inhibition and cure.
Key Words: TQ, THQ, Breast Cancer, Colorectal cancer, phyto-chemical components,
anti-cancer agents, Nigella sativa, Thymus vulgaris, apoptosis and anti-inflammatory
effects.
INTRODUCTION
Thymoquinone (2-isopropyl-5-methyl-benzoquinone) is a promising compound with
significant in vitro and in vivo antitumor activities against different tumor models. 1 It
proved to be effective against several types of cancer cell lines in which the classical
hallmark of apoptosis such as chromatin condensation, translocation of phosphatidyl
serine across the plasma membrane, and DNA fragmentation have been documented in
TQ-treated cells.2
Thymohydroquinone (2-Methyl-5-isopropyl hydroquinone) is also the major
component along with the TQ. The present knowledge about antitumor activity of THQ
is very limited and till today there is no data in vivo.3 Both TQ and THQ exhibited good
anti-proliferative activity against tumor cells in vitro which is in agreement with other
literature findings.3
Nigella sativa is widely used medicinal plant and is emerging as most important
medicinal herb having wide spectrum of pharmacological potential. It has been strongly
recommended by Tibb-e-Nabwi as remedy of all diseases except death.4 Several
studies on N. sativa have shown therapeutic potential and biological activities as
antidiabetic, immunomodulatory, anticancer, antihypersenstivity, diuretic, analgesic,
anti-inflammatory, antimicrobial, bronchodialator, gastroprotective, renal protective,
hepatoprotective and antioxidant properties due to many active compounds including
TQ and THQ.5,6 Sing et al., (2014) by analysis of N. sativa with Gas chromatographymass spectrometry (GC-MS), followed the extraction procedure in Clevenger apparatus
with Soxhelt extractor, revealed the major components such as TQ (37.6%) and THQ
(3.4%). 3
Thymus vulgaris shows a wide range of biological and medicinal properties such as
antiseptic, expectorant, antispasmodic, anthelminthic, anti- inflammatory, antioxidants
and lately as anti-cancer agents.7,8 Thyme extraction from thymus species as an
essential oil, containing thymol as a main compound, can be easily converted to oil with
TQ and THQ as the main component. With the appearance of even small quantities of
these compounds, the thyme essential oil becomes a more potent antioxidant and
serious drug phyto-therapy showing potent anti-cancer activities.9
Cancer is one of the highest frightened diseases that are spreading with persistence
and increasing incidence all over the world.10 Experimental investigations demonstrated
that many naturally occurring agents and plant extracts have shown anticancer potential
in a variety of bioassay systems and animal models.11,12 The assumed mechanism of
TQ action involves manifold paths which play significant roles in cancer development. It
was reported that TQ prompt intrinsic pathways of apoptosis through the activation of
caspases cascade. The activation of caspase-8 highlights the effect of TQ on Bcl2 and
the role of mitochondria in Thymoquinone-induced apoptosis in human squamous cell
carcinoma, in human osteosarcoma p53-null MG63 cells and in p53-null HL-60
Myeloblastic leukaemia.13 An increase of TP53 expression level in MCF7/DOX cells
indicated the p53-dependent apoptosis after treatment with TQ resulting in reduction of
Bcl2 protein and reduction in the Bcl2/Bax ratio.14 Studies showed anticancer effect of
TQ on different type of cancer cells through in vitro and in vivo which indicate the
involvement of TQ in different cell death signaling pathways including apoptosis,
proliferation, angiogenesis and tumor induced immunosuppression.15 Every type of cell
can secrete transforming growth which is dependent on the cell response to the TGF-s
receptors. Increase or decrease in their functions and its downstream pathway can lead
to cancer. So far, the anticancer mechanism of TQ is not fully understood; however,
several modes of action have been described depending on the stimulus and the
cellular context.16
TQ and THQ against Colorectal cancer
In C26 colorectal cell TQ showed anti-invasive activities against DMH-induced colon
cancer when administered at the initiation or post-initiation phases. The apoptotic
effects of TQ in human colorectal cancer cell cultures and xenografts indicated that this
relatively non-toxic and inexpensive compound evidences for further clinical
investigation, particularly as there are only a few effective and nontoxic anticancer
agents available for clinical use. Interestingly, TQ was found to have only limited toxicity
to normal intestinal cells in vitro and not to disturb the survival or diseased of animals
when used at doses up to 25 mg/kg in colorectal cancer animal models.17 Previous
works by some authors documented TQ as growth inhibitor and apoptosis triggering
effects on colon and other dense tumors such as breast, uterine sarcoma and
pancreatic cancer in a dose- and time-dependent manner.18 Furthermore, TQ revealed
to reduce tumor growth and to induce apoptosis in several murine cancer models.16 So
far despite a few reports, the interaction of TQ with the kinase network of colon cancer
