METFORMIN AS AN EFFECTIVE ANTI-CANCER DRUG

Imagine that there is an effective new anti-cancer drug tomorrow that is cheap, proven to be safe and widely available in any GP clinic because it's been in use for more than 50 years in the treatment of another medical condition (type II diabetes).  Imagine that its side-effects are usually mild and self-limited (epigastric discomfort, nausea and diarrhoea).  Imagine that its purported worst-case side-effect, lactic acidosis, though serious, is rare and its causation by the drug has been put in serious doubt by the available evidence.  This sounds like a long-awaited dream for cancer sufferers everywhere.

Yet, increasingly, that dream appears destined to become reality!  Metformin, a natural product of the French lilac, is set to become The Next Big Thing in our battle against cancer.

THEORETICAL POSSIBILITIES

Metformin can act in three ways:

(1)  Indirect insulin-mediated mechanism

Through the mediation of AMP-activated protein kinase (AMPK), metformin suppresses gluconeogenesis in the liver, thereby lowering the level of circulating insulin levels.  This leads to decreased binding of insulin to insulin/insulin-like growth factor-1 receptors (IR/IGF-1R) that are present on cancer cells.  This reduces stimulation of the Ras and phosphatidylinositol-3-kinase (PI3K) pathways.  This results in the inhibition of the mammalian target of rapamycin (mTOR) and reduced cancer-cell proliferation but increased tendency of cancer-cell apoptosis (cell death).

(2) Direct mechanism

Metformin may also inhibit the complex-I of the respiratory chain in the mitochondria.  This results in increased levels of adenosine monophosphate (AMP) and increased activation of AMPK through the mediation of liver kinase B1 (LKB1).  This leads to downstream inhibition of mammalian target of rapamycin (mTOR) and decreased protein production, reduced cancer-cell proliferation and increased apoptosis.

It is already known that the time-proven measures of caloric restriction, exercise, weight loss and bariatric surgery are effective ways in preventing cancer by activating AMPK, the crucial cellular energy sensor and master switch.  Metformin merely mimics their effect.

(3) Several additional anti-proliferative mechanisms independent of the AMPK energy-sensing pathway.

SCIENTIFIC EVIDENCE

Over the last 5 years, supporting scientific evidence for metformin's great promise has been gathering.

(1) Retrospective epidemiological analysis, have shown that metformin use in diabetics had significantly reduced their rates of cancer incidence and mortality including for cancers of the breast, colorectum, pancreas, lung and liver.  It also may have reversed the increased cancer risk associated with the the use of insulin injections.  Better clinical outcomes were also found in those already diagnosed with cancer.

(2)  Clinical studies also showed metformin use induced a significantly increased pathologic complete response (pCR) rate from neoadjuvant breast cancer chemotherapy, a lower rate of metastasis and cancer-related death and a reduction in proliferation and aberrant crypt foci in the rectal epithelium of patients without diabetes who have had previous colorectal polyps.

(3)  In-vitro preclinical research with metformin demonstrated increased apoptosis of melanoma skin cancer cells in culture media in 96 hours.  In-vivo research showed that metformin prevented colorectal tumors in laboratory animals, suppressed intestinal polyp growth in mice predisposed to that disease, protected mice from developing lung cancers after exposure to a potent tobacco carcinogen, and reduced the proliferation of cancer-prone breast cells in mice.

All it needs now is an authoritative endorsement from the medical community.