Download Berberine Use in Stimulating Apoptosis

1
Berberine use in Stimulating
Caspase Apoptotic Pathways in
Cancer Patients
Dr. Kevin Conners
Dr. Kevin Conners | 1654 County Road E E, Vadnais Hts, MN 55110 |
www.connersclinic.com
CONTENTS
Section One
Section Two
Section Three
Section Four
References
A Brief Synopsis of Apoptosis
Berberine’s History
Berberine’s Role in Cancer
Using Berberine in Practice
Dr. Kevin Conners | 1654 County Road E E, Vadnais Hts, MN 55110 |
www.connersclinic.com
3
SECTION ONE – A Brief Synopsis of
Apoptosis
The normal life and death of a human cell is governed by a variety of factors.
Apoptosis is the normal, programmed cell death mechanism that is responsible
for cleanup of cells that have reached the end of life and cells that are damaged
through another mechanism. There are numerous intracellular properties that
aide in such destruction that can become damaged. One, very important pathway
involves a family of endoproteases that provide these critical links in cell
regulatory networks – the caspases. Caspases are important for maintaining
homeostasis through regulating cell death and inflammation.
Accordingly, caspases have been broadly classified by their known roles in
apoptosis (caspase-3, -6, -7, -8, and -9 in mammals), and in inflammation
(caspase-1, -4, -5, -12 in humans and caspase-1, -11, and -12 in mice) (Fig.
below). The functions of caspase-2, -10, and -14 are less easily categorized.
Caspases involved in apoptosis have been subclassified by their mechanism of
action and are either initiator caspases (caspase-8 and -9) or executioner
caspases (caspase-3, -6, and -7).
Dr. Kevin Conners | 1654 County Road E E, Vadnais Hts, MN 55110 |
www.connersclinic.com
There exist both intrinsic and extrinsic (in relation to the cel) pathways of
apoptosis. The extrinsic apoptosis pathway is activated through the binding of a
ligand to a death receptor (apoptotic receptor on the cell membrane), which in
turn leads, with the help of the adapter proteins and ultimately involves caspase
stimulation to achieve cell death. The intrinsic or mitochondrial apoptosis
pathway can be activated through various cellular stresses that lead to
Cytochrome C release from the mitochondria and the formation of the
apoptosome but also involve caspase initiation to kill the cell.
Apoptosis is programmed cell death that involves the controlled dismantling of
intracellular components while avoiding inflammation and damage to surrounding
cells that is imperative in preventing cancer. Initiator caspases activate
executioner caspases that subsequently coordinate their activities to demolish
key structural proteins and activate other enzymes.
Dr. Kevin Conners | 1654 County Road E E, Vadnais Hts, MN 55110 |
www.connersclinic.com
5
Let’s make it clear that breakdown in any of these complicated processes may
result in down-regulation of normal cell death programming that is the first stage
in achieving a diagnosis of cancer. Therefore, as this paper suggests, stimulation
of caspase pathways through the use of pharmaceutical or nutraceutical means
may prove beneficial in both the prevention and treatment of cancer.
SECTION TWO – Berberine’s History
Berberine is one of the active alkaloid extracts, derived from a variety of plants
(i.e. Oregon grape, barberry, tree turmeric, goldenseal, Amor cork tree, Chinese
goldthread etc.) that have been traditionally used in Ayurvedic and Chinese
medicines for the treatment of diabetes, infections and gastrointestinal problems.
Within these plants, the berberine alkaloid can be found in the stem bark, roots,
and rhizomes, and stem bark of the plants. Most commonly used in diabetic
patients to reduce blood sugar, other uses have exhibited significant
antimicrobial activity against a variety of organisms including bacteria, viruses,
fungi, protozoans, parasitic worms, and chlamydia.
Much research has centered on berberine’s properties to reduce glucose load
and regulate blood sugar in diabetic patients but this paper explores the more
recent studies on berberine’s role in cancer therapy and prevention.
SECTION THREE – Berberine’s Role in
Cancer
Metabolic regulation as well as energy production is largely dependent on
mitochondria, which play an important role in cellular homeostasis. Imbalance
between energy intake and expenditure leads to mitochondrial dysfunction,
characterized by a reduced ratio of energy production (ATP production) to
respiration. Due to the role of mitochondrial factors/events in several apoptotic
pathways involving caspases as described above, the possibility of targeting
mitochondria in the tumor cell, leading to its elimination is very attractive.
Berberine, a benzyl-tetra isoquinoline alkaloid extracted from plants of the
Dr. Kevin Conners | 1654 County Road E E, Vadnais Hts, MN 55110 |
www.connersclinic.com
Berberidaceae family (Oregon Grape root), has been extensively used for many
centuries, especially in the traditional Chinese and Native American medicine.
Several evidences suggest that berberine possesses several therapeutic uses,
including anti-tumoral activity. The present review supplies evidence that
berberine is a safe anti-cancer agent, exerting several effects on mitochondria,
including inhibition of mitochondrial Complex I and interaction with the adenine
nucleotide translocator, which can explain several desired effects on tumor cells.
In short, berberine stimulates caspase apoptotic pathways.
