New Studies Show How Key ABC Transporter Protein (P-gp) in Multidrug Resistance Changes Shape and Reacts to Cancer Therapy Drugs; Offer Clues to Battling Resistance to Chemotherapy

Cancer patients fear the possibility that one day their cells might start rendering many different chemotherapy regimens ineffective. This phenomenon, called multidrug resistance, leads to tumors that defy treatment. Now, scientists at The Scripps Research Institute (TSRI) in La Jolla, California, have published a pair of studies showing how the primary protein responsible for multidrug chemotherapy resistance changes shape and reacts to therapeutic drugs. “This information will help us design better molecules to inhibit or evade multidrug resistance,” said TSRI Associate Professor Qinghai Zhang, a senior author of both studies. The findings were published recently in two papers: a March 3, 2015 study in the journal Structure, co-led by Dr. Bridget Carragher, a Professor at TSRI with a joint appointment at the New York Structural Biology Center; and a March 2015 study in Acta Crystallographica Section D, co-led by Dr. Geoffrey Chang, Professor in the UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences. The proteins at work in multidrug resistance are V-shaped proteins called ABC transporters. ABC transporters are found in all kingdoms of life—from bacteria to humans. In humans, an important ABC transporter is P-glycoprotein (P-gp) (image), which catches harmful toxins in a “binding pocket” and expels them from cells. The problem is that, in cancer patients, P-gp sometimes begins recognizing chemotherapy drugs and expelling them, too. Over time, more and more cancer cells can develop multidrug resistance, eliminating all possible treatments. “Virtually all cancer deaths can be attributed to the failure of chemotherapy,” said Dr. Zhang. To design more effective cancer drugs, scientists would benefit from a better understanding of P-gp and how it binds to molecules.
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