Drug Combination Selectively Prevents Cancer Cell Growth

The antihypertension drug syrosingopine has been found to drastically reduce the concentration of the diabetes medication metformin required to destroy cancer cells in culture and in a mouse liver cancer model.

Metformin is the most widely used antidiabetic drug in the world, and there is increasing evidence of a potential efficacy of this agent as an anticancer drug. First, epidemiological studies showed a decrease in cancer incidence in metformin-treated patients. Second, metformin decreased insulin resistance and indirectly reduced insulin level, a beneficial effect because insulin promotes cancer cell growth. Third, several reports outlined a direct inhibitory effect of metformin on cancer cell growth and an anti-tumor action. Finally, metformin activated the AMP activated protein kinase (AMPK) pathway, a major sensor of the energetic status of the cell, which has been proposed as a promising therapeutic target in cancer.

Since the concentration of metformin needed to inhibit the growth of cancer cells induces unwanted side effects, investigators at the University of Basel screened over a thousand drugs for any that could enhance the anticancer action of the diabetes drug.

The investigators reported in the December 23, 2016, online edition of the journal Science Advances that the antihypertensive syrosingopine, a derivative of reserpine, was synthetically lethal with metformin and that both compounds interacted synergistically to kill a broad variety of cancer cell types while demonstrating no activity against normal cells. In mice with malignant liver cancer, enlargement of the liver was reduced after combination therapy. Furthermore, treated animals had fewer tumor nodules, and in some animals the tumors disappeared completely.

In addition to promoting the anticancer effect of metformin, synthetic lethality with syrosingopine was also observed with every inhibitor of the mitochondrial electron transport chain tested. The synthetic lethal interaction evoked by syrosingopine and mitochondrial inhibitors occurred at concentrations substantially below the toxic threshold for either compound alone.

"We have been able to show that the two known drugs lead to more profound effects on cancer cell proliferation than each drug alone," said first author Dr. Don Benjamin, a post-doctoral researcher at the University of Basel. "The data from this study support the development of combination approaches for the treatment of cancer patients. For example, in samples from leukemia patients, we demonstrated that almost all tumor cells were killed by this cocktail and at doses that are actually not toxic to normal cells, and the effect was exclusively confined to cancer cells, as the blood cells from healthy donors were insensitive to the treatment."