Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy     

Ni Chonghaile T  Sarosiek KA  Vo TT  Ryan JA  Tammareddi A  Moore Vdel G  Deng J  Anderson KC  Richardson P  Tai YT  Mitsiades CS  Matulonis UA  Drapkin R  Stone R  Deangelo DJ  McConkey DJ  Sallan SE  Silverman L  Hirsch MS  Carrasco DR  Letai A 《Science (New York, N.Y.)》2011,334(6059):1129-1133

Cytotoxic chemotherapy targets elements common to all nucleated human cells, such as DNA and microtubules, yet it selectively kills tumor cells. Here we show that clinical response to these drugs correlates with, and may be partially governed by, the pretreatment proximity of tumor cell mitochondria to the apoptotic threshold, a property called mitochondrial priming. We used BH3 profiling to measure priming in tumor cells from patients with multiple myeloma, acute myelogenous and lymphoblastic leukemia, and ovarian cancer. This assay measures mitochondrial response to peptides derived from proapoptotic BH3 domains of proteins critical for death signaling to mitochondria. Patients with highly primed cancers exhibited superior clinical response to chemotherapy. In contrast, chemoresistant cancers and normal tissues were poorly primed. Manipulation of mitochondrial priming might enhance the efficacy of cytotoxic agents.  相似文献