efficient elimination of cancer cells by deoxyglucose-abt-263737 combination therapy有效消除癌症细胞的脱氧葡萄糖- abt - 263737联合治疗.pdfVIP

Efficient Elimination of Cancer Cells by Deoxyglucose-ABT-263/737 Combination Therapy 1,4 2 3 3 1 1 Ryuji Yamaguchi *, Edith Janssen , Guy Perkins , Mark Ellisman , Shinichi Kitada , John C. Reed 1 Program of Cell Death and Apoptosis, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America, 2 Division of Molecular Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America, 3 Department of Neurosciences, University of California San Diego, La Jolla, California, United States of America, 4 Department of Molecular Biology, Kyushu University Medical School, Fukuoka, Japan Abstract As single agents, ABT-263 and ABT-737 (ABT), molecular antagonists of the Bcl-2 family, bind tightly to Bcl-2, Bcl-xL and Bcl- w, but not to Mcl-1, and induce apoptosis only in limited cell types. The compound 2-deoxyglucose (2DG), in contrast, partially blocks glycolysis, slowing cell growth but rarely causing cell death. Injected into an animal, 2DG accumulates predominantly in tumors but does not harm other tissues. However, when cells that were highly resistant to ABT were pre- treated with 2DG for 3 hours, ABT became a potent inducer of apoptosis, rapidly releasing cytochrome c from the mitochondria and activating caspases at submicromolar concentrations in a Bak/Bax-dependent manner. Bak is normally sequestered in complexes with Mcl-1 and Bcl-xL. 2DG primes cells by interfering with Bak-Mcl-1 association, making it easier for ABT to dissociate Bak from Bcl-xL, freeing Bak to induce apoptosis. A highly active glucose transporter and Bid, as an agent of the mitochondrial apoptotic signal amplification loop