Journal
BLOOD
Volume 110, Issue 2, Pages 709-718Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2006-10-052845
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Funding
- Intramural NIH HHS Funding Source: Medline
- NCI NIH HHS [N01CO12400, P0-1 CA78373, P50 CA100707, N01-CO12400] Funding Source: Medline
- PHS HHS [R0-1 A50947] Funding Source: Medline
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Here we investigated the cytotoxicity of JS-K, a prodrug designed to release nitric oxide (NO center dot) 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 interieukin-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 center dot in MM cells. Furthermore, JS-K induced DNA doublestrand 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.
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