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Blood, 15 July 2007, Vol. 110, No. 2, pp. 709-718. Prepublished online as a Blood First Edition Paper on March 23, 2007; DOI 10.1182/blood-2006-10-052845. This Article Full Text Full Text (PDF) Supplemental Table and Figure Erratum (v110,p4187) All Versions of this Article: blood-2006-10-052845v1 110/2/709    most recent 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kiziltepe, T. Articles by Anderson, K. C. Search for Related Content PubMed PubMed Citation Articles by Kiziltepe, T. Articles by Anderson, K. C. Related Collections Apoptosis Signal Transduction Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA JS-K, a GST-activated nitric oxide generator, induces DNA double-strand breaks, activates DNA damage response pathways, and induces apoptosis in vitro and in vivo in human multiple myeloma cells Tanyel Kiziltepe1, Teru Hideshima1, Kenji Ishitsuka1, Enrique M. Ocio1, Noopur Raje1, Laurence Catley1, Chun-Qi Li2, Laura J. Trudel1, Hiroshi Yasui1, Sonia Vallet1, Jeffery L. Kutok3, Dharminder Chauhan1, Constantine S. Mitsiades1, Joseph E. Saavedra4, Gerald N. Wogan2, Larry K. Keefer5, Paul J. Shami6, and Kenneth C. Anderson1 1 Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; 2 Biological Engineering Division and Department of Chemistry, Massachusetts Institute of Technology, Cambridge; 3 Departments of Pathology and Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; 4 Science Applications International Corporation (SAIC)–Frederick, Frederick, MD; 5 Laboratory of Comparative Carcinogenesis, National Cancer Institute–National Institutes of Health, Frederick, MD; 6 Division of Medical Oncology, University of Utah, Salt Lake City Here we investigated the cytotoxicity of JS-K, a prodrug designed to release nitric oxide (NO) following reaction with glutathione S-transferases, in multiple myeloma (MM). JS-K showed significant cytotoxicity in both conventional therapy-sensitive and -resistant MM cell lines, as well as patient-derived MM cells. JS-K induced apoptosis in MM cells, which was associated with PARP, caspase-8, and caspase-9 cleavage; increased Fas/CD95 expression; Mcl-1 cleavage; and Bcl-2 phosphorylation, as well as cytochrome c, apoptosis-inducing factor (AIF), and endonuclease G (EndoG) release. Moreover, JS-K overcame the survival advantages conferred by interleukin-6 (IL-6) and insulin-like growth factor 1 (IGF-1), or by adherence of MM cells to bone marrow stromal cells. Mechanistic studies revealed that JS-K–induced cytotoxicity was mediated via NO in MM cells. Furthermore, JS-K induced DNA double-strand breaks (DSBs) and activated DNA damage responses, as evidenced by neutral comet assay, as well as H2AX, Chk2 and p53 phosphorylation. JS-K also activated c-Jun NH2-terminal kinase (JNK) in MM cells; conversely, inhibition of JNK markedly decreased JS-K–induced cytotoxicity. Importantly, bortezomib significantly enhanced JS-K–induced cytotoxicity. Finally, JS-K is well tolerated, inhibits tumor growth, and prolongs survival in a human MM xenograft mouse model. Taken together, these data provide the preclinical rationale for the clinical evaluation of JS-K to improve patient outcome in MM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: N. Katayama, K. Nakajou, H. Komori, K. Uchida, J.-i. Yokoe, N. Yasui, H. Yamamoto, T. Kai, M. Sato, T. Nakagawa, et al. Design and Evaluation of S-Nitrosylated Human Serum Albumin as a Novel Anticancer Drug J. Pharmacol. Exp. Ther., April 1, 2008; 325(1): 69 - 76. [Abstract] [Full Text] [PDF] S. Vallet, N. Raje, K. Ishitsuka, T. Hideshima, K. Podar, S. Chhetri, S. Pozzi, I. Breitkreutz, T. Kiziltepe, H. Yasui, et al. MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts Blood, November 15, 2007; 110(10): 3744 - 3752. [Abstract] [Full Text] [PDF]

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