Cancer cells were treated with a control (left) and the overstimulating compound MCB-613 (right). Credit: Lei Wang
The demands of rapid cell division put a strain on cancer cells, and the approach works by tipping cell stress over the edge. Researchers show that the drug candidate inhibits tumor growth in a mouse model of breast cancer and efficiently kills a broad range of human cancer cells.
Because cancer cells acquire mutations in oncogenes to support their growth and survival, a great deal of research has focused on identifying oncogenes that could be targeted by cancer drugs. Members of the steroid receptor coactivator (SRC) family of oncogenes are especially promising as therapeutic targets because these proteins sit at the nexus of key signaling pathways that cancer cells use to quickly grow, spread to other tissues, and acquire drug resistance.
What if they could disrupt key signaling pathways and kill cancer cells by overstimulating SRCs? After all, cancer cells rely heavily on SRCs to delicately orchestrate a wide range of cellular events, so SRC stimulation might be just as effective as SRC inhibition at disrupting the balance of signaling activity in cancer cells.
To test this idea, they screened hundreds of thousands of compounds to identify a potent SRC activator called MCB-613. This compound killed human breast, prostate, lung, and liver cancer cells, while sparing normal cells. When the researchers administered MCB-613 to 13 mice with breast cancer, the drug candidate almost completely eliminated tumor growth without causing toxicity, whereas tumors continued to grow by about 3-fold over 7 weeks in the control group of 14 mice.
MCB-613 killed cancer cells by causing the accumulation of unfolded proteins in the ER. Overstimulation of SRCs places extra demands on the ER when it is already operating at maximum capacity, causing the accumulation of a large number of unfolded proteins. This triggers a cell stress response that in turn causes the build-up of reactive oxygen species.
CONC: Elevating SRC activity beyond the already high levels present in cancer cells further pressures their maximized stress response system and selectively kills them. In future studies, the researchers will continue to explore the mechanisms by which SRCs kill cancer cells and will screen for even better SRC activators. http://www.eurekalert.org/pub_releases/2015-08/cp-dc080415.php
Recent Comments