Though cancer cells seem to rebel against orderly cell life and death, breaking all the rules like a misfit, growing wildly and dangerously, there is actually a balance between a cancer cell’s fiery metabolism and skyrocketing levels of cellular stress–it is dependant on a hyperactive metabolism to fuel its rapid growth as well as antioxidant enzymes to rein in potentially toxic reactive oxygen species (ROS) generated by such high metabolic demand.
Now a study from scientists at the Broad Institute and Massachusetts General Hospital (MGH) reveals a novel compound that successfully but selectively blocks this response to oxidative stress in cancer cells, sparing normal cells. In fact, its effectiveness surpasses even a chemotherapy drug currently used for breast cancer. The compound? It’s actually derived from the fruit of a pepper plant native to southern India and Southeast Asia, a compound called plant-based piperlongumine or PL. Cancer cells are killed by jamming the machinery that dissipates high oxidative stress and the resulting ROS. Because of their more modest metabolism, normal cells maintain low levels of ROS, making high levels of the anti-oxidant enzymes unnecessary 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.”
Some of the best discoveries in history are found by accident, and Sam w. Lee and Anna MAndinova, both senior co-authors from the Cutaneous Biology Research Center (CBRC) at MGH certainly weren’t looking for a ROS inhibitor when they found PL. Their target was in the tumor suppressor gene p53, mutated in more than haf of all cancer types. They were looking for something to increase the levels of the properly functioning p53 gene. A promising signal for PL occurred, but they only assumed it worked by the enhancement of the p53 gene. When PL induced cancer cell death independent of the p53′s activity as the tumor suppressor gene, they sat up and took notice. PL was tested in normal cells – they weren’t killed.
“The novelty of this compound was that it was able to recognize cancer cells from normal cells,” said Mandinova, a Broad associate member and a faculty member at MGH and Harvard Medical School. “It has a mode of action that targets something especially important to the cancer cell.”
And yet another surprise- after the Proteomics Platform’s quantitative analysis identified the target of PL, they found an indirect process on which cancer cells depend, in the stead of the assumed oncogene (a protein encoded by a cancer-causing gene being inhibited). There is a small number of new cancer drugs that target oncogenes directly, but they may not be the only promising new direction for treating cancers. See, cancer genes don’t act alone and PL exploits a dependency developed after oncogenes transform normal cells into cancer cells.
“Our studies suggest that piperlongumine’s ROS-associated mechanism is especially relevant to the transformed cancer cell,” said co-author Andrew M. Stern, associate director of Novel Therapeutics at the Broad. “And this in part may underlie the observed selectivity of PL.”
The scientists tested PL against cancer and normal cells engineered to develop cancer in mice injected with human bladder, lung, breast, or melanoma cancer cells. The PL inhibited tumor growth but showed no toxicity in normal mice. The tougher test of mice that spontaneously developed breast cancer revealed PL blocking both tumor growth and metastasis, whereas the chemotherapy drug paclitaxel (Taxol), even at high levels, proved less effective.
“This compound is selectively reducing the enzyme activity involved in oxidative stress balance in cancer cells, so the ROS level can go up above the threshold for cell death,” said Lee, a Broad associate member and associate director of CBRC at MGH. “We hope we can use this compound as a starting point for the development of a drug so patients can benefit.”
Much more work needs doing to gain a better understanding of how the ROS process differs between normal and cancer cells before the launch of clinical trials. Further studies will focus on different forms of cancer and their genotypes, or genetic information. So while the authors remain cautious, they’re hopeful.
“Our next set of goals is to learn if there are specific cancer genotypes that will be more sensitive to this compound than others,” said Alykhan F. Shamji, associate director of the Broad’s Chemical Biology Program. “We hope our experiments will help be predictive of whether patients with the same genotypes in their tumors would respond the same way. It would help us to pick the right patients.”
Cooney, Elizabeth. “Taking out a Cancer’s Co-dependency.” Broad Institute News and Multimedia. Broad Institute, 13 July 2011. Web. 25 July 2011. http://www.broadinstitute.org/news/2979.