title: The glutathione synthesis inhibitor buthionine sulfoximine synergistically enhanced melphalan activity against preclinical models of multiple myeloma.
abstract: Melphalan (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.
authors.affiliation: 1] Cancer Center, School of Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA [2] Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Tagde
authors.affiliation: 1] Cancer Center, School of Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA [2] Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Singh
authors.affiliation: 1] Cancer Center, School of Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA [2] Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA [3] Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Kang
authors.affiliation: 1] Cancer Center, School of Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA [2] Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA [3] Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA [4] Department of Pediatrics, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA [5] Department of Internal Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Reynolds
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D018572:Disease-Free Survival; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008558:Melphalan / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D011897:Random Allocation; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D019328:Buthionine Sulfoximine; D008558:Melphalan