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.
Blood. 2007 Mar 23
Kiziltepe T, Hideshima T, Ishitsuka K, Ocio EM, Raje N, Catley L, Li CQ, Trudel LJ, Yasui H, Vallet S, Kutok JL, Chauhan D, Mitsiades CS, Saavedra JE, Wogan GN, Keefer LK, Shami PJ, Anderson KC.
Jerome Lipper Multiple Myeloma Center, Dept of Medical Oncology, Dana-Farber Cancer Institute & Harvard Medical School, Boston, MA.
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. |
