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To Kill Cancer, Do Not Repress It, Excite It

저자:   업로드:2015-08-13  조회수:

    The momentum of a cancer’s attack can be used against the cancer, say scientists who practice a form of molecular judo. Instead of directly blocking the action of cancer-causing genes, the scientists use this action against cancer cells, throwing them off balance. Committed to a super-stimulated state, cancer genes can’t help but generate a super-abundance of proteins, which pile up, unfolded, overwhelming the cancer cells’ protein-processing machinery, triggering a stress response, and—finally—bringing the cancer cells down.


    This counterintuitive strategy was not developed in a dojo. Rather, it emerged from a drug development program at Baylor College of Medicine. The program had started in the usual way, searching for compound that could inhibit oncogenes, in this case, members of the steroid receptor coactivator (SRC) family of oncogenes. But then two Baylor scientists, David Lonard, Ph.D., and Bert O’Malley, M.D., hit upon an unconventional idea: What if they overstimulated SRC oncogenes? Why not look for drugs that would overload, not squeeze, key signaling pathways? This alternative disruption, Drs. Lonard and O’Malley reasoned, could also kill cancer cells.


    To test this idea, the scientists screened hundreds of thousands of compounds to identify a potent SRC activator called MCB-613. Then the scientists tested the drug, a small molecule stimulator (SMS), in a mouse model of breast cancer.


    The results appeared August 10 in the journal Cancer Cell, in an article entitled, “Characterization of a Steroid Receptor Coactivator Small Molecule Stimulator that Overstimulates Cancer Cells and Leads to Cell Stress and Death.” This article reported that 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 threefold over seven weeks in the control group of 14 mice.


    The article also described MCB-613’s mechanism of action: super-stimulated transcriptional activity. Essentially, MCB-613 killed cancer cells by causing the accumulation of unfolded proteins in a cell structure called the endoplasmic reticulum (ER). To support their rapid proliferation, cancer cells must synthesize a large number of proteins, putting a strain on the ER to keep up with its heavy workload of properly folding proteins.


    “Further investigation revealed that MCB-613 increases SRCs’ interactions with other coactivators and markedly induces ER stress coupled to the generation of reactive oxygen species (ROS),” wrote the article’s authors. “Because cancer cells overexpress SRCs and rely on them for growth, we show that we can exploit MCB-613 to selectively induce excessive stress in cancer cells.”


    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 unfold

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