HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kojima, H. Articles by Datta, R. Search for Related Content PubMed PubMed Citation Articles by Kojima, H. Articles by Datta, R.

J Biol Chem, Vol. 273, Issue 27, 16647-16650, July 3, 1998

COMMUNICATION
Abrogation of Mitochondrial Cytochrome c Release and Caspase-3 Activation in Acquired Multidrug Resistance

Hiromi Kojima, Kazuya Endo^¶, Hiroshi Moriyama, Yasuhiro Tanaka, Emad S. Alnemri, Christopher A. Slapak^**, Beverly Teicher^**, Donald Kufe^¶, and Rakesh Datta^¶

From the ^¶ Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, the  Department of Otolaryngology, The Jikei University School of Medicine, Tokyo 105, Japan, the  Department of Microbiology and Immunology, Kimmel Cancer Institute, Philadelphia, Pennsylvania 19107, and the ^** Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285

Acquired multidrug resistance to anti-cancer agents has been associated with overexpression of the P-glycoprotein and other members of the ATP-binding cassette superfamily. The present studies demonstrate that SCC-25 cells selected for resistance to the alkylating agent cisplatin (CDDP) overexpress the anti-apoptotic Bcl-x_L protein. In contrast to parental cells, the SCC-25/CDDP-resistant variant failed to exhibit activation of caspase-3, cleavage of protein kinase C , and other characteristics of apoptosis in response to CDDP. Similar results were obtained when SCC-25/CDDP cells were exposed to the structurally and functionally unrelated antimetabolite 1--D-arabinofuranosyl-cytosine (ara-C). Other cells selected for resistance to doxorubicin or vincristine also exhibited overexpression of Bcl-x_L and failed to respond to CDDP and ara-C with activation of caspase-3. The results further demonstrate that multidrug-resistant cells exhibit a block in the release of mitochondrial cytochrome c into the cytosol and that this effect is dependent on overexpression of Bcl-x_L. The demonstration that lysates from the resistant cells respond to the addition of cytochrome c with activation of caspase-3 confirms that the block in apoptosis is because of inhibition of mitochondrial cytochrome c release. These findings demonstrate that cells respond to diverse classes of anti-cancer drugs with overexpression of Bcl-x_L and that this response represents another mechanism of acquired multidrug resistance.

---

Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

This article has been cited by other articles:

				O. Fantappie, M. Solazzo, N. Lasagna, F. Platini, L. Tessitore, and R. Mazzanti P-Glycoprotein Mediates Celecoxib-Induced Apoptosis in Multiple Drug-Resistant Cell Lines Cancer Res., May 15, 2007; 67(10): 4915 - 4923. [Abstract] [Full Text] [PDF]

				D. Raina, S. Kharbanda, and D. Kufe The MUC1 Oncoprotein Activates the Anti-apoptotic Phosphoinositide 3-Kinase/Akt and Bcl-xL Pathways in Rat 3Y1 Fibroblasts J. Biol. Chem., May 14, 2004; 279(20): 20607 - 20612. [Abstract] [Full Text] [PDF]

				A. Holleman, M. L. d. Boer, K. M. Kazemier, G. E. Janka-Schaub, and R. Pieters Resistance to different classes of drugs is associated with impaired apoptosis in childhood acute lymphoblastic leukemia Blood, December 15, 2003; 102(13): 4541 - 4546. [Abstract] [Full Text] [PDF]

				A. S. RAIT, K. F. PIROLLO, D. ULICK, K. CULLEN, and E. H. CHANG HER-2-Targeted Antisense Oligonucleotide Results in Sensitization of Head and Neck Cancer Cells to Chemotherapeutic Agents Ann. N.Y. Acad. Sci., December 1, 2003; 1002(1): 78 - 89. [Abstract] [Full Text] [PDF]

				I. A. Vasilevskaya, T. V. Rakitina, and P. J. O'Dwyer Geldanamycin and its 17-Allylamino-17-Demethoxy Analogue Antagonize the Action of Cisplatin in Human Colon Adenocarcinoma Cells: Differential Caspase Activation as a Basis for Interaction Cancer Res., June 15, 2003; 63(12): 3241 - 3246. [Abstract] [Full Text] [PDF]

				G. Nowak Protein Kinase C-alpha and ERK1/2 Mediate Mitochondrial Dysfunction, Decreases in Active Na+ Transport, and Cisplatin-induced Apoptosis in Renal Cells J. Biol. Chem., November 1, 2002; 277(45): 43377 - 43388. [Abstract] [Full Text] [PDF]

				V. M. Gonzalez, M. A. Fuertes, C. Alonso, and J. M. Perez Is Cisplatin-Induced Cell Death Always Produced by Apoptosis? Mol. Pharmacol., April 1, 2001; 59(4): 657 - 663. [Full Text]

				X. Li, M. Marani, R. Mannucci, B. Kinsey, F. Andriani, I. Nicoletti, L. Denner, and M. Marcelli Overexpression of BCL-XL Underlies the Molecular Basis for Resistance to Staurosporine-induced Apoptosis in PC-3 Cells Cancer Res., February 1, 2001; 61(4): 1699 - 1706. [Abstract] [Full Text]

				X.-H. Yang, T. L. Sladek, X. Liu, B. R. Butler, C. J. Froelich, and A. D. Thor Reconstitution of Caspase 3 Sensitizes MCF-7 Breast Cancer Cells to Doxorubicin- and Etoposide-induced Apoptosis Cancer Res., January 1, 2001; 61(1): 348 - 354. [Abstract] [Full Text]

				U. Zangemeister-Wittke, S. H. Leech, R. A. Olie, A. P. Simões-Wüst, O. Gautschi, G. H. Luedke, F. Natt, R. Häner, P. Martin, J. Hall, et al. A Novel Bispecific Antisense Oligonucleotide Inhibiting Both bcl-2 and bcl-xL Expression Efficiently Induces Apoptosis in Tumor Cells Clin. Cancer Res., June 1, 2000; 6(6): 2547 - 2555. [Abstract] [Full Text]

				H. Kojima, H. Miyazaki, Y. Tanaka, M. Shiwa, T. Koga, and H. Moriyama Role of Bcl-xL Protein in Differentiation and Apoptosis of Human Middle Ear Cholesteatoma Epithelium Arch Otolaryngol Head Neck Surg, July 1, 1999; 125(7): 738 - 742. [Abstract] [Full Text] [PDF]

				M. Wartenberg, F. C. Ling, M. Schallenberg, A. T. Baumer, K. Petrat, J. Hescheler, and H. Sauer Down-regulation of Intrinsic P-glycoprotein Expression in Multicellular Prostate Tumor Spheroids by Reactive Oxygen Species J. Biol. Chem., May 11, 2001; 276(20): 17420 - 17428. [Abstract] [Full Text] [PDF]

				R. Datta, E. Oki, K. Endo, V. Biedermann, J. Ren, and D. Kufe XIAP Regulates DNA Damage-induced Apoptosis Downstream of Caspase-9 Cleavage J. Biol. Chem., October 6, 2000; 275(41): 31733 - 31738. [Abstract] [Full Text] [PDF]