Small Molecule Stimulates TRAIL-induced Apoptosis in Cancer Cells
May 08, 2015
Harnessing apoptosis, a natural cell death process to eliminate damaged cells, has long been a key strategy in cancer research. Recently, the collaboration of Harvard’s Roya Khosravi-Far, PhD and Dartmouth’s Dale Mierke, PhD led to identification of a small molecule that binds to caspase 8 and enhances its activation in response to TRAIL, a central step in apoptosis. Their findings written in, “A novel caspase 8 selective small molecule potentiates TRAIL-induced cell death,” were published recently in Scientific Reports LINK.
“We provide preliminary data that demonstrate the feasibility of enhancing TRAIL-based therapeutics, an approach currently being tested in clinical trials,” said Mierke. “Such a molecule, in combination with death receptor activators such as soluble TRAIL or stimulatory DR4/DR5 antibodies, would provide significant advantages in the treatment of many cancers.”
Many investigators have pursued activation of death receptors DR4 and DR5 because they show great promise in cancer therapy due to selective toxicity towards cancer cells. Unfortunately, up to 60 percent of cancer cells become resistant to TRAIL, developing mechanisms to avoid apoptosis. This is an important issue facing cancer research. An alternative strategy is to sensitize malignancies resistant to TRAIL-induced cell death by using small molecules designed to target and promote caspase 8 activation.
The collaborators describe the discovery and characterization of a small molecule that directly binds caspase 8 and enhances its activation when combined with TRAIL. The molecule was identified through an in silico chemical screen for compounds with affinity for the caspase 8 homodimer’s interface. The compound was experimentally validated to directly bind caspase 8, and to promote caspase 8 activation and cell death in single living cells, or a population of cells, upon TRAIL stimulation.
“Our approach is a proof-of-concept strategy that led to the discovery of a novel small molecule that not only stimulates TRAIL-induced apoptosis in cancer cells, but may also provide insight into the structure-function relationship of caspase 8 homodimers as a putative target for cancer,” explained Mierke.
Looking forward, the team has demonstrated that the molecule can sensitize three different cancer cell lines to TRAIL-induced death and they plan to further test the compound on additional cancer cells lines as well as in animal models to establish a safety profile.
The team used Dartmouth’s Biomedical NMR (Nuclear Magnetic Resonance) Research Center for the characterization of the binding of the small molecule to caspase 8. This and all of Dartmouth’s Shared Resources are open to outside investigators by arrangement.
Mierke is Professor and Chair of Chemistry at Dartmouth College where he is the Director of the Biomedical NMR Research Center. His work in cancer is facilitated by Dartmouth’s Norris Cotton Cancer Center where he is a Member of the Molecular Therapeutics Research Program. Khosravi-Far is Associate Professor of Pathology at Harvard Medical School and Senior Scientist in Experimental Pathology at Beth Israel Deaconess Medical Center.
Support for this project was provided by the National Institutes of Health grants GM05482, CA105306, CA131664, and HL080192 (to Profs. Mierke and Khosravi-Far), and a fellowship from the Lady TATA Memorial Trust, London, UK (to Octavian Bucur).
About Norris Cotton Cancer Center at Dartmouth-Hitchcock
Norris Cotton Cancer Center combines advanced cancer research at Dartmouth and the Geisel School of Medicine with patient-centered cancer care provided at Dartmouth-Hitchcock Medical Center in Lebanon, NH, at Dartmouth-Hitchcock regional locations in Manchester, Nashua, and Keene, NH, and St. Johnsbury, VT, and at 12 partner hospitals throughout New Hampshire and Vermont. It is one of 41 centers nationwide to earn the National Cancer Institute's "Comprehensive Cancer Center" designation. Learn more about Norris Cotton Cancer Center research, programs, and clinical trials online at cancer.dartmouth.edu.
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