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Pretreatment Mitochondrial Priming Correlates with Clinical Response to Cytotoxic Chemotherapy

2011; American Association for the Advancement of Science; Volume: 334; Issue: 6059 Linguagem: Inglês

10.1126/science.1206727

1095-9203

Tríona Ní Chonghaile, Kristopher A. Sarosiek, Thanh-Trang T. Vo, Jeremy Ryan, Anupama Tammareddi, Victoria Del Gaizo Moore, Jing Deng, Kenneth C. Anderson, Paul G. Richardson, Yu‐Tzu Tai, Constantine S. Mitsiades, Ursula A. Matulonis, Ronny Drapkin, Richard M. Stone, Daniel J. DeAngelo, David J. McConkey, Stephen E. Sallan, Lewis B. Silverman, Michelle S. Hirsch, Daniel R. Carrasco, Anthony Letai,

Brain Metastases and Treatment

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.