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Chemico-biological Interactions Apr 1998L-S,R-buthionine sulfoximine (L-S,R BSO) is a potent specific inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting step in glutathione (GSH) biosynthesis....
L-S,R-buthionine sulfoximine (L-S,R BSO) is a potent specific inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting step in glutathione (GSH) biosynthesis. GSH is an important component of tumor drug resistance based on a strong association and recent transfection studies. Depletion of intracellular GSH by BSO significantly enhances the cytotoxicity of many cytotoxic agents, principally alkylating agents and platinating compounds but also irradiation and anthracyclines. Phase I clinical trials of BSO + melphalan (L-PAM)have been carried out and observed little toxicity with BSO alone and increased myelosuppression with BSO + L-PAM. Consistent and profound (< 10% of control) GSH depletion was observed in serial determinations of tumor GSH levels in patients receiving continuous infusion (CI) BSO. Evidence of clinical activity has been observed in patients with alkylating or platinating agent-refractory tumors. Phase II evaluation of CI BSO with L-PAM is in progress.
Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Buthionine Sulfoximine; Drug Resistance; Enzyme Inhibitors; Female; Glutamate-Cysteine Ligase; History, 20th Century; Humans; Male; Melphalan; Neoplasms
PubMed: 9679558
DOI: 10.1016/s0009-2797(97)00164-6 -
The Journal of Surgical Research Dec 2007Glutathione (GSH) is one of the most highly concentrated intracellular antioxidants. Exogenous GSH has been shown to increase random-pattern skin flap survival. However,...
BACKGROUND
Glutathione (GSH) is one of the most highly concentrated intracellular antioxidants. Exogenous GSH has been shown to increase random-pattern skin flap survival. However, the effects of endogenous GSH depletion on random-pattern skin flap viability have never been studied.
MATERIALS AND METHODS
To evaluate the effects of systemic glutathione depletion on random-pattern skin flap survival in rats, 28 Wistar albino rats were divided into control, sham, and BSO (buthionine sulfoximide, a selective inhibitor for gamma-glutamylcysteine synthetase) groups. Dorsal, cranial-based random-pattern skin-flaps were elevated and the percentage of flap necrosis was measured in all rats at the postoperative day 7.
RESULTS
BSO-treated rats showed increased skin flap necrosis when compared with untreated animals (P < 0.001). High-dose BSO treatment group had more clinically evident necrosis than low dose group (P < 0.05).
CONCLUSIONS
This study reveals the importance of endogenous GSH for random skin-flap viability.
Topics: Animals; Antioxidants; Buthionine Sulfoximine; Dermatologic Surgical Procedures; Enzyme Inhibitors; Female; Glutathione; Ischemia; Necrosis; Postoperative Complications; Rats; Rats, Wistar; Skin; Surgical Flaps
PubMed: 17583742
DOI: 10.1016/j.jss.2007.02.042 -
Toxicology Sep 2011Gender is a factor that influences susceptibility of individuals to drug-induced liver injury in experimental animals and humans. In this study, we investigated the...
Gender is a factor that influences susceptibility of individuals to drug-induced liver injury in experimental animals and humans. In this study, we investigated the mechanisms underlying resistance of female mice to acetaminophen (APAP)-induced hepatotoxicity. Overnight-fasted male and female CD-1 mice were administered APAP intraperitoneally. A minor increase in serum alanine aminotransferase levels was observed in female mice after APAP administration at a dose that causes severe hepatotoxicity in males. Hepatic glutathione (GSH) depleted rapidly in the both genders prior to development of hepatotoxicity, whereas its recovery was more rapid in female than in male mice. This was consistent with higher induction of hepatic glutamate-cysteine ligase (GCL) in females. Pretreatment of mice with L-buthionine sulfoximine (BSO), an inhibitor of GCL, exaggerated APAP hepatotoxicity only in female mice, resulting in much higher hepatotoxicity in female than in male mice. In addition, hepatic GSH was markedly depleted in BSO-pretreated female mice compared with male mice, which supports severe hepatotoxicity in BSO-pretreated females. APAP treatment highly induced multidrug resistance-associated protein 4 (Mrp4) only in female mice. The resulting high Mrp4 expression could thus contribute to decreased hepatic GSH levels via sinusoidal efflux when GCL is inhibited. In conclusion, resistance to APAP hepatotoxicity in female mice and its reversal by pretreatment with BSO could be attributed to sex differences in disposition of hepatic GSH, which may generally determine susceptibility to drug-induced liver injury.
Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Buthionine Sulfoximine; Disease Susceptibility; Female; Glutamate-Cysteine Ligase; Glutathione; Liver; Male; Mice; Multidrug Resistance-Associated Proteins; RNA, Messenger; Sex Characteristics
PubMed: 21672600
DOI: 10.1016/j.tox.2011.05.018 -
Blood Advances Jan 2024Cysteine is a nonessential amino acid required for protein synthesis, the generation of the antioxidant glutathione, and for synthesizing the nonproteinogenic amino acid...
Cysteine is a nonessential amino acid required for protein synthesis, the generation of the antioxidant glutathione, and for synthesizing the nonproteinogenic amino acid taurine. Here, we highlight the broad sensitivity of leukemic stem and progenitor cells to cysteine depletion. By CRISPR/CRISPR-associated protein 9-mediated knockout of cystathionine-γ-lyase, the cystathionine-to-cysteine converting enzyme, and by metabolite supplementation studies upstream of cysteine, we functionally prove that cysteine is not synthesized from methionine in acute myeloid leukemia (AML) cells. Therefore, although perhaps nutritionally nonessential, cysteine must be imported for survival of these specific cell types. Depletion of cyst(e)ine increased reactive oxygen species (ROS) levels, and cell death was induced predominantly as a consequence of glutathione deprivation. nicotinamide adenine dinucleotide phosphate hydrogen oxidase inhibition strongly rescued viability after cysteine depletion, highlighting this as an important source of ROS in AML. ROS-induced cell death was mediated via ferroptosis, and inhibition of glutathione peroxidase 4 (GPX4), which functions in reducing lipid peroxides, was also highly toxic. We therefore propose that GPX4 is likely key in mediating the antioxidant activity of glutathione. In line, inhibition of the ROS scavenger thioredoxin reductase with auranofin also impaired cell viability, whereby we find that oxidative phosphorylation-driven AML subtypes, in particular, are highly dependent on thioredoxin-mediated protection against ferroptosis. Although inhibition of the cystine-glutamine antiporter by sulfasalazine was ineffective as a monotherapy, its combination with L-buthionine-sulfoximine (BSO) further improved AML ferroptosis induction. We propose the combination of either sulfasalazine or antioxidant machinery inhibitors along with ROS inducers such as BSO or chemotherapy for further preclinical testing.
Topics: Humans; Cysteine; Reactive Oxygen Species; Antioxidants; Ferroptosis; Cystathionine; Sulfasalazine; Amino Acids; Glutathione; Buthionine Sulfoximine; Leukemia, Myeloid, Acute
PubMed: 37906522
DOI: 10.1182/bloodadvances.2023010786 -
Alcoholism, Clinical and Experimental... Oct 1996The adverse effects of the maternal consumption of alcohol on the fetus have been recognized for centuries. Fetal alcohol syndrome is characterized by pre- and postnatal...
The adverse effects of the maternal consumption of alcohol on the fetus have been recognized for centuries. Fetal alcohol syndrome is characterized by pre- and postnatal growth retardation, mental retardation, behavioral deficits, and facial deformities. Despite numerous animal studies, the biochemical mechanism(s) by which alcohol produces teratogenic effects on the developing fetus are not well understood. Several studies have shown that administration of alcohol to adult rats produces a decrease in hepatic levels of glutathione (GSH). In utero administration of alcohol has also been shown to produce a decrease in GSH levels, as well as prenatal growth retardation and intrauterine death. In an effort to determine if GSH may have a vital role in protecting the fetus against the teratogenic effects of alcohol, buthionine (SR)-sulfoximine (BSO) was used to deplete GSH levels in the mother and fetus. Timed pregnant Sprague-Dawley rats were placed on a liquid BioServ diet containing either 0%, 11%, 23%, 29%, 31%, 33%, or 35% ethanol-derived calories, with or without BSO (888 mg/kg/24 hr), starting on day 1 of pregnancy. Another set of mothers were fed lab chow and water as a control group for the liquid diet. The mothers were maintained on the diet until gestation day 21 when they were anesthetized with sodium pentobarbital and the pups delivered by cesarean section. The offspring were counted, weighed, killed, and the brain and liver weighed. The effects of BSO on the alcohol dose-response curves (body weights, brain weights, and litter number) were then determined to ascertain if a depletion in GSH potentiated the effects of alcohol. In utero administration of BSO, aside from the depletion of GSH in the liver and brain in the developing fetus, produced a shift to the left in the alcohol dose-response curve.
Topics: Animals; Antimetabolites; Buthionine Sulfoximine; Cerebellum; Embryonic and Fetal Development; Ethanol; Female; Fetal Alcohol Spectrum Disorders; Glutathione; Phosphopyruvate Hydratase; Pregnancy; Rats; Rats, Sprague-Dawley
PubMed: 8904978
DOI: 10.1111/j.1530-0277.1996.tb01119.x -
Cancer Letters May 2008We have previously reported that buthionine sulfoximine (BSO) enhances sodium borocaptate (BSH) uptake by down regulating glutathione (GSH) synthesis in cultured cells....
