Pretreatment Mitochondrial Priming Correlates with Clinical Response to Cytotoxic Chemotherapy

Overview

Journal Science

Specialty Science

Date 2011 Oct 29

PMID 22033517

Citations 331

Authors

Triona Ni Chonghaile

Kristopher A Sarosiek

Thanh-Trang Vo

Jeremy A Ryan

Anupama Tammareddi

Victoria Del Gaizo Moore

Jing Deng

Kenneth C Anderson

Paul Richardson

Yu-Tzu Tai

Constantine S Mitsiades

Ursula A Matulonis

Ronny Drapkin

Richard Stone

Daniel J DeAngelo

David J McConkey

Stephen E Sallan

Lewis Silverman

Michelle S Hirsch

Daniel Ruben Carrasco

Anthony Letai

Affiliations

Soon will be listed here.

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.

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References

Anderson K . Lenalidomide and thalidomide: mechanisms of action--similarities and differences. Semin Hematol. 2005; 42(4 Suppl 4):S3-8. DOI: 10.1053/j.seminhematol.2005.10.001. View

McMillin D, Delmore J, Weisberg E, Negri J, Geer D, Klippel S . Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity. Nat Med. 2010; 16(4):483-9. PMC: 3786785. DOI: 10.1038/nm.2112. View

Arumugam T, Ramachandran V, Fournier K, Wang H, Marquis L, Abbruzzese J . Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 2009; 69(14):5820-8. PMC: 4378690. DOI: 10.1158/0008-5472.CAN-08-2819. View

Chauhan D, Singh A, Ciccarelli B, Richardson P, Palladino M, Anderson K . Combination of novel proteasome inhibitor NPI-0052 and lenalidomide trigger in vitro and in vivo synergistic cytotoxicity in multiple myeloma. Blood. 2009; 115(4):834-45. PMC: 2815518. DOI: 10.1182/blood-2009-03-213009. View

Chipuk J, Moldoveanu T, Llambi F, Parsons M, Green D . The BCL-2 family reunion. Mol Cell. 2010; 37(3):299-310. PMC: 3222298. DOI: 10.1016/j.molcel.2010.01.025. View

Gaizo Moore V, Brown J, Certo M, Love T, Novina C, Letai A . Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest. 2007; 117(1):112-21. PMC: 1716201. DOI: 10.1172/JCI28281. View

Bosch F, Ferrer A, Villamor N, Gonzalez M, Briones J, Gonzalez-Barca E . Fludarabine, cyclophosphamide, and mitoxantrone as initial therapy of chronic lymphocytic leukemia: high response rate and disease eradication. Clin Cancer Res. 2008; 14(1):155-61. DOI: 10.1158/1078-0432.CCR-07-1371. View

Deng J, Carlson N, Takeyama K, Dal Cin P, Shipp M, Letai A . BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents. Cancer Cell. 2007; 12(2):171-85. DOI: 10.1016/j.ccr.2007.07.001. View

Danial N, Korsmeyer S . Cell death: critical control points. Cell. 2004; 116(2):205-19. DOI: 10.1016/s0092-8674(04)00046-7. View

10.

Evan G, Vousden K . Proliferation, cell cycle and apoptosis in cancer. Nature. 2001; 411(6835):342-8. DOI: 10.1038/35077213. View

11.

Chauhan D, Pandey P, Ogata A, Teoh G, Treon S, Urashima M . Dexamethasone induces apoptosis of multiple myeloma cells in a JNK/SAP kinase independent mechanism. Oncogene. 1997; 15(7):837-43. DOI: 10.1038/sj.onc.1201253. View

12.

Hurwitz J, McCoy F, Scullin P, Fennell D . New advances in the second-line treatment of small cell lung cancer. Oncologist. 2009; 14(10):986-94. DOI: 10.1634/theoncologist.2009-0026. View

13.

Chen L, Willis S, Wei A, Smith B, Fletcher J, Hinds M . Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell. 2005; 17(3):393-403. DOI: 10.1016/j.molcel.2004.12.030. View

14.

Weinstein G, McCullough J, Ross P . Cell proliferation in normal epidermis. J Invest Dermatol. 1984; 82(6):623-8. DOI: 10.1111/1523-1747.ep12261462. View

15.

Gudkov A, Komarova E . The role of p53 in determining sensitivity to radiotherapy. Nat Rev Cancer. 2003; 3(2):117-29. DOI: 10.1038/nrc992. View

16.

Oltersdorf T, Elmore S, Shoemaker A, Armstrong R, Augeri D, Belli B . An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005; 435(7042):677-81. DOI: 10.1038/nature03579. View

17.

Pasieka J . Anaplastic thyroid cancer. Curr Opin Oncol. 2002; 15(1):78-83. DOI: 10.1097/00001622-200301000-00012. View

18.

Brunelle J, Ryan J, Yecies D, Opferman J, Letai A . MCL-1-dependent leukemia cells are more sensitive to chemotherapy than BCL-2-dependent counterparts. J Cell Biol. 2009; 187(3):429-42. PMC: 2779245. DOI: 10.1083/jcb.200904049. View

19.

Wei M, Zong W, Cheng E, LINDSTEN T, Panoutsakopoulou V, Ross A . Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science. 2001; 292(5517):727-30. PMC: 3049805. DOI: 10.1126/science.1059108. View

20.

Burnett A, Wetzler M, Lowenberg B . Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011; 29(5):487-94. DOI: 10.1200/JCO.2010.30.1820. View