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Blood, 15 October 2004, Vol. 104, No. 8, pp. 2458-2466. Prepublished online as a Blood First Edition Paper on June 24, 2004; DOI 10.1182/blood-2004-02-0547. This Article Full Text (PDF) All Versions of this Article: 2004-02-0547v1 104/8/2458    most recent Alert me when this article is cited Alert me if a correction is posted 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chauhan, D. Articles by Anderson, K. C Search for Related Content PubMed PubMed Citation Articles by Chauhan, D. Articles by Anderson, K. C Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 12, 2004 Accepted March 30, 2004 Targeting mitochondria to overcome conventional and Bortezomib/proteasome inhibitor PS-341 resistance in multiple myeloma (MM) cells Dharminder Chauhan, Guilan Li, Klaus Podar, Teru Hideshima, Constantine Mitsiades, Robert Schlossman, Nikhil Munshi, Paul Richardson, Finbarr E Cotter, and Kenneth C Anderson* Department of Medical Oncology, The Jerome Lipper Multiple Myeloma Center, Dana Farber Cnacer Institute, Harvard Medical School, Boston, MA, USA Department of Experimental Haematology, The Royal School of Medicine, London, London, United Kingdom * Corresponding author; email: kenneth_anderson{at}dfci.harvard.edu. Bortezomib (PS-341), a selective inhibitor of proteasomes induces apoptosis in MM cells; however, prolonged drug exposure may result in cumulative toxicity and the development of chemo-resistance. Here we show that combining PK-11195 (PK), an antagonist to mitochondrial peripheral benzodiazepine receptors (PBRs), with Bortezomib triggers synergistic anti-MM activity even in doxorubicin-, melphalan-, thalidomide-, dexamethasone-, and Bortezomib-resistant MM cells. No significant cytotoxicity was noted in normal lymphocytes. Low dose combined PK and Bortezomib treatment overcomes the growth, survival, and drug-resistance conferred by interleukin-6 or insulin growth factor within the MM bone marrow milieu. The mechanism of PK + Bortezomib-induced apoptosis includes: loss of mitochondrial membrane potential; superoxide generation; release of mitochondrial proteins cytochrome-c and Smac; and activation of caspases-8/9/3. Furthermore, PK + Bortezomib activates c-Jun NH2 terminal kinase (JNK), which translocates to mitochondria, thereby facilitating release of cyto-c and Smac from mitochondria to cytosol. Blocking JNK, by either dominant-negative mutant (DN-JNK) or cotreatment with a specific JNK inhibitor SP600125, abrogates both PK + Bortezomib-induced release of cyto-c/Smac and induction of apoptosis. Together, these preclinical studies suggest that combining Bortezomib and PK may enhance its clinical efficacy, reduce attendant toxicity, and overcome conventional and Bortezomib-resistance in patients with relapsed refractory MM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. M. Huber, A. Tagwerker, D. Heininger, G. Mayer, A. R. Rosenkranz, and K. Eller The proteasome inhibitor Bortezomib aggravates renal ischemia-reperfusion injury Am J Physiol Renal Physiol, August 1, 2009; 297(2): F451 - F460. [Abstract] [Full Text] [PDF] B. Sung, A. B. Kunnumakkara, G. Sethi, P. Anand, S. Guha, and B. B. 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