[1] Introduction.
Berberine has long been used in TCM (traditional Chinese medicine). It is a yellow pigment, found in a number of plants, including the Berberis family.
It has poor bioavailability.
It shares certain properties with Metformin - see [3].
[2] Berberine & PCa. (These are all cell studies.)
{A note on the cell cycle phases that lead to cell division. It is not necessary to kill PCa cells to control the cancer. If the cell cycle can be arrested, the cell will not divide. There are four basic phases: G1, S, G2 & M [2a].
In [2b] the cycle was halted in the G1 phase. G1 is where cell contents other than chromosomes are duplicated.
In [2f] & [2j], cell division was arrested in the G1 or G2/M phase, depending on dose. G2 is where viability for cell division is checked & repairs made, if necessary/possible. The M phase is mitosis - the nucleus divides, followed by the entire cell.}
{A note on cell death. Apoptosis is considered to be the most natural form of cell death. Internal regulators, in effect, trigger the suicide of the cell. Cancer cells must neutralize those regulators. Halting the cell cycle may often be easier than inducing apoptosis.
In [2g], berberine induce two forms of cell death - apoptosis & the rarer necrosis.)
{A note on the Epithelial–mesenchymal transition (EMT). A vexing issue in PCa is the plasticity of tumor cells, that allow them to morph from anchored epithelial cells to mesenchymal stem cells. The cells lose adhesion, break through the cellular matrix to become metastatic. Mobility achieved, they later reverse the transition.
In [2i], berberine inhibited EMT.}
[2b] (2006 - U.S.)
"In our present investigation, we show that a naturally occurring isoquinoline alkaloid, berberine, significantly inhibits the proliferation and reduces the viability of DU145 and PC-3 as well as LNCaP cells (Fig. 1), which suggests that berberine may be an effective chemotherapeutic agent against both androgen-sensitive and androgen-insensitive prostate cancer cells. Importantly, we found that berberine did not exhibit toxicity to nonneoplastic human prostate epithelial cells under the conditions used, except for a moderate reduction in cell viability at higher concentrations when cells were treated in vitro for an extended period of time.
"Control of cell cycle progression in cancer cells is considered to be a potentially effective strategy for the control of tumor growth as the molecular analyses of human cancers have revealed that cell cycle regulators are frequently mutated in most common malignancies. Our in vitro data indicated that treatment of both androgen-sensitive (LNCaP) and androgen-insensitive (DU145, PC-3) cells with berberine resulted in significant G1-phase arrest of cell cycle progression, which indicates that one of the mechanisms by which berberine may act to inhibit the proliferation of cancer cells is inhibition of cell cycle progression. Notably, this effect was not seen in a normal prostate epithelial cell line."
"G1-phase arrest of cell cycle progression provides an opportunity for cells to either undergo repair mechanisms or follow the apoptotic pathway. In the case of advanced prostate cancer, cancer cells become resistant to apoptosis and do not respond to the cytotoxic effects of most of the available chemotherapeutic agents. Therefore, identification of agents that can induce apoptosis in hormone-refractory prostate cancer cells is of high priority. We therefore determined the effect of berberine on the induction of apoptosis in both DU145 and LNCaP cells. Our flow cytometry data indicate that treatment of DU145 and LNCaP cells with berberine resulted in significant induction of apoptosis and that this effect was not seen in normal prostate epithelial PWR-1E cells."
[2c] (2008 - U.S. - same lab as [2b])
"Berberine-induced apoptosis in human prostate cancer cells is initiated by reactive oxygen species generation."
I have known a number of men try to manage their cancer (partially) via antioxidants, based on an idea of turning back the clock & making the cells more normal (better differentiated). But in fact, almost all positive PCa studies using antioxidants, have used high doses that turn them into pro-oxidants. And the key event has always been the generation of ROS (reactive oxygen species).
[2d] (2009 - U.S.)
This study looked at Nexrutine, a product made from Phellodendron amurense bark extract. A butanol (an alcohol) fraction of Nexrutine replicated the results:
"The results suggest that berberine or closely related component of butanol fraction may be responsible for the observed biological activities and induce apoptosis in prostate cancer cells by targeting critical cell survival signaling pathways both in vitro and in vivo."
Activation of NF-kB, the major cell survival response to bacterial & viral attack, was inhibited. PCa chronically activates NF-kB.
[2e] (2010 - S. Korea)
"Berberine inhibited radioresistant effects and enhanced anti-tumor effects in the irradiated-human prostate cancer cells."
"ROS generation was elevated by berberine"
"Berberine inhibited the anti-apoptotic signal pathway involving the activation of the HO-1/NF-κB-mediated survival pathway, which prevents radiation-induced cell death."
[2f] (2012 - China)
"Berberine dose-dependently induced DNA double-strand breaks and apoptosis."
"At low concentrations, berberine was observed to induce G1 arrest"
"Upon exposure to berberine at a higher concentration (50 μM) for 24h, cells exhibited G2/M arrest."
