Tagde, AshujitSingh, HarshabadKang, M HReynolds, C P2015-10-062014Tagde, A, H Singh, M H Kang, and C P Reynolds. 2014. “The Glutathione Synthesis Inhibitor Buthionine Sulfoximine Synergistically Enhanced Melphalan Activity Against Preclinical Models of Multiple Myeloma.” Blood Cancer Journal 4 (7) (July 18): e229. doi:10.1038/bcj.2014.45.2044-5385http://nrs.harvard.edu/urn-3:HUL.InstRepos:23017285Melphalan (L-PAM) has been an integral part of multiple myeloma (MM) treatment as a conditioning regimen before stem cell transplant (SCT). After initial response, most treated patients experience relapse with an aggressive phenotype. Increased glutathione (GSH) in MM may mediate resistance to L-PAM. We demonstrated that the GSH synthesis inhibitor buthionine sulfoximine (BSO) synergistically enhanced L-PAM activity (inducing 2–4 logs of cell kill) against nine MM cell lines (also in the presence of marrow stroma or cytokines) and in seven primary MM samples (combination indices <1.0). In MM cell lines, BSO significantly (P<0.05) depleted GSH, increased L-PAM-induced single-strand DNA breaks, mitochondrial depolarization, caspase cleavage and apoptosis. L-PAM depleted GSH, but GSH rapidly recovered in a L-PAM-resistant MM cell line unless also treated with BSO. Treatment with N-acetylcysteine antagonized BSO+L-PAM cytotoxicity without increasing GSH. In human MM xenografted into beige-nude-xid mice, BSO significantly depleted MM intracellular GSH and significantly increased apoptosis compared with L-PAM alone. BSO+L-PAM achieved complete responses (CRs) in three MM xenograft models including maintained CRs >100 days, and significantly increased the median event-free survival relative to L-PAM alone. Combining BSO with L-PAM warrants clinical testing in advanced MM.en-USJournal Article2015-06-14Ashujit Tagde, Hardeep Singh, Min H Kang, C P Reynolds2015-10-0610.1038/bcj.2014.45