A new study published in the journal Proceedings of the National Academy of Sciences shown that experimental diabetes drugs can make cancer cells more vulnerable to traditional chemotherapy agents, and such combinations should be explored to potentially improve outcomes for cancer patients.

The investigators demonstrated in cancer cell lines and animal models that the research compounds – similar to 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 researchers noted.

The scientists, led by cancer biologist Bruce Spiegelman, said, "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."

First author of the study is Melin Khandekar, a radiation oncologist at Massachusetts General Hospital who carries out research in the Spiegelman lab. Other authors are at the Scripps Research Institute Department of Molecular Therapeutics.

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.

A previous study led by Spiegelman and team reported that combination of rosiglitazone and platinum chemotherapy agent halted or shrank mouse tumors as much as three times more effectively than either of the drugs given alone. The results showed that this combination might improve control of cancers that eventually become resistant to platinum chemotherapy agents.

The new research involves drugs developed at Scripps by Patrick Griffin, a co-author of the study. They 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.

The newly developed drugs 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 study 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 Spiegelman.

Khandekar said, "These drugs may provide an even safer alternative [than the older TZD anti-diabetes drugs] that you could combine with existing chemotherapies" to enhance the treatment of patients with certain cancers.