[2g] (2014 - China)
"Our data found that in prostate cancer cells, berberine induced reactive oxygen species (ROS) production ..."
"In the current study, we found that berberine induced apoptosis and programmed necrosis in cultured prostate cancer cells (LNCaP and PC-82 lines), and necrosis weighted more than apoptosis in contributing berberine's cytotoxicity."
[2h] (2015 - China)
"A cell proliferation assay demonstrated that berberine inhibited cell growth in a dose‑and time‑dependent manner. Further investigation revealed berberine significantly accumulated inside cells that were in the G1 phase of the cell cycle and enhanced apoptosis."
"... 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."
EGFR (epidermal growth factor receptor) is one of the growth factors commonly implicated in proliferation.
[2i] (2015 - Taiwan)
"Berberine exerted inhibitory effects on the migratory and invasive abilities of highly metastatic prostate cancer cells. These inhibitory effects of berberine resulted in significant repression of a panel of mesenchymal genes that regulate the developmental EMT."
[2j] (2015 - China)
"Berberine inhibits the proliferation of prostate cancer cells and induces G₀/G₁ or G₂/M phase arrest at different concentrations."
[2k] (2016 - China)
I posted on aldo-keto reductase 1C3 (AKR1C3) a few days ago (in Indomethacin / Xtandi). It gives a back-door way for cells to create androgen, & is a reason for drug resistance.
"Berberine inhibits androgen synthesis by interaction with aldo-keto reductase 1C3 in 22Rv1 prostate cancer cells."
[2l] (2016 - U.S.)
Interesting account of a berberine [Brb] nanoparticle delivery system. Rationale:
"Despite its low systemic toxicity, several pharmaceutical challenges limit the application of Brb in cancer therapy (ie, extremely low solubility and permeability, very poor pharmacokinetics (PKs), and oral bioavailability). Among lipid-based nanocarriers investigated recently for Brb, stealth amphiphilic micelles of polymeric phospholipid conjugates were studied here as a promising strategy to improve Brb delivery to tumors."
[3] Berberine as an alternative to Metformin. (Non-PCa studies.)
[3a] (2012 - China)
"A clinical study on the short-term effect of berberine in comparison to metformin on the metabolic characteristics of women with polycystic ovary syndrome."
"Polycystic ovary syndrome (PCOS) is a frequent reproductive and metabolic disorder associated with insulin resistance (IR)."
"Treatment with BBR in comparison to MET showed decrease in waist circumference and waist-to-hip ratio .., total cholesterol .., triglycerides .., and low-density lipoprotein cholesterol ... as well as increase in high-density lipoprotein cholesterol ..."
[3b] (2014 - U.S.)
"Olanzapine is a first line medication for the treatment of schizophrenia, but it is also one of the atypical antipsychotics carrying the highest risk of weight gain."
"Neither metformin nor berberine treatment demonstrated a significant inhibition of olanzapine-increased food intake. But interestingly, a significant loss of brown adipose tissue caused by olanzapine treatment was prevented by the addition of metformin or berberine. Our gene expression analysis also demonstrated that the weight gain prevention efficacy of metformin or berberine treatment was associated with changes in the expression of multiple key genes controlling energy expenditure."
[3c] (2015 - Korea)
"... drug-drug interaction potential between berberine and metformin."
"Co-administration of berberine increased the initial plasma concentration and AUC of metformin and decreased systemic clearance and volume of distribution of metformin in rats, suggesting that berberine inhibited disposition of metformin ..."
[3d] (2014 - U.S.)
"We propose that berberine and metformin inhibit mitogenic signaling in {pancreatic ductal adenocarcinoma} cells through dose-dependent AMPK-dependent and independent pathways."
[3e] (2015 - China)
Interesting paper on how berberine & metformin may profoundly alter gut bacteria.
-Patrick
[1] en.wikipedia.org/wiki/Berbe...
[2a] www2.le.ac.uk/departments/g...
[2b] mct.aacrjournals.org/conten...
[2c] ncbi.nlm.nih.gov/pubmed/182...
[2d] ncbi.nlm.nih.gov/pmc/articl...
[2e] ncbi.nlm.nih.gov/pmc/articl...
[2f] ncbi.nlm.nih.gov/pubmed/225...
[2g] ncbi.nlm.nih.gov/pubmed/249...
[2h] ncbi.nlm.nih.gov/pubmed/253...
[2i] ncbi.nlm.nih.gov/pubmed/255...
[2j] ncbi.nlm.nih.gov/pubmed/255...
[2k] ncbi.nlm.nih.gov/pubmed/266...
[2l] ncbi.nlm.nih.gov/pmc/articl...
[3a] ncbi.nlm.nih.gov/pubmed/220...
[3b] ncbi.nlm.nih.gov/pubmed/246...
[3c] ncbi.nlm.nih.gov/pubmed/253...
