Featured Research

from universities, journals, and other organizations

How diabetes drugs may work against cancer

Date:
March 17, 2014
Source:
Whitehead Institute for Biomedical Research
Summary:
A major mitochondrial pathway that imbues cancer cells with the ability to survive in low-glucose environments has been pinpointed by researchers. By identifying cancer cells with defects in this pathway or with impaired glucose utilization, the scientists can predict which tumors will be sensitive to these anti-diabetic drugs known to inhibit this pathway.

For several years, a class of anti-diabetic drugs known as biguanides, has been associated with anti-cancer properties. A number of retrospective studies have shown that the widely used diabetes drug metformin can benefit some cancer patients. Despite this intriguing correlation, it has been unclear how metformin might exert its anti-cancer effects and, perhaps more importantly, in which patients.

Now, Whitehead Institute scientists are beginning to unravel this mystery, identifying a major mitochondrial pathway that imbues cancer cells with the ability to survive in low-glucose environments. By finding cancer cells with defects in this pathway or with impaired glucose utilization, the scientists can predict which tumor will be sensitive to the anti-diabetic drugs known to inhibit the pathway in question. Their work is described online this week in the journal Nature.

To study how cancer cells survive in the kind of low-glucose environment found within cancerous tumors, Kıvanη Birsoy and Richard Possemato, postdoctoral researchers in Whitehead Member David Sabatini’s lab, developed a system that circulates low-nutrient media continuously around cells. Of the 30 cancer cell lines tested within this system, most appeared unaffected by a lack of glucose. However, a few of the lines thrived and reproduced rapidly, while others struggled. The varied responses to a glucose shortage were puzzling.

“No one really understood why cancer cells had these responses or whether they were important for the formation of the tumor,” says Possemato, who coauthored the Nature paper with Birsoy. “The cancer-relevance of the alterations that we found as underlying this response to low glucose will still need to be investigated.”

Birsoy and Possemato wondered whether certain cancer cells’ susceptibility to a low glucose environment could be exploited to attack tumors. They screened overly distressed cells for genes whose suppression improved or further hindered the cells’ survival rates. The screen flagged genes involved in glucose transportation and oxidative phosphorylation, a metabolic pathway in mitochondria. The powerhouses of a cell, mitochondria are membrane-bound organelles with their own DNA, including genes that control oxidative phosphorylation.

Birsoy and Possemato hypothesized that cancer cells with mutations in these genes are over-taxing their mitochondria under normal conditions. When placed in a harsh, low-glucose environment, the mitochondria are maxed out, and the cells suffer. If true, the hypothesis would suggest that further impairing mitochondrial function, with biguanides—which are known oxidative phosphorylation inhibitors—could push the mitochondria beyond their limits, to the detriment of the cancer cells.

They first tested their hypothesis in vitro on 13 cell lines with glucose utilization defects and mitochondrial DNA mutations. Compared to control cells, those sensitive to low glucose were five to 20 times more susceptible to phenformin, a more potent biguanide than metformin. Birsoy and Possemato then tested phenformin’s effectiveness in mice implanted with tumors derived from low-glucose-sensitive cancer cells. The drug inhibited the tumors’ growth.

“These results show that mitochondrial DNA mutations and glucose import defects can be used as biomarkers for biguanide sensitivity to determine if a cancer patient might benefit from these drugs,” says Birsoy. “And this is the first time that anyone has shown that the direct cytotoxic effects of this class of drugs, including metformin and phenformin, on cancer cells are mediated through their effect on mitochondria.”

To confirm the accuracy of their proposed biomarkers, Birsoy and Possemato want to analyze previous clinical trials to see if cancer patients with the proposed biomarkers fared better with metformin treatment than patients without the biomarkers.


Story Source:

The above story is based on materials provided by Whitehead Institute for Biomedical Research. The original article was written by Nicole Giese Rura. Note: Materials may be edited for content and length.


Journal Reference:

  1. Kıvanη Birsoy, Richard Possemato, Franziska K. Lorbeer, Erol C. Bayraktar, Prathapan Thiru, Burcu Yucel, Tim Wang, Walter W. Chen, Clary B. Clish, David M. Sabatini. Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature, 2014; DOI: 10.1038/nature13110

Cite This Page:

Whitehead Institute for Biomedical Research. "How diabetes drugs may work against cancer." ScienceDaily. ScienceDaily, 17 March 2014. <www.sciencedaily.com/releases/2014/03/140317095841.htm>.
Whitehead Institute for Biomedical Research. (2014, March 17). How diabetes drugs may work against cancer. ScienceDaily. Retrieved October 20, 2014 from www.sciencedaily.com/releases/2014/03/140317095841.htm
Whitehead Institute for Biomedical Research. "How diabetes drugs may work against cancer." ScienceDaily. www.sciencedaily.com/releases/2014/03/140317095841.htm (accessed October 20, 2014).

Share This



More Health & Medicine News

Monday, October 20, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Microneedle Patch Promises Painless Pricks

Microneedle Patch Promises Painless Pricks

Reuters - Innovations Video Online (Oct. 18, 2014) — Researchers at The National University of Singapore have invented a new microneedle patch that could offer a faster and less painful delivery of drugs such as insulin and painkillers. Video provided by Reuters
Powered by NewsLook.com
Raw: Nurse Nina Pham Arrives in Maryland

Raw: Nurse Nina Pham Arrives in Maryland

AP (Oct. 17, 2014) — The first nurse to be diagnosed with Ebola at a Dallas hospital walked down the stairs of an executive jet into an ambulance at an airport in Frederick, Maryland, on Thursday. Pham will be treated at the National Institutes of Health. (Oct. 16) Video provided by AP
Powered by NewsLook.com
Raw: Cruise Ship Returns to US Over Ebola Fears

Raw: Cruise Ship Returns to US Over Ebola Fears

AP (Oct. 17, 2014) — A Caribbean cruise ship carrying a Dallas health care worker who is being monitored for signs of the Ebola virus is heading back to Texas, US, after being refused permission to dock in Cozumel, Mexico. (Oct. 17) Video provided by AP
Powered by NewsLook.com
Spanish Govt: Four Suspected Ebola Cases in Spain Test Negative

Spanish Govt: Four Suspected Ebola Cases in Spain Test Negative

AFP (Oct. 17, 2014) — All four suspected Ebola cases admitted to hospitals in Spain on Thursday have tested negative for the deadly virus in a first round of tests, the government said Friday. Duration: 00:55 Video provided by AFP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:

Strange & Offbeat Stories

 

Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins