Of Prostate Cancer, Glucose, Metabolism and Metformin

A study conducted by Canadian investigators and reported in the September 1, 2013 issue of the Journal of Clinical Oncology examined the impact of Metformin use on mortality in men with diabetes and prostate cancer (Margel D. Urbach DR., Lipscombe LL, Metformin Use and All-Cause and Prostate Cancer-Specific Mortality Among Men with Diabetes, Journal of Clinical Oncology, volume 31, #25, pgs 3069-3075, 2013). The investigators examined 3837 patient with a median age of 75 years. They conducted a retrospective analysis examining the Ontario Province heath care records. The intent was to examine duration of exposure to Metformin as a diabetes management in patients with prostate cancer to assess the impact on all-cause and prostate cancer-specific mortality.

The results are impressive and instructive. There was a significant decrease in the risk of prostate cancer-specific and all-cause mortality, which related to the dose and duration of exposure to Metformin. The adjusted hazard ratio for the study of 0.76 indicates that there is a 24% reduction in mortality for prostate cancer-specific events with the use of Metformin. This study was not perfect, as it was retrospective, there was no randomization and it was impossible to control for all other variables such as exercise, smoking history and clinical parameters of prostate cancer. Nonetheless, there is a clear and important trend toward reduced prostate cancer and even overall mortality. This is but one of a series of clinical studies that have examined the impact of Metformin upon not only prostate cancer but also breast cancer. Much of this work was originally pioneered by Dr. Michael Pollack from McGill University in Montreal.

The biguanide class of antidiabetic drugs, originates from the French lilac or goat's rue (Galega officinalis), a plant used in folk medicine for several centuries.  (Wikipedia)

The biguanide class of antidiabetic drugs, originates from the French lilac or goat’s rue (Galega officinalis). (Wikipedia)

Metformin and the closely related Phenformin are members of the class of drugs known as biguanides. While the exact mode of action of the biguanides is not fully understood, they are known to disrupt mitochondrial respiration at complex I. This upregulates an enzyme known as adenosine monophosphate kinase (AMPK) thereby altering energy metabolism within the cell and down regulating mTOR. In diabetics, this drives down blood glucose to control the disease. However, in cancer patients, a profound effect is observed that suppresses synthetic pathways necessary for energy metabolism, cellular survival and cellular proliferation. These effects appear responsible for the impact upon prostate cancer. Interestingly, these drugs are more effective in controlling already transformed cells and less effective in the prevention of cancer. This is consistent with the observation that malignantly transformed cells change their state of metabolism.

This article is interesting on many levels. The first and most obvious is that this relatively inexpensive and well-tolerated drug can have an impact on prostate cancer.

Secondly, these effects appear to cross the lines of different cancer types, such that breast cancer and other forms of cancer might also be successfully treated.

The third note of interest shows that even patients without diabetes can tolerate Metformin, suggesting this as an adjunct to many different treatments. Finally and most importantly this represents the new and important recognition that cancer is not a genomic disorder, but a metabolic disorder. Cancer may utilize normal genetic elements to its own advantage. AMP kinase, LKB1 and mTOR are not unique to cancer, but instead, are found in every cell. These normal proteins are simply altered in their function in malignantly transformed cells. Metformin is one of what will soon be a large number of metabolomic agents entering the clinical arena as cancer research moves from the nucleus to the mitochondrion.

About Dr. Robert A. Nagourney
Dr. Nagourney received his undergraduate degree in chemistry from Boston University and his doctor of medicine at McGill University in Montreal, where he was a University Scholar. After a residency in internal medicine at the University of California, Irvine, he went on to complete fellowship training in medical oncology at Georgetown University, as well as in hematology at the Scripps Institute in La Jolla. During his fellowship at Georgetown University, Dr. Nagourney confronted aggressive malignancies for which the standard therapies remained mostly ineffective. No matter what he did, all of his patients died. While he found this “standard of care” to be unacceptable, it inspired him to return to the laboratory where he eventually developed “personalized cancer therapy.” In 1986, Dr. Nagourney, along with colleague Larry Weisenthal, MD, PhD, received a Phase I grant from a federally funded program and launched Oncotech, Inc. They began conducting experiments to prove that human tumors resistant to chemotherapeutics could be re-sensitized by pre-incubation with calcium channel blockers, glutathione depletors and protein kinase C inhibitors. The original research was a success. Oncotech grew with financial backing from investors who ultimately changed the direction of the company’s research. The changes proved untenable to Dr. Nagourney and in 1991, he left the company he co-founded. He then returned to the laboratory, and developed the Ex-vivo Analysis - Programmed Cell Death ® (EVA-PCD) test to identify the treatments that would induce programmed cell death, or “apoptosis.” He soon took a position as Director of Experimental Therapeutics at the Cancer Institute of Long Beach Memorial Medical Center. His primary research project during this time was chronic lymphocytic leukemia. He remained in this position until the basic research program funding was cut, at which time he founded Rational Therapeutics in 1995. It is here where the EVA-PCD test is used to identity the drug, combinations of drugs or targeted therapies that will kill a patient's tumor - thus providing patients with truly personalized cancer treatment plans. With the desire to change how cancer care is delivered, he became Medical Director of the Todd Cancer Institute at Long Beach Memorial in 2003. In 2008, he returned to Rational Therapeutics full time to rededicate his time and expertise to expand the research opportunities available through the laboratory. He is a frequently invited lecturer for numerous professional organizations and universities, and has served as a reviewer and on the editorial boards of several journals including Clinical Cancer Research, British Journal of Cancer, Gynecologic Oncology, Cancer Research and the Journal of Medicinal Food.

2 Responses to Of Prostate Cancer, Glucose, Metabolism and Metformin

  1. Michelle says:

    This makes so much more sense than the errant gene theory – I’ve always had trouble with insulin control to the point of gestational diabetes with two pregnancies – however returned to non diabetic after deliveries – still crash after a heavy carb meal – now on a vegetable and protein diet with few carbs – maybe the metformin would have kept the CLL at bay -

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

Follow

Get every new post delivered to your Inbox.

Join 106 other followers

%d bloggers like this: