Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy.
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.
Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
Triona
T
Ni Chonghaile
Kristopher A
KA
Sarosiek
Thanh-Trang
TT
Vo
Jeremy A
JA
Ryan
Anupama
A
Tammareddi
Victoria Del Gaizo
Vdel G
Moore
Jing
J
Deng
Kenneth C
KC
Anderson
Paul
P
Richardson
Yu-Tzu
YT
Tai
Constantine S
CS
Mitsiades
Ursula A
UA
Matulonis
Ronny
R
Drapkin
Richard
R
Stone
Daniel J
DJ
Deangelo
David J
DJ
McConkey
Stephen E
SE
Sallan
Lewis
L
Silverman
Michelle S
MS
Hirsch
Daniel Ruben
DR
Carrasco
Anthony
A
Letai
D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002648:Child; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008928:Mitochondria / Q000502:physiology*; D009101:Multiple Myeloma / Q000188:drug therapy / Q000503:physiopathology; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000503:physiopathology; D010446:Peptide Fragments / Q000378:metabolism; D010539:Permeability; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000503:physiopathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism; D012074:Remission Induction; D015398:Signal Transduction
D000970:Antineoplastic Agents; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2