L-Buthionine-(S,R)-sulfoximine hydrochloride is a potent, cell-permeable, fast-acting, irreversible inhibitor of G-glutamylcysteine synthetase (γ-GCS) that depletes cellular glutathione levels. It has IC50s of 1.9 μM, 8.6 μM, and 29 μM in melanoma, breast, and ovarian tumor specimens, respectively [1] [2].

L-Buthionine-(S,R)-sulfoximine synergistically enhanced BCNU activity against melanoma cell lines and human tumors. BSO (50 μM) treatment for 48 hr causes a 95% decrease in ZAZ and M14 melanoma cell line GSH levels, and a 60% decrease in GST enzyme activity. GST-μ protein and mRNA levels are significantly reduced in both cell lines. GST-π expression is unaffected. BSO enhancement of alkylator action may be related in part to down regulation of GST [1]. L-Buthionine-(S,R)-sulfoximine (BSO) induces oxidative stress in a cell by irreversibly inhibiting gamma-glutamylcysteine synthetase which is an essential enzyme for the synthesis of glutathione (GSH) [2]. L-Buthionine-(S,R)-sulfoximine (BSO) was demonstrated to induce ferroptosis in cancer cells [3].

BSO treatment resulted in a significantly increased frequency of DNA deletions and decreased concentrations of GSH and cysteine. BSO treatment reduced GSH concentration in mouse fetuses by 27% and 55% at 2 mM and 20 mM BSO doses, respectively, compared with untreated mice. Co-treatment with 2 mM BSO and 20 mM NAC depleted GSH to a similar extent as 2 mM BSO, consistent with the function of BSO inhibiting the g-GCS enzyme indispensable for GSH synthesis [2].