Pretreatment Mitochondrial Priming Correlates with Clinical Response to Cytotoxic Chemotherapy

被引：471

作者：

Chonghaile, Triona Ni ^{[1
]}

Sarosiek, Kristopher A. ^{[1
]}

Thanh-Trang Vo ^{[1
,4
]}

Ryan, Jeremy A. ^{[1
]}

Tammareddi, Anupama ^{[1
]}

Moore, Victoria Del Gaizo ^{[2
]}

Deng, Jing ^{[1
]}

Anderson, Kenneth C. ^{[1
]}

Richardson, Paul ^{[1
]}

Tai, Yu-Tzu ^{[1
]}

Mitsiades, Constantine S. ^{[1
]}

Matulonis, Ursula A. ^{[1
]}

Drapkin, Ronny ^{[1
,5
]}

Stone, Richard ^{[1
]}

DeAngelo, Daniel J. ^{[1
]}

McConkey, David J. ^{[3
]}

Sallan, Stephen E. ^{[6
]}

Silverman, Lewis ^{[6
]}

Hirsch, Michelle S. ^{[5
]}

Carrasco, Daniel Ruben ^{[1
]}

Letai, Anthony ^{[1
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[2] Elon Univ, Dept Chem, Elon, NC 27244 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA

[4] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[5] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[6] Childrens Hosp Boston, Dana Farber Canc Inst, Dept Pediat Hematol Oncol, Boston, MA 02215 USA

来源：

SCIENCE | 2011年 / 334卷 / 6059期

关键词：

CHRONIC LYMPHOCYTIC-LEUKEMIA; MULTIPLE-MYELOMA CELLS; IN-VIVO; APOPTOSIS; PROLIFERATION; INHIBITOR; PROTEINS; THERAPY; DEATH; LENALIDOMIDE;

D O I：

10.1126/science.1206727

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：1129 / 1133

页数：6

共 32 条

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