Metformin Protects Against Several Cancers

VBCC - May 2012, Volume 3, No 3 - AACR Annual Meeting
Richard Hyer

Chicago, IL—Metformin cannot seem to stay out of the news. This antidiabetes drug that is derived from the French lilac is now also thought to possibly protect against liver cancer, lower the risk for oral cancer, improve prognosis of pancreatic cancer in diabetic patients, and increase response to melanoma tumors with BRAF mutations when used in combination with a common cancer drug, according to several studies presented at the 2012 American Association for Cancer Research meeting.

Metformin suppresses the liver’s production of glucose and may actually protect against liver cancer, according to a recent study (Bhalla K, et al. Cancer Prev Res [Phila]. 2012;5:544-552).

“There has been a lot of interest in metformin in the last several years, because of its role as an anticancer agent,” said coauthor Geoffrey Girnun, PhD, Assistant Professor of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore. “We were surprised that there were no actual direct studies looking at the role of metformin in liver cancer in any preclinical models, so that is what we did.”

When liver tumors were chemically induced in mice, the mice taking metformin displayed minimal tumor activity, whereas the controls displayed significant tumor growth. Dr Girnun said that the mechanism by which metformin prevents liver cancer may be transferable to other patient populations at risk for the disease, including those with hepatitis, nonalcoholic fatty liver disease, and obese persons.

In an unrelated study, the incidence of oral cancer was reduced by 70% to 90% in mice receiving metformin (Vitale-Cross L, et al. Cancer Prev Res [Phila]. 2012;5:562-573). The study showed that metformin acts against the mTOR protein to prevent lesion progression. The mTOR protein regulates cell growth, proliferation, motility, survival, protein synthesis, and transcription. Investigators induced premalignant lesions into laboratory mice and then studied metformin’s effect on the progression to oral cancer. Metformin reduced the size and number of oral tumor lesions in the mice, and reduced the development of squamous-cell carcinoma by 70% to 90%.

Metformin inhibited the mTORC1 (metformin complex 1), function in the basal layer of oral premalignancies and prevented their development into head and neck squamous-cell carcinoma. Results of yet another study suggest that patients with concomitant diabetes and pancreatic cancer who are prescribed metformin may have improved survival compared with those who are not prescribed metformin (Sadeghi N, et al. Clin Cancer Res. 2012 Mar 31).

Patients with pancreatic cancer have a high prevalence of diabetes and impaired glucose tolerance. In this retrospective study of 302 patients with diabetes and pancreatic cancer, 117 were prescribed metformin. At 1 year, 63.9% of the patients prescribed metformin were still alive, whereas 46.3% of those who were not receiving metformin survived. By 2 years, 30.1% of the metformin group remained alive compared with 15.4% of the nonmetformin group. Patients using metformin had a 32% reduced risk of mortality.

According to this study, metformin’s protective effect was evident at all disease stages, except metastatic disease, where metformin had no measurable effect.

Combining metformin with vascular endothelial growth factor-A (VEGF-A) inhibitors increased suppression of tumor growth in melanoma tumors with BRAF mutations compared with treatment with the VEGF-A inhibitors alone, according to a new study (Martin MJ, et al. Cancer Discov. 2012;2:344-355).

The investigators first tested metformin on NRAS-mutated and BRAFmutated melanoma cells grown in culture, then grew BRAF-mutated melanoma tumors in mice. They found that metformin caused BRAF-mutated cells to secrete increased levels of VEGF-A, a molecule that promotes blood vessel formation and increases tumor growth. This prompted the investigators to use an animal model in combination with often used VEGF-A inhibitors.

Tumor growth increased 2-fold with metformin alone, but when combined with the tyrosine kinase inhibitor axitinib (Inlyta), tumor growth was suppressed by 45%. When metformin was combined with bevacizumab (Avastin), tumor growth was suppressed by 64% compared with 34% with bevacizumab alone.

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