cells is only poorly understood. Wang et al., (2013) performed a measurable phosphoproteomic analysis to recognize new targets in TQ- treated HCT116 colorectal cancer
cells.19 El-Najar et al., (2010) shown a function of ERK1/2 under TQ, since inhibition of
ERK1/2 by the MEK inhibitor PD98059 resulted in enhanced apoptosis.17 In the their
study Wang et al., (2013) documented first time TQ directly binds to PAK1/ERK kinase
complex, induces considerable conformational changes of PAK1 and intrudes its
scaffold function.19 Upon TQ the interference of Thr423 phosphorylation with the kinase
domain is disrupted inhibiting the PAK1 kinase activity and its apoptosis signaling.20 TQinduced loss of ERK1/2 dependent phosphorylation at Thr212 of PAK1 provides another
negative feedback of apoptosis PAK1/MEK/ERK1/2 signaling. Schneider- Stock et al.,
(2014) suggested the approaches of several new TQ targets which could be used in the
future to estimate the therapeutic advantage of combination therapies.21
TQ and THQ against Breast Cancer
In MCF7 breast cancer cell line after treatment with TQ, different studies suggested the
involvement of mitochondrial pathway and extrinsic pathway.15 Recent research also
revealed interesting inhibitory effects of TQ in breast cancer cell lines MCF-7, MDA-MB231 and BT-474. Woo et al., 2012 suggested a new molecular target for TQ anticancer
activity against breast cancer cell lines, which is the peroxisome proliferator-activated
receptors (PPARs).22 Abu Khader (2015) presented molecular reducing studies showing
that TQ for activation could make contact with amino-acids within the ligand binding
pocket of PPAR-γ.23 The activation of PPAR-γ was found to play a pivotal role in TQinduced apoptosis through the activation of caspases and down-regulate PPAR-γ
related genes, including Bcl-2, Bcl-xL and surviving at both mRNA and protein
expression levels in MCF-7 cells. In addition, TQ was able to reduce the migration and
invasion of MDA-MB-231 cells.
Arafa et al., 2011 examined the anticancer effects of TQ in doxorubicin-resistant human
breast cancer cells (MCF-7/DOX cells). The authors investigated the potential
mechanism by which TQ may regulate cell proliferation and apoptosis in MCF-7/DOX
cells. The suggested mechanism is that TQ induces apoptosis in doxorubicin-resistant
breast cancer cells through the up-regulation of phosphatase and PTEN at the
transcription level.14 The up-regulated PTEN, in turn, inhibits the phosphatidylinositol-3
kinase/Akt pathway and induces p53 and p21 protein expression, thereby causing G2/M
cell cycle arrest and apoptosis. The possible risk of gender sensitivity to TQ toxicity with
female breast cancer patients can be eliminated by adopting combinatorial drug therapy
of TQ with doxorubicin, which is commonly used in chemotherapy to treat breast
cancer.23,24
There is no doubt that cancer research has demonstrated the beneficial potential of TQ
against breast cancer cell lines and animal models with the emphasis on its
nmechanism of action. In spite of this, there is however a lack of clinical studies testing
TQ in human patients with breast cancer. In general, in the process of drug discovery a
potential lead compound has to undergo preclinical evaluation prior to clinical trials.25
This includes understanding of the drug mechanism of action, drug toxicity and
determination of its absorption, distribution, metabolism and excretion (ADME) of the
drug.26 The lipophilic nature of TQ presents a solubility challenge, which could results its
bioavailability and cause constraint drug formulation. TQ exhibited to be safe when it is
delivered orally in several disease animal models. A large number of studies used oral
sub-acute and sub-chronic TQ in the range of 10-100 mg/kg body weight without any
reported toxicity or deaths.23
Ravindran et al., 2010 tested a novel delivery approach for TQ-loaded poly (lactide-coglycolide) nanoparticles against colon cancer (HCT 116), breast cancer (MCF7),
prostate cancer (PC-3), and multiple myeloma cells lines (U266). The results showed a
better anticancer activity of the encapsulated TQ in nanoparticles than free TQ due to
enhanced bioavailability and cellular uptake.27 Ganea et al., 2010 tested the anticancer
activity of TQ-loaded poly (lactide-co-glycolide) nanoparticles against other breast
cancer cell line (MDA-MB-231) and showed to be more effective than free TQ.28 A
recent research done by Odeh et al., 2012 tested TQ-loaded liposomes particles
against MCF-7 breast cancer cell line and proved to be effective in constraining the
proliferation in this cell line. These results confirm the defensive effect of the delivery
vehicle against serum protein binding and biotransformation of TQ allowing better
anticancer activity.29 The study by Effenberger et al., (2010) can be optimized and taken
further with either the use of combination therapy of TQ with, for example, doxorubicin
or the use of TQ-loaded nanoparticles to treat cancer patients. Moreover, TQ analogs
such as caryophyllyl and germacryl conjugates as well as fatty acid conjugates showed
a potent anticancer activity against sensitive and resistant MCF-7 breast cancer cell
lines.30
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