Novel diabetes drugs sensitize cancer cells to chemotherapy agents

January 02, 2018

Scientists at Dana-Farber Cancer Institute 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, led by cancer biologist Bruce Spiegelman, PhD, 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."

First author of the report is Melin Khandekar, MD, PhD, 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.

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 Khandekar. "The earlier reports kind of tarnished this idea" of combining diabetes drugs with chemotherapy, he said.

The new research involves drugs developed at Scripps by Patrick Griffin, PhD, a co-author on the PNAS paper. 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. 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 Spiegelman.

Khandekar adds, "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.
-end-
The research was supported by grants from the National Cancer Institute-Massachusetts General Hospital Federal Share Program NCI-C06-CA-059267, Department of Defense Lung Cancer Research Program Career Development Award LC140129 and National Institutes of Health Grants DK31405 and DK107717.

Dana-Farber Cancer Institute

Related Chemotherapy Articles from Brightsurf:

Chemotherapy is used to treat less than 25% of people with localized sarcoma
UCLA researchers have found that chemotherapy is not commonly used when treating adults with localized sarcoma, a rare type of cancer of the soft tissues or bone.

Starved cancer cells became more sensitive to chemotherapy
By preventing sugar uptake, researchers succeeded in increasing the cancer cells' sensitivity to chemotherapeutic treatment.

Vitamin D could help mitigate chemotherapy side effects
New findings by University of South Australia researchers reveal that Vitamin D could potentially mitigate chemotherapy-induced gastrointestinal mucositis and provide relief to cancer patients.

Less chemotherapy may have more benefit in rectal cancer
GI Cancers Symposium: Colorado study of 48 patients with locally advanced rectal cancer receiving neoadjuvant chemotherapy, found that patients receiving lower-than-recommended doses in fact saw their tumors shrink more than patients receiving the full dose.

Male fertility after chemotherapy: New questions raised
Professor Delb├Ęs, who specializes in reproductive toxicology, conducted a pilot study in collaboration with oncologists and fertility specialists from the McGill University Health Centre (MUHC) on a cohort of 13 patients, all survivors of pediatric leukemia and lymphoma.

'Combo' nanoplatforms for chemotherapy
In a paper to be published in the forthcoming issue in NANO, researchers from Harbin Institute of Technology, China have systematically discussed the recent progresses, current challenges and future perspectives of smart graphene-based nanoplatforms for synergistic tumor therapy and bio-imaging.

Nanotechnology improves chemotherapy delivery
Michigan State University scientists have invented a new way to monitor chemotherapy concentrations, which is more effective in keeping patients' treatments within the crucial therapeutic window.

Novel anti-cancer nanomedicine for efficient chemotherapy
Researchers have developed a new anti-cancer nanomedicine for targeted cancer chemotherapy.

Ending needless chemotherapy for breast cancer
A diagnostic test developed at The University of Queensland might soon determine if a breast cancer patient requires chemotherapy or would receive no benefit from this gruelling treatment.

A homing beacon for chemotherapy drugs
Killing tumor cells while sparing their normal counterparts is a central challenge of cancer chemotherapy.

Read More: Chemotherapy News and Chemotherapy Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.