Studies evaluating Berberine for antitumor activity against malignant brain tumors
revealed that berberine has potent antitumor activity against human and rat
malignant brain tumors. Another study on cervical cancer further proved its
potential as a promising chemotherapeutic agent in cervical cancer. Berberine is
capable of inhibiting the proliferation of multiple cancer cell lines.
A prostate cancer study demonstrated that berberine inhibited the expression of
prostate‑ specific antigen (PSA) and the activation of epidermal growth factor
receptor (EGFR), and it attenuated EGFR activation. The study results indicate
that berberine inhibits the proliferation of prostate cancer cells through apoptosis
and/or cell cycle arrest by inactivation of the EGFR signaling pathway.
Treatment of human breast cancer cells (MCF-7 and MDA-MB-231 cells) with
berberine induced inhibition of cell viability in concentration- and time-dependent
manner irrespective of their estrogen receptor (ER) expression.
This study revealed that Berberine was responsible for down-regulation of antiapoptotic Bcl-2 family protein and increased the release of Cytochrome C and
apoptosis-inducing factor (AIF) from mitochondria, and eventually triggered the
caspase-dependent and caspase-independent apoptosis.
There are numerous other studies that may be cited, however, taken together,
berberine may exert an antitumor activity in cancer cells by reactive oxygen
species generation and mitochondrial-related apoptotic pathways. These findings
provide an insight into the potential of berberine for cancer therapy.
SECTION FOUR – Using Berberine in
Practice
It may be advisable for patients with cancer to supplement berberine to their daily
protocol. However, care must be given as to correct dosage and timeliness of
Dr. Kevin Conners | 1654 County Road E E, Vadnais Hts, MN 55110 |
www.connersclinic.com
7
use. The half-life of berberine alkaloids is relatively short so the prescription
might best be administered TID at a dosage of 200-600mg per adult dose. The
only dangers in berberine supplementation may be alleviated by supporting liver
detoxification pathways as stated below as berberine supplementation has been
shown to down-regulate cytochrome P450 in some patients.
A possible recommendation may be:




500mg Berberine (through mixed sources of Oregon Grape Extract
and Bayberry Extract) – TID
Balanced whole-food Vitamin B Complex
CoQ10 – 50mg BID
Methyl tetrahydrofolate (MTHF) – 1g/day
References:
Berberine as a promising safe anti-cancer agent - is there a role for
mitochondria? Curr Drug Targets. 2011 Jun;12(6):850-9.
Diogo CV1, Machado NG, Barbosa IA, Serafim TL, Burgeiro A, Oliveira P
Center for Neuroscience and Cell Biology, Department of Life Sciences,
University of Coimbra, Portugal.
Caspase Functions in Cell Death and Disease
David R. McIlwain, Thorsten Berger and Tak W. Mak
Taylor RC, Cullen SP, Martin SJ. 2008. Apoptosis: Controlled demolition at the
cellular level. Nat Rev Mol Cell Biol 9: 231–241.
Riedl SJ, Shi Y. 2004. Molecular mechanisms of caspase regulation during
apoptosis. Nat Rev Mol Cell Biol 5: 897–907.
Dr. Kevin Conners | 1654 County Road E E, Vadnais Hts, MN 55110 |
www.connersclinic.com
Juo P, Kuo CJ, Yuan J, Blenis J. 1998. Essential requirement for caspase8/FLICE in the initiation of the Fas-induced apoptotic cascade. Curr Biol 8: 1001–
1008.
Laboratory studies of berberine used alone and in combination with 1,3-bis(2chloroethyl)-1-nitrosourea to treat malignant brain tumors. Chin Med J (Engl).
1990 Aug;103(8):658-65.
Zhang RX, Dougherty DV, Rosenblum ML
Berberine alters epigenetic modifications, disrupts microtubule network, and
modulates HPV-18 E6-E7 oncoproteins by targeting p53 in cervical cancer cell
HeLa: A mechanistic study including molecular docking. Eur J Pharmacol. 2014
Dec 5;744:132-46. doi: 10.1016/j.ejphar.2014.09.048. Epub 2014 Oct 18. Saha
SK1, Khuda-Bukhsh AR2.
Berberine targets epidermal growth factor receptor signaling to suppress prostate
cancer proliferation in vitro. Mol Med Rep. 2015 Mar;11(3):2125-8. doi:
10.3892/mmr.2014.2929. Epub 2014 Nov 12.
Huang ZH, Zheng HF, Wang WL, Wang Y, Zhong LF, Wu JL, Li QX
Berberine suppresses MEK/ERK-dependent Egr-1 signaling pathway and inhibits
vascular smooth muscle cell regrowth after in vitro mechanical injury. Biochem
Pharmacol. 2006 Mar 14;71(6):806-17. Epub 2006 Jan 31.
Liang KW1, Ting CT, Yin SC, Chen YT, Lin SJ, Liao JK, Hsu SL.
Berberine-induced apoptosis in human breast cancer cells is mediated by
reactive oxygen species generation and mitochondrial-related apoptotic pathway.
Tumour Biol. 2014 Oct 29. [Epub ahead of print]
Dr. Kevin Conners | 1654 County Road E E, Vadnais Hts, MN 55110 |
www.connersclinic.com