TY - JOUR
T1 - Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy
AU - Chonghaile, Triona Ni
AU - Sarosiek, Kristopher A.
AU - Vo, Thanh Trang
AU - Ryan, Jeremy A.
AU - Tammareddi, Anupama
AU - Moore, Victoria Del Gaizo
AU - Deng, Jing
AU - Anderson, Kenneth C.
AU - Richardson, Paul
AU - Tai, Yu Tzu
AU - Mitsiades, Constantine S.
AU - Matulonis, Ursula A.
AU - Drapkin, Ronny
AU - Stone, Richard
AU - DeAngelo, Daniel J.
AU - McConkey, David J.
AU - Sallan, Stephen E.
AU - Silverman, Lewis
AU - Hirsch, Michelle S.
AU - Carrasco, Daniel Ruben
AU - Letai, Anthony
PY - 2011/11/25
Y1 - 2011/11/25
N2 - 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.
AB - 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.
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U2 - 10.1126/science.1206727
DO - 10.1126/science.1206727
M3 - Article
C2 - 22033517
AN - SCOPUS:82255192310
SN - 0036-8075
VL - 334
SP - 1129
EP - 1133
JO - Science
JF - Science
IS - 6059
ER -