A cancer cell may seem out of control, growing wildly and breaking all the rules of orderly cell life and death. But amid the seeming chaos there is a balance between a cancer cell's revved-up metabolism and skyrocketing levels of cellular stress. Just as a cancer cell depends on a hyperactive metabolism to fuel its rapid growth, it also depends on anti-oxidative enzymes to quench potentially toxic reactive oxygen species (ROS) generated by such high metabolic demand.
Scientists at the Broad Institute and Massachusetts General Hospital (MGH) have discovered a novel compound that blocks this response to oxidative stress selectively in cancer cells but spares normal cells, with an effectiveness that surpassed a chemotherapy drug currently used to treat breast cancer. Their findings, based on experiments in cell culture and in mice, appear online in Nature on July 13.
The plant-based compound piperlongumine (PL), derived from the fruit of a pepper plant found in southern India and southeast Asia, appears to kill cancer cells by jamming the machinery that dissipates high oxidative stress and the resulting ROS. Normal cells have low levels of ROS, in tune with their more modest metabolism, so they don't need high levels of the anti-oxidant enzymes that PL stymies once they pass a certain threshold.
"Piperlongumine targets something that's not thought to be essential in normal cells," said Stuart L. Schreiber, a senior co-author and director of the Broad's Chemical Biology Program. "Cancer cells have a greater dependence on ROS biology than normal cells."
Sam W. Lee and Anna Mandinova, senior co-authors from the Cutaneous Biology Research Center (CBRC) at MGH, weren't looking for a ROS inhibitor when they found PL. Their interest lay in the tumor suppressor gene p53, which is mutated in more than half of all cancer types. Teaming up with the Broad's Chemical Biology Program and Platform to screen libraries of chemical compo
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Broad Institute of MIT and Harvard