Disease relevance of BUTHIONINE SULFOXIMINE

• BSO enhanced depth and duration of responses induced by melphalan in animal models of multiple myeloma and the combination treatment doubled the survival of animals as compared to melphalan and BSO alone. [1]
• Treatment of human umbilical vein endothelial cell (HUVEC) monolayers for 6 hours with 0.2 mmol/L diamide and 1 mmol/L buthionine sulfoximine (BSO) decreased GSH levels and increased the ratio of GSSG to GSH without cell toxicity [2].
• Synergism between melphalan and DL-buthionine-S,R-sulfoximine was also demonstrated in the OVCAR cell lines derived from previously treated ovarian cancer patients [3].
• The enhancement factors calculated from survival curves (a ratio of the dose decreasing cell survival by 1 log10 for L-PAM alone to that for L-PAM combined with modulating factor) were 1.67, 1.58, and 3.07 for BSO, hyperthermia, and BSO plus hyperthermia, respectively [4].
• On the other hand, oxidizing conditions, achieved using L-buthionine sulfoximine (BSO) dampen the hypoxia response [5].
• Similarly, exposure of human peripheral blood lymphocytes (PBLs) to low, nontoxic levels of BSO resulted in an approximately 80% decline in HIV-1 replication as indicated by Western blot analysis of viral proteins [6].

High impact information on BUTHIONINE SULFOXIMINE

• Glutathione deficiency in newborn rats, produced by administration of L-buthionine-(S,R)-sulfoximine, a transition-state inactivator of gamma-glutamylcysteine synthetase, decreases ascorbate levels of kidney, liver, brain, and lung [7].
• Diamide plus BSO-induced thiol/disulfide imbalance was associated with a biphasic increase in neutrophil adhesion to HUVECs with peak responses observed at 15 minutes (phase 1) and 240 minutes (phase 2) [2].
• Glutathione depletion by L-buthionine-(S,R)-sulfoximine (BSO) was found to inhibit osteoclastogenesis by blocking nuclear import of NF-kappaB and AP-1 in RANKL-propagated signaling and bone pit formation by increasing BSO concentrations in mature osteoclasts [8].
• For each compound, greater than 60% depletion of GSH was achieved; however, in the case of BSO, this depletion did not cause nuclear translocation of Nrf2 [9].
• BLM and BSO-induced nigral apoptosis was blocked by inhibitors for caspase-3 or c-Jun/AP-1 [10].

Chemical compound and disease context of BUTHIONINE SULFOXIMINE

• In the presence of nanomolar alpha-tocotrienol, neurons were resistant to glutamate-, homocysteine-, and l-buthionine sulfoximine-induced toxicity [11].
• Lens opacities developed within 48-72 hr in mice that received a series of eight injections of L-buthionine sulfoximine, a specific inhibitor of glutathione (GSH) biosynthesis, on postnatal days 8 and 9 [12].
• Lenses from mice were more susceptible to A23187-induced cataract and BSO cataracts than rats [13].
• Here we investigated whether L-buthionine-(S,R)-sulphoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase, alters endothelial and vascular smooth muscle injury in response to peroxynitrite in vitro and during endotoxic shock in vivo [14].
• Using buthionine sulfoximine (BSO) to decrease cellular GSH levels, we found a marked increase in the sensitivity of BL-10 cells to SR 4233 killing under hypoxia, but a much smaller increase in the sensitivity of CHO cells [15].

Biological context of BUTHIONINE SULFOXIMINE

• In the present study, we examined the effect of buthionine sulfoximine (BSO) on mutation frequency and the formation of 8-hydroxydeoxyguanosine (8-OHdG) in human-hamster hybrid (A(L)) cells induced by crocidolite fibers in an attempt to determine the role of oxyradicals in mediating fiber mutagenesis [16].
• Moreover, in contrast to AA, l-buthionine-(S,R)-sulfoximine toxicity is not prevented by plasmid Nrf2 probably because protective GSH cannot be synthesized [17].
• Inhibition of glutathione synthesis, using L-buthionine-(S,R)-sulfoximine reversed the effects of NAc-cys on intracellular glutathione, as well as cellular proliferation and cytotoxicity [18].
• Raising intracellular ROS by depletion of glutathione with buthionine sulfoximine (BSO) or glutamine starvation resulted in down-regulation of Pgp and p27Kip1, whereas ERK1,2 and JNK were activated [19].
• RESULTS: In rats given BSO for 2 weeks, the plasma lipid hydroperoxide level doubled, indicating increased oxidative stress [20].

