Novel diabetes drugs sensitize cancer cells to chemotherapy agents

Novel diabetes drugs sensitize cancer cells to chemotherapy agents

Scientists have shown that experimental diabetes drugs can make cancer cells more vulnerable to traditional chemotherapy agents, and they say such combinations should be explored to potentially improve outcomes for cancer patients.

Reporting in the Proceedings of the National Academy of Sciences, investigators demonstrated in cancer cell lines and animal models that the research compounds - similar to common anti-diabetic agents known as thiazolidinediones (TZDs) - sensitized lung tumor cells to carboplatin chemotherapy. Tumors in rodents treated with the combination of carboplatin and one of the experimental compounds, SR1664, weighed less than those in animals treated with carboplatin alone.

The research also showed that the combination sensitized triple-negative breast cancer cells in the laboratory, causing them to self-destruct. However, not all types of cancer cells appear to be made vulnerable to chemotherapy combined with the experimental compounds, the authors note.

The scientists say "these data strongly suggest that [the experimental anti-diabetes compounds] should be explored for clinical use in combination with traditional chemotherapy for a variety of malignancies."

The experimental compounds used in the study target a newly discovered cellular process by which cells repair themselves in response to DNA damage, such as the damage caused by a number of chemotherapy agents. The process involves a change called phosphorylation of PPAR-gamma, a receptor discovered by Spiegelman that is essential for fat cell development. PPAR-gamma is also a target of the TZD class of anti-diabetic agents, which include rosiglitazone and pioglitazone. PPAR-gamma is expressed in a number of cancers, including lung, triple-negative breast, colorectal, and pancreatic cancers.

The potential for diabetes drugs to enhance chemotherapy goes back a number of years. In 2007, Spiegelman and colleagues reported that rosiglitazone, sold as Avandia, combined with a platinum chemotherapy agent halted or shrank mouse tumors as much as three times more effectively than either of the drugs given alone. These results suggested that giving the diabetes drug with platinum-based chemotherapies might improve control of cancers that eventually become resistant to platinum chemotherapy agents. However, reports of heart attacks in patients taking rosiglitazone led to a federal warning label being placed on the drug - a warning that was later removed, according to the author. "The earlier reports kind of tarnished this idea" of combining diabetes drugs with chemotherapy, author said.

The new drugs also act on PPAR-gamma but in a way different from the conventional TZD drugs; the scientists refer to the novel compounds as "non-canonical agonist ligands" or NAL, of PPAR-gamma. They retain many of the properties of the TZD anti-diabetes drugs but have fewer side effects such as weight gain, bone loss, and fluid retention, according to the report's authors.

By identifying the phosphorylation of PPAR-gamma as a mechanism by which cancer cells can repair DNA damage, "we now have a rational basis for using these non-canonical agonist ligands of PPAR-gamma" to render cancer cells more sensitive to chemotherapy, explains the senior author.