Buthionine sulfoximine and chemoresistance in cancer treatments: a systematic review with meta-analysis of preclinical studies

ABSTRACTButhionine sulfoximine (BSO) is a synthetic amino acid that blocks the biosynthesis of reduced glutathione (GSH), an endogenous antioxidant cellular component present in tumor cells. GSH levels have been associated with tumor cell resistance to chemotherapeutic drugs and platinum compounds. Consequently, by depleting GSH, BSO enhances the cytotoxicity of chemotherapeutic agents in drug-resistant tumors. Therefore, the aim of this study was to conduct a systematic review with meta-analysis of preclinical studies utilizing BSO in cancer treatments. The systematic search was carried out using the following databases: PubMed, Web of Science, Scopus, and EMBASE up until March 20, 2023, in order to collect preclinical studies that evaluated BSO, alone or in association, as a strategy for antineoplastic therapy. One hundred nine investigations were found to assess the cytotoxic potential of BSO alone or in combination with other compounds. Twenty-one of these met the criteria for performing the meta-analysis. The evidence gathered indicated that BSO alone exhibits cytotoxic activity. However, this compound is generally used in combination with other antineoplastic strategies, mainly chemotherapy ones, to improve cytotoxicity to carcinogenic cells and treatment efficacy. Finally, this review provides important considerations regarding BSO use in cancer treatment conditions, which might optimize future studies as a potential adjuvant antineoplastic therapeutic tool.KEYWORDS: Adjuvant treatmentbuthionine sulfoximinechemotherapyglutathioneoxidative damage AcknowledgmentsWe wish to thank the public Brazilian agency "Fundação de Amparo à Pesquisa do Estado do Piauí" (FAPEPI, Teresina, Brazil) in the form of scholarships for Joedna Cavalcante Pereira. Dr Paulo Michel Pinheiro Ferreira is also grateful to the "Conselho Nacional de Desenvolvimento Científico e Tecnológico" for his personal scholarship (CNPq #304803/2022-7).Disclosure statementNo potential conflict of interest was reported by the author(s).Authorship contributionsCRO and JCP: Conceptualization, Methodology, Investigation, Formal analysis, Data curation, Writing – Original Draft, Writing – review & editing. ABI: Conceptualization, Methodo-logy. IRRM: Writing – review & editing. JMCS: Formal analysis. PMPF: Formal analysis, Writing – review & editing. FCCS: Conceptualization, Project administration, Resources, Supervision.Supplementary materialSupplemental data for this article can be accessed online at https://doi.org/10.1080/10937404.2023.2246876Abbreviations 17AAG=17-(allylamino)-17-demethoxygeldanamycin2DG=2-deoxyglucoseATN-224=TetrathiomolybdateATO=Arsenic trioxideBCNU=1,3-bis(2-chloroethyl)-1-nitrosourea/CarmustineBSO=Buthionine sulfoximineCDDP=CisplatinCDX=Cell-line-derived xenographic modelsCFA=CyclophosphamideCOX-2=Cyclooxygenase-2DOX=DoxorubicinGPX=Glutathione peroxidaseGSH=GlutathioneGSS=Gutathione synthetaseL-PAM=MelphalanMRP1=Multidrug resistance protein 1NA-CAP=N-acetyl-4-S-cysteaminylphenolROS=Reactive oxygen speciesSN-38=Active metabolite of irinotecanTETRAC=Tetraiodothyroacetic acidVEGF=Vascular endothelial growth factorµGCS=µ-glutamil-cisteína sintetaseγGCS=γ-glutamylcysteineMSO=methionine sulfoximineSYRCLE=Systematic Review Center for Laboratory Animal ExperimentationTNF-α=Alpha tumor necrosis factorATCC=American Type Culture Collectionm@Au-d/B NCs=Cell membrane-camouflaged gold nanocagesPDT=Photodynamic therapySMD=Standardized mean differenceSD=Standard deviationsSEM=Standard error of the meanAdditional informationFundingThis research did not receive any specific grant from funding agencies in the public, private, or not-for-profit sectors.