This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 Landowski, T. H. Articles by Dorr, R. T. Search for Related Content PubMed PubMed Citation Articles by Landowski, T. H. Articles by Dorr, R. T.

Mitochondrial-Mediated Disregulation of Ca²⁺ Is a Critical Determinant of Velcade (PS-341/Bortezomib) Cytotoxicity in Myeloma Cell Lines

¹ College of Medicine, Departments of ² Pharmacology and ³ Physiology, and ⁴ Arizona Cancer Center, University of Arizona, Tucson, Arizona

Requests for reprints: Terry H. Landowski, Department of Medicine, Arizona Cancer Center, University of Arizona, Room 4901, 1515 North Campbell Avenue, Tucson, AZ 85724. Phone: 520-626-3719; Fax: 520-626-2751; E-mail: tlandowski{at}azcc.arizona.edu.

The proteasome inhibitor bortezomib (also known as PS-341/Velcade) is a dipeptidyl boronic acid that has recently been approved for use in patients with multiple myeloma. Bortezomib inhibits the activity of the 26S proteasome and induces cell death in a variety of tumor cells; however, the mechanism of cytotoxicity is not well understood. In this report, oligonucleotide microarray analysis of the 8226 multiple myeloma cell line showed a predominant induction of gene products associated with the endoplasmic reticulum secretory pathway following short-term, high-dose exposure to bortezomib. Examination of mediators of endoplasmic reticulum stress–induced cell death showed specific activation of caspase 12, as well as of caspases 8, 9, 7, and 3, and cleavage of bid. Treatment of myeloma cells with bortezomib also showed disregulation of intracellular Ca²⁺ as a mechanism of caspase activation. Cotreatment with a panel of Ca²⁺-modulating agents identified the mitochondrial uniporter as a critical regulatory factor in bortezomib cytotoxicity. The uniporter inhibitors ruthenium red and Ru360 prevented caspase activation and bid cleavage, and almost entirely inhibited bortezomib-induced cell death, but had no effect on any other chemotherapeutic drug examined. Additional Ca²⁺-modulating agents, including 2-amino-ethoxydiphenylborate, 1,2-bis (o-aminophenoxy) ethane-tretraacetic acid (acetoxymethyl) ester, and dantrolene, did not alter bortezomib cytotoxicity. Analysis of intracellular Ca²⁺ showed that the ruthenium-containing compounds inhibited Ca²⁺ store loading and abrogated the desensitized capacitative calcium influx associated with bortezomib treatment. These data support the hypothesis that intracellular Ca²⁺ disregulation is a critical determinant of bortezomib cytotoxicity.

This article has been cited by other articles:

				B. Hoang, A. Benavides, Y. Shi, P. Frost, and A. Lichtenstein Effect of autophagy on multiple myeloma cell viability Mol. Cancer Ther., July 1, 2009; 8(7): 1974 - 1984. [Abstract] [Full Text] [PDF]

				H. E. Moore, E. L. Davenport, E. M. Smith, S. Muralikrishnan, A. S. Dunlop, B. A. Walker, D. Krige, A. H. Drummond, L. Hooftman, G. J. Morgan, et al. Aminopeptidase inhibition as a targeted treatment strategy in myeloma Mol. Cancer Ther., April 1, 2009; 8(4): 762 - 770. [Abstract] [Full Text] [PDF]

				S. T. Nawrocki, J. S. Carew, K. H. Maclean, J. F. Courage, P. Huang, J. A. Houghton, J. L. Cleveland, F. J. Giles, and D. J. McConkey Myc regulates aggresome formation, the induction of Noxa, and apoptosis in response to the combination of bortezomib and SAHA Blood, October 1, 2008; 112(7): 2917 - 2926. [Abstract] [Full Text] [PDF]

				A. A. Argyriou, G. Iconomou, and H. P. Kalofonos Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature Blood, September 1, 2008; 112(5): 1593 - 1599. [Abstract] [Full Text] [PDF]