Combined use of sodium borocaptate and buthionine sulfoximine in boron neutron capture therapy enhanced tissue boron uptake and delayed tumor growth in a rat subcutaneous tumor model.
We have previously reported that buthionine sulfoximine (BSO) enhances sodium borocaptate (BSH) uptake by down regulating glutathione (GSH) synthesis in cultured cells. This study investigated the influence of BSO on tissue BSH uptake in vivo and the efficacy of BSH-BSO-mediated boron neutron capture therapy (BNCT) on tumor growth using a Fisher-344 rat subcutaneous tumor model. With BSO supplementation, boron uptake in subcutaneous tumor, blood, skin, muscle, liver, and kidney was significantly enhanced and maintained for 12h. Tumor growth was significantly delayed by using BSO. With further improvement in experimental conditions, radiation exposure time, together with radiation damage to normal tissues, could be reduced.
Topics: Animals; Borohydrides; Boron; Boron Neutron Capture Therapy; Buthionine Sulfoximine; Isotopes; Male; Neoplasm Transplantation; Neoplasms, Experimental; Rats; Rats, Inbred F344; Sulfhydryl Compounds
PubMed: 18272285
DOI: 10.1016/j.canlet.2008.01.016 -
FEMS Microbiology Letters Apr 1999Changes in composition of the principal low molecular mass thiols of Leishmania donovani were monitored during the transformation of promastigotes, first to stationary...
Changes in composition of the principal low molecular mass thiols of Leishmania donovani were monitored during the transformation of promastigotes, first to stationary phase metacyclic forms and then to amastigotes. No consistent variation in the thiol composition of the parasite which could account for the known increase in resistance of metacyclic and amastigote lifecycle forms to oxidant stress could be established. Amastigotes cultivated at 37 degrees C also produced ovothiol A, as judged by incorporation of radiolabel from [3-methyl]methionine and [14C]histidine, and the incorporation of radiolabel from [35S]cysteine into ovothiol A represented about 10-15% of the total label recovered in ovothiol A, glutathione and trypanothione. Amastigotes were less susceptible than promastigotes to the effects of the redox cyclers paraquat and menadione and grew in culture in the presence of up to 20 mM buthionine sulfoximine, which completely blocked the synthesis of glutathione and its spermidine conjugates. Glutathione and trypanothione biosynthesis is, therefore, not necessary for the replication of L. donovani amastigotes in culture. Inhibition of the formation of glutathione and trypanothione did not result in an upregulation of ovothiol A production.
Topics: Animals; Buthionine Sulfoximine; Culture Media; Glutathione; Leishmania donovani; Methylhistidines; Oxidation-Reduction; Spermidine; Time Factors
PubMed: 10220890
DOI: 10.1111/j.1574-6968.1999.tb13495.x -
Mutagenesis May 1998Arecoline (ARC), an alkaloid of the betel nut (Areca catechu), is a major ingredient of betel quid. The carcinogenic potentiality as well as its cell transformation...
Arecoline (ARC), an alkaloid of the betel nut (Areca catechu), is a major ingredient of betel quid. The carcinogenic potentiality as well as its cell transformation ability has already been reported. Reduced glutathione (GSH), a major non-protein thiol substance plays an important role in protection of cells against the toxic effect of exogenous compounds. In order to understand the role of factors which affect ARC sensitivity, we have made an attempt to establish a relationship between ARC-induced DNA damage and the endogenous GSH status of the cells. ARC was administered to untreated and buthionine sulfoximine (BSO) (a GSH-depleting agent)-treated mice. Exogenous GSH was also added to ARC-administered mice. Cells were fixed at 20 h and both chromosome aberrations (CAs) and sister chromatid exchanges (SCEs) were scored. Both CAs and SCEs were significantly induced by ARC and the frequency of both these parameters were increased further when ARC was given to BSO-treated mice. However, GSH reduced the frequency of CAs induced by ARC but failed to do so for SCEs. The data indicate that ARC-induced DNA damage is influenced by endogenous GSH level. The failure of GSH to reduce the frequency of SCEs indicates that the mechanism of induction of CAs and SCEs by ARC are different.
Topics: Animals; Arecoline; Bone Marrow Cells; Buthionine Sulfoximine; Chromosome Aberrations; Dose-Response Relationship, Drug; Drug Implants; Glutathione; Injections, Intraperitoneal; Male; Mice; Sister Chromatid Exchange
PubMed: 9643582
DOI: 10.1093/mutage/13.3.243 -
Pediatric Blood & Cancer Aug 2016Myeloablative therapy for high-risk neuroblastoma commonly includes melphalan. Increased cellular glutathione (GSH) can mediate melphalan resistance. Buthionine...
