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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.
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Submitted October 19, 2006
Accepted March 12, 2007
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 Kiziltepe*, Teru Hideshima, Kenji Ishitsuka, Enrique M Ocio, Noopur Raje, Laurence Catley, Chun-Qi Li, Laura J Trudel, Hiroshi Yasui, Sonia Vallet, Jeffery L Kutok, Dharminder Chauhan, Constantine S. Mitsiades, Joseph E Saavedra, Gerald N Wogan, Larry K Keefer, Paul J Shami, and Kenneth C. Anderson
Jerome Lipper Multiple Myeloma Center, Dept of Medical Oncology, Dana-Farber Cancer Institute & Harvard Medical School, Boston, MA
Biology Engineering Division & Dept of Chemistry, Massachusetts Institute of Technology, Cambridge, MA
Depts of Pathology & Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
SAIC, Frederick, MD
Laboratory of Comparative Carcinogenesis, NCI-NIH, Frederick, MD
Division of Medical Oncology, Univeristy of Utah, Salt Lake City, UT
* Corresponding author; email: tanyel_kiziltepe{at}dfci.harvard.edu.
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; Bcl-2 phosphorylation; as well as cyt c, AIF and EndoG release. Moreover, JS-K overcame the survival advantages conferred by IL-6 and 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 and activated DNA damage responses, as evidenced by neutral comet assay, as well as H2AX, Chk2 and p53 phosphorylation. JS-K also activated 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 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.
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