Anatomical context of BUTHIONINE SULFOXIMINE

• Exposure of K562 cells to 50 microM DL-buthionine-S,R-sulfoximine for 24 h resulted in a depletion of cellular GSH content to 10% of control values without toxicity [21].
• In the presence of L-buthionine-(S,R)-sulfoximine, an inhibitor of GSH synthesis, IL-2-induced LAK activity and proliferation of NK cells in medium without L-cystine and GSH, could be restored, at least in part, by addition of GSH, but not 2-ME or L-cystine [22].
• Treatment of HeLa cells with 2 mm l-buthionine sulfoximine promoted the formation of ox-HSF1 and blocked the heat-induced activation of HSF DNA binding activity [23].
• BSO treatment also impaired insulin-induced glucose uptake and GLUT4 translocation in 3T3-L1 adipocytes [20].
• In BSO-treated rat muscle, adipose tissue and 3T3-L1 adipocytes, insulin-induced IRS-1 phosphorylation in the low-density microsome (LDM) fraction was specifically decreased, while that in whole cell lysates was not altered, and subsequent translocation of phosphatidylinositol (PI) 3-kinase from the cytosol and the LDM fraction was disrupted [20].

Associations of BUTHIONINE SULFOXIMINE with other chemical compounds

• Time-dependent pharmacodynamic models in cancer chemotherapy: population pharmacodynamic model for glutathione depletion following modulation by buthionine sulfoximine (BSO) in a Phase I trial of melphalan and BSO [24].
• The effects of L-buthionine sulfoximine (L-BSO) and L-phenylalanine mustard (L-PAM), alone and in combination, on human and murine marrow were explored using in vitro clonogenic assays to establish whether enhanced myelotoxicity might limit the clinical utility of this potent chemotherapeutic combination [25].
• This induced apoptosis could be effectively inhibited or abrogated by an antioxidant N-acetyl-l-cysteine, whereas l-buthionine-(S,R)-sulfoximine enhanced it [26].
• Treatment with l-buthionine-(S,R)-sulfoximine reduced glutathione content by 99% and prevented glucose deprivation-induced dissociation of GRX from ASK1 [27].
• Arachidonic acid (AA) and l-buthionine-(S,R)-sulfoximine (BSO), which lowers GSH levels, cause cytochrome P450 2E1 (CYP2E1)-dependent oxidative injuries in HepG2 cells (E47 cells) [28].

Gene context of BUTHIONINE SULFOXIMINE

• The protective effects of Nrf2 against CYP2E1-dependent toxicity can be blocked by l-buthionine-(S,R)-sulfoximine, a specific inhibitor of glutamate-cysteine ligase, which is a rate-limiting enzyme in the synthesis of GSH and is regulated by Nrf2 [17].
• Buthionine-sulfoximine (BSO), which reduces the GSH content, not only increased the As2O3 sensitivity but also conquered the MRP1-related cross resistance in HL60/AD [29].
• Combined addition of VEGF and L-buthionine sulfoximine, a GSH synthesis inhibitor, reversed both GSH levels and the protective effect of VEGF on Ox-LDL-induced cytotoxicity [30].
• Treatment of control cells with L-buthionine sulfoximine decreases GSH to levels of c-Myc low expressing cells, but it does not modify the growth kinetic of the cells [31].
• Thus, depletion of thiol antioxidants by BSO, like ovariectomy, causes bone loss through TNFalpha signaling [32].

Analytical, diagnostic and therapeutic context of BUTHIONINE SULFOXIMINE

• GSH values obtained by flow cytometry (FCM) agree well with those obtained by an enzymatic assay, over a wide range of GSH values, for EMT6/SF cells treated with L-buthionine sulfoximine to vary GSH content [33].
• Glutathione depletion was achieved by exposing dissociated mesencephalic cell cultures to L-buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, at four different concentrations (1, 10,100, and 1,000 microM) [34].
• Further study of BSO radiosensitization on retinoblastoma in vivo using nude mouse xenograft is needed [35].
• Following a single 2.5 mmol kg-1 dose of BSO, tumour GSH reached a nadir of approximately 40% of control 12-16 h after treatment [36].
• We depleted GSH in the brains of newborn wild-type (WT) and transgenic (Tg) mice overproducing either human Cu/Zn-superoxide dismutase (h-CuZnSOD) or human Bcl2 (h-Bcl-2), by subcutaneous injection of l-buthionine sulfoximine (BSO), a specific inhibitor of gamma-glutamylcysteine synthetase [37].

References