Blood Journal
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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

  1. Tanyel Kiziltepe1,
  2. Teru Hideshima1,
  3. Kenji Ishitsuka1,
  4. Enrique M. Ocio1,
  5. Noopur Raje1,
  6. Laurence Catley1,
  7. Chun-Qi Li2,
  8. Laura J. Trudel1,
  9. Hiroshi Yasui1,
  10. Sonia Vallet1,
  11. Jeffery L. Kutok3,
  12. Dharminder Chauhan1,
  13. Constantine S. Mitsiades1,
  14. Joseph E. Saavedra4,
  15. Gerald N. Wogan2,
  16. Larry K. Keefer5,
  17. Paul J. Shami6, and
  18. Kenneth C. Anderson1
  1. 1Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA;
  2. 2Biological Engineering Division and Department of Chemistry, Massachusetts Institute of Technology, Cambridge;
  3. 3Departments of Pathology and Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
  4. 4Science Applications International Corporation (SAIC)–Frederick, Frederick, MD;
  5. 5Laboratory of Comparative Carcinogenesis, National Cancer Institute–National Institutes of Health, Frederick, MD;
  6. 6Division of Medical Oncology, University of Utah, Salt Lake City
This article has an Erratum 110(13):4187

Abstract

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.

  • Submitted October 19, 2006.
  • Accepted March 12, 2007.
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