Mo’ Metformin

WASHINGTON — The commonly prescribed anti-diabetes drug metformin appears to improve the ability of bicalutamide (Casodex), an androgen ablation drug, to slow proliferation in hormone-resistant prostate cancer cell lines, researchers reported here.

“Combining metformin with bicalutamide significantly reduces prostate cancer cell colony formation rates more effectively than either drug in monotherapy,” said Vasundara Venkateswaran, PhD, assistant professor of surgery at the University of Toronto.

In her poster presentation at the annual meeting of the American Association for Cancer Research here, Venkateswaran also suggested that “this combination regimen may potentially improve prostate cancer specific survival through a direct anti-proliferation mechanism.”

The researchers assessed the effect of bicalutamide and/or metformin on cell proliferation rates in sensitive and hormone-resistant prostate cancer cell lines, exposing the cell lines to micromolar concentrations of bicalutamide or millimolar concentrations of metformin resulted in significant dose-dependent reductions in cellular proliferation.

For example, the combination reduced colony formation rates by about 50% (P<0.0001) compared with monotherapy arms in androgen-resistant PC3 cells. Combined treatment with bicalutamide and metformin caused about a 90% reduction in cell proliferation.

“These preliminary results are being further evaluated to determine whether this positive interaction is additive or synergistic,” Venkateswaran told MedPage Today. “We are also assessing the combination regimen in vivo using a murine xenograft model and are performing mechanistic studies to determine how bicalutamide and metformin interact.”

She said further studies will also determine if therapeutic levels of the drugs will have similar effects on cell lines and in vivo models of prostate cancer.

Venkateswaran said research has shown that prostate cancers can be driven by insulin and often insulin growth factor receptors are overexpressed in prostate cancer patients — especially in men who may be overweight or express the so-called metabolic syndrome.

“The incidence of prostate cancer varies dramatically by geographic location, with developed countries exhibiting significantly higher levels of disease,” she noted. “Some attribute this to the ‘Westernized lifestyle’ of high energy diets coupled with lack of physical activity and consequent obesity. Rising obesity levels have been mirrored by increased diagnoses of non-insulin dependent diabetes.”

While the evidence for a causal association between obesity and prostate cancer is mixed, clear evidence exists that obese prostate cancer sufferers have higher levels of prostate cancer-specific mortality, she said.

In addition, previous research has found that metformin has anti-neoplastic effects in vitro and in vivo, and clinical studies have suggested that patients on the drug are diagnosed with cancer less frequently and have lower prostate cancer-specific mortality.

She suggested that metformin use, in addition to impacting prostate cancer growth, “may improve overall survival rates by reducing the cardiovascular morbidity and mortality that accompanies hormone-induced metabolic syndrome.”

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