Compounds Found to Promote Cell Death, Blocking Cancer Cell Growth

The compounds, called nonphosphoinositide PIP3 inhibitors (PITs), limited tumor growth in mice by inducing cell death.

"PITs cause cells to self-destruct by interfering with the signaling pathways that regulate cell survival. As compounds that promote cell death, PITs show promise in halting the harmful, unwanted growth characteristic of cancer," said senior author Alexei Degterev, Ph.D., assistant professor in the biochemistry department at Tufts University School of Medicine (TUSM) and member of the biochemistry program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts.

Dr. Degterev teamed up with colleagues at TUSM, Northeastern University (Boston, MA, USA), Massachusetts General Hospital (Boston, MA, USA), Harvard Medical School (Boston, MA, USA), and the National Chemical Laboratory (Pune, India), to identify compounds that could disrupt a cell signaling molecule called PIP3. Out of 50,000 small molecules screened, the team identified two that inhibited PIP3. The study's findings were published online November 1, 2010, in the Proceedings of the [US] National Academy of Sciences (PNAS) early edition.

"We tested the more stable of these two molecules in mice and found that it inhibited tumor growth and induced cancer cell death," said co-first author Benchun Miao, PhD, formerly a postdoctoral associate in the biochemistry department at TUSM and fellow in Dr. Degterev's lab and now a postdoctoral associate in the Nutrition and Cancer Laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University.

"We also found that PITs showed an even stronger antitumor effect in cells with high PIP3 levels. In humans, these high-PIP3 cells are responsible for aggressive forms of cancer such as glioblastoma," said co-first author Igor Skidan, PhD, formerly a postdoctoral fellow in the department of pharmaceutical sciences at Northeastern University (Boston, MA, USA) and now a senior scientist at Morphotek, Inc. (Exton, PA, USA).

According to Dr. Degterev, PITs are a promising and comparatively unexplored approach to cancer treatment. He reported that PITs are a new class of compounds that suppress PIP3, positioned at an early point in a cell-signaling pathway over-activated in many human tumors. The study also presents a methodology for identifying other molecules similar to PITs. Dr. Degterev hopes that this approach will help researchers isolate other new compounds that halt cancer growth. "We are not yet at the stage of considering PITs as leads for therapeutics. Our next focus, with our collaborators at National Chemical Laboratory, will be to develop PITs to be more effective," said Dr. Degterev.

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Tufts University School of Medicine
Northeastern University
Massachusetts General Hospital
Harvard Medical School
National Chemical Laboratory