Scientists at Dana-Farber Cancer Institute have shown that experimental diabetes drugs can make cancer cells more defenseless to traditional chemotherapy agents and further said such combinations should be explored to potentially improve outcomes for cancer patients.
They demonstrated in cancer cell lines and animal models that the research compounds - similar to common anti-diabetic agents known as thiazolidinediones (TZDs) - sensitised lung tumor cells to carboplatin chemotherapy.
Tumors in rodents are 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 sensitised triple-negative breast cancer cells in the laboratory, causing them to self-destruct. However, not all types of cancer cells appear to be made defenseless to chemotherapy combined with the experimental compounds.
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 new research involves drugs developed at Scripps which act on PPAR-gamma but in a way different from the conventional TZD drugs; the scientists refer to these 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.
By identifying the phosphorylation of PPAR-gamma as a mechanism by which cancer cells can repair DNA damage, now a rational basis for using these ‘non-canonical agonist ligands’ of PPAR-gamma to render cancer cells more sensitive to chemotherapy.
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.