				A. Shanker, A. D. Brooks, C. A. Tristan, J. W. Wine, P. J. Elliott, H. Yagita, K. Takeda, M. J. Smyth, W. J. Murphy, and T. J. Sayers Treating Metastatic Solid Tumors With Bortezomib and a Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor Agonist Antibody J Natl Cancer Inst, May 7, 2008; 100(9): 649 - 662. [Abstract] [Full Text] [PDF]

				D. Chauhan, A. Singh, M. Brahmandam, K. Podar, T. Hideshima, P. Richardson, N. Munshi, M. A. Palladino, and K. C. Anderson Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma Blood, February 1, 2008; 111(3): 1654 - 1664. [Abstract] [Full Text] [PDF]

				P. Zhou, J. Teruya-Feldstein, P. Lu, M. Fleisher, A. Olshen, and R. L Comenzo Calreticulin expression in the clonal plasma cells of patients with systemic light-chain (AL-) amyloidosis is associated with response to high-dose melphalan Blood, January 15, 2008; 111(2): 549 - 557. [Abstract] [Full Text] [PDF]

				E. L. Davenport, H. E. Moore, A. S. Dunlop, S. Y. Sharp, P. Workman, G. J. Morgan, and F. E. Davies Heat shock protein inhibition is associated with activation of the unfolded protein response pathway in myeloma plasma cells Blood, October 1, 2007; 110(7): 2641 - 2649. [Abstract] [Full Text] [PDF]

				H.-Q. Wang, Z.-X. Du, H.-Y. Zhang, and D.-X. Gao Different Induction of GRP78 and CHOP as a Predictor of Sensitivity to Proteasome Inhibitors in Thyroid Cancer Cells Endocrinology, July 1, 2007; 148(7): 3258 - 3270. [Abstract] [Full Text] [PDF]

				Y. Ishii, A. Pirkmaier, J. V. Alvarez, D. A. Frank, I. Keselman, D. Logothetis, J. Mandeli, M. J. O'Connell, S. Waxman, and D. Germain Cyclin d1 overexpression and response to bortezomib treatment in a breast cancer model. J Natl Cancer Inst, September 6, 2006; 98(17): 1238 - 1247. [Abstract] [Full Text] [PDF]

				M. Bazzaro, M. K. Lee, A. Zoso, W. L.H. Stirling, A. Santillan, I.-M. Shih, and R. B.S. Roden Ubiquitin-proteasome system stress sensitizes ovarian cancer to proteasome inhibitor-induced apoptosis. Cancer Res., April 1, 2006; 66(7): 3754 - 3763. [Abstract] [Full Text] [PDF]

				S. T. Nawrocki, J. S. Carew, M. S. Pino, R. A. Highshaw, R. H.I. Andtbacka, K. Dunner Jr., A. Pal, W. G. Bornmann, P. J. Chiao, P. Huang, et al. Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. Cancer Res., April 1, 2006; 66(7): 3773 - 3781. [Abstract] [Full Text] [PDF]

				A. F. Kisselev, A. Callard, and A. L. Goldberg Importance of the Different Proteolytic Sites of the Proteasome and the Efficacy of Inhibitors Varies with the Protein Substrate J. Biol. Chem., March 31, 2006; 281(13): 8582 - 8590. [Abstract] [Full Text] [PDF]

				N. Yanamandra, N. M. Colaco, N. A. Parquet, R. W. Buzzeo, D. Boulware, G. Wright, L. E. Perez, W. S. Dalton, and D. M. Beaupre Tipifarnib and Bortezomib Are Synergistic and Overcome Cell Adhesion-Mediated Drug Resistance in Multiple Myeloma and Acute Myeloid Leukemia Clin. Cancer Res., January 15, 2006; 12(2): 591 - 599. [Abstract] [Full Text] [PDF]

				S. T. Nawrocki, J. S. Carew, M. S. Pino, R. A. Highshaw, K. Dunner Jr., P. Huang, J. L. Abbruzzese, and D. J. McConkey Bortezomib Sensitizes Pancreatic Cancer Cells to Endoplasmic Reticulum Stress-Mediated Apoptosis Cancer Res., December 15, 2005; 65(24): 11658 - 11666. [Abstract] [Full Text] [PDF]