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Science 334 (6059): 1129-1133

Copyright © 2011 by the American Association for the Advancement of Science

Pretreatment Mitochondrial Priming Correlates with Clinical Response to Cytotoxic Chemotherapy

Triona Ni Chonghaile,1,* Kristopher A. Sarosiek,1,* Thanh-Trang Vo,1,4 Jeremy A. Ryan,1 Anupama Tammareddi,1 Victoria Del Gaizo Moore,2 Jing Deng,1 Kenneth C. Anderson,1 Paul Richardson,1 Yu-Tzu Tai,1 Constantine S. Mitsiades,1 Ursula A. Matulonis,1 Ronny Drapkin,1,5 Richard Stone,1 Daniel J. DeAngelo,1 David J. McConkey,3 Stephen E. Sallan,6 Lewis Silverman,6 Michelle S. Hirsch,5 Daniel Ruben Carrasco,1 Anthony Letai1,{dagger}

Abstract: 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.

1 Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
2 Department of Chemistry, Elon University, 400 South O’Kelly Avenue, Elon, NC 27244, USA.
3 Department of Cancer Biology, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
4 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
5 Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
6 Department of Pediatric Hematology/Oncology, Children’s Hospital Boston, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: anthony_letai{at}dfci.harvard.edu

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