A Phase I New Approaches to Neuroblastoma Therapy Study of Buthionine Sulfoximine and Melphalan With Autologous Stem Cells for Recurrent/Refractory High-Risk Neuroblastoma.
BACKGROUND
Myeloablative therapy for high-risk neuroblastoma commonly includes melphalan. Increased cellular glutathione (GSH) can mediate melphalan resistance. Buthionine sulfoximine (BSO), a GSH synthesis inhibitor, enhances melphalan activity against neuroblastoma cell lines, providing the rationale for a Phase 1 trial of BSO-melphalan.
PROCEDURES
Patients with recurrent/resistant high-risk neuroblastoma received BSO (3 gram/m(2) bolus, then 24 grams/m(2) /day infusion days -4 to -2), with escalating doses of intravenous melphalan (20-125 mg/m(2) ) days -3 and -2, and autologous stem cells day 0 using 3 + 3 dose escalation.
RESULTS
Among 28 patients evaluable for dose escalation, one dose-limiting toxicity occurred at 20 mg/m(2) melphalan (grade 3 aspartate aminotransferase/alanine aminotransferase) and one at 80 mg/m(2) (streptococcal bacteremia, grade 4 hypotension/pulmonary/hypocalcemia) without sequelae. Among 25 patients evaluable for response, there was one partial response (PR) and two mixed responses (MRs) among eight patients with prior melphalan exposure; one PR and three MRs among 16 patients without prior melphalan; one stable disease with unknown melphalan history. Melphalan pharmacokinetics with BSO were similar to reports for melphalan alone. Melphalan Cmax for most patients was below the 10 μM concentration that showed neuroblastoma preclinical activity with BSO.
CONCLUSIONS
BSO (75 gram/m(2) ) with melphalan (125 mg/m(2) ) is tolerable with stem cell support and active in recurrent/refractory neuroblastoma. Further dose escalation is feasible and may increase responses.
Topics: Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Buthionine Sulfoximine; Child; Child, Preschool; Drug Synergism; Female; Glutamate-Cysteine Ligase; Glutathione; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Male; Melphalan; Myeloablative Agonists; Neoplasm Recurrence, Local; Neuroblastoma
PubMed: 27092812
DOI: 10.1002/pbc.25994 -
Bone Marrow Transplantation Aug 2002Patients with high-risk neuroblastoma (NB) initially respond to aggressive, alkylator-based therapy only to die from recurrent disease that is refractory to...
Patients with high-risk neuroblastoma (NB) initially respond to aggressive, alkylator-based therapy only to die from recurrent disease that is refractory to chemotherapy, including alkylating agents. We examined the ability of buthionine sulfoximine (BSO)-mediated glutathione (GSH) depletion to modulate melphalan (L-PAM) resistance in five NB cell lines established after progressive disease following myeloablative therapy (high-dose melphalan, carboplatin, etoposide and total body irradiation) supported by autologous hematopoietic stem cell transplant (AHSCT), and in 15 NB cell lines established at diagnosis or after non-myeloablative therapy (pre-AHSCT). Four of five post-AHSCT NB cell lines and 10 of 15 pre-AHSCT NB cell lines were sensitive to single agent BSO (LC(90) <300 microM BSO), while two of five post-AHSCT lines and one of 15 pre-AHSCT lines showed high-level resistance to L-PAM (LC(90)>30 microM). Fixed ratio analysis demonstrated BSO/L-PAM synergy (combination index <1) for all five post-AHSCT and for all 15 pre-AHSCT cell lines tested. Multi-log cytotoxicity (often exceeding four logs of cell kill) was observed in post-AHSCT L-PAM-resistant cell lines (including p53 non-functional lines) only when clinically achievable concentrations of BSO were combined with myeloablative concentrations of L-PAM. We conclude that most neuroblastoma cell lines, including post-AHSCT NB cell lines that are highly resistant to myeloablative levels of L-PAM and lack p53 function, are sensitive to clinically achievable concentrations of L-PAM and BSO. However, some L-PAM-resistant NB cell lines (especially those lacking p53 function) require dose escalation of L-PAM to myeloablative concentrations in order to demonstrate significant synergistic cytotoxicity. Thus, optimal clinical application of BSO/L-PAM may require AHSCT.
Topics: Antineoplastic Combined Chemotherapy Protocols; Buthionine Sulfoximine; Cell Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Synergism; Glutathione; Humans; Melphalan; Myeloablative Agonists; Neuroblastoma; Recurrence; Tumor Cells, Cultured
PubMed: 12189530
DOI: 10.1038/sj.bmt.1703605