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Journal of Toxicology and Environmental... Nov 2023Buthionine sulfoximine (BSO) is a synthetic amino acid that blocks the biosynthesis of reduced glutathione (GSH), an endogenous antioxidant cellular component present in... (Meta-Analysis)
Meta-Analysis Review
Buthionine 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.
Topics: Humans; Buthionine Sulfoximine; Methionine Sulfoximine; Drug Resistance, Neoplasm; Neoplasms; Antineoplastic Agents
PubMed: 37606035
DOI: 10.1080/10937404.2023.2246876 -
Biomaterials Oct 2022The appropriate design of multifunctional nanocarriers for chloroperoxidase (CPO) delivery and the simultaneous improvement of the efficiency of enzyme dynamic therapy...
The appropriate design of multifunctional nanocarriers for chloroperoxidase (CPO) delivery and the simultaneous improvement of the efficiency of enzyme dynamic therapy (EDT) remain significant challenges. Herein, we report a facile one-step route to obtain a multifunctional nanocarrier for the formation of sodium hyaluronate-modified hollow calcium peroxide spheres with encapsulated L-buthionine sulfoximine (BSO), followed by delivery of CPO for enhanced EDT. After effective accumulation at the tumor sites, the nanocomposite rapidly decomposes and releases Ca, BSO molecules, CPO, and concurrently generates a large volume of hydrogen peroxide (HO) in the endogenous tumor microenvironment (TME). BSO molecules inhibit the biosynthesis of glutathione (GSH) by inactivating γ-glutamyl cysteine synthetase. Due to BSO-induced GSH depletion and self-supply of HO, the EDT efficiency of CPO was significantly enhanced to achieve high tumor therapy efficiency. Additionally, overloaded Ca caused mitochondrial damage and amplified the oxidative stress. Moreover, calcification resulted from the unbalanced calcium transport channel caused by enhanced oxidative stress, accelerating tumor apoptosis and improving the efficacy of computed tomography (CT) imaging visual tumor therapy. This simple and efficient design for multifunctional nanocomposites will likely take an important place in the field of combined tumor therapeutics.
Topics: Buthionine Sulfoximine; Calcium; Chloride Peroxidase; Cysteine; Glutathione; Hyaluronic Acid; Hydrogen Peroxide; Ligases; Peroxides
PubMed: 36084482
DOI: 10.1016/j.biomaterials.2022.121746 -
Nutrition Reviews Apr 1992The development of buthionine sulfoximine, a selective inhibitor of glutathione biosynthesis, is an important new tool to elucidate the in vivo role of glutathione.... (Review)
Review
The development of buthionine sulfoximine, a selective inhibitor of glutathione biosynthesis, is an important new tool to elucidate the in vivo role of glutathione. Recent investigations have shown that ascorbic acid can serve as an essential antioxidant in the presence of severe glutathione deficiency.
Topics: Animals; Animals, Newborn; Antioxidants; Ascorbic Acid; Buthionine Sulfoximine; Disease Models, Animal; Glutathione; Methionine Sulfoximine; Rats
PubMed: 1614638
DOI: 10.1111/j.1753-4887.1992.tb01298.x -
Molecules (Basel, Switzerland) Aug 2019l-Buthionine sulfoximine (l-BSO) is an adjuvant drug that is reported to increase the sensitivity of cancer cells to neoplastic agents. Dendrimers are exceptional drug...
l-Buthionine sulfoximine (l-BSO) is an adjuvant drug that is reported to increase the sensitivity of cancer cells to neoplastic agents. Dendrimers are exceptional drug delivery systems and l-BSO nanoformulations are envisaged as potential chemotherapeutics. The absorption of l-BSO at a low wavelength limits its detection by conventional analytical tools. A simple and sensitive method for l-BSO detection and quantification is now reported. In this study, l-BSO was encapsulated in a folate-targeted generation four polyurea dendrimer (PURE-FA) and its release profile was followed for 24 h at pH 7.4 and 37 °C. The protocol uses in situ l-BSO derivatization, by the formation of a catechol-derived -quinone, followed by visible detection of the derivative at 503 nm. The structure of the studied l-BSO derivative was assessed by NMR spectroscopy.
Topics: Buthionine Sulfoximine; Dendrimers; Magnetic Resonance Spectroscopy; Molecular Structure; Nanoparticles; Polymers
PubMed: 31461931
DOI: 10.3390/molecules24173111 -
Autophagy Jul 2023Ferroptosis is a newly characterized form of programmed cell death, which is driven by the lethal accumulation of lipid peroxides catalyzed by the intracellular...
Ferroptosis is a newly characterized form of programmed cell death, which is driven by the lethal accumulation of lipid peroxides catalyzed by the intracellular bioactive iron. Targeted induction of ferroptotic cell death holds great promise for therapeutic design against other therapy-resistant cancers. To date, multiple post-translational modifications have been elucidated to impinge on the ferroptotic sensitivity. Here we report that the Ser/Thr protein kinase ATM, the major sensor of DNA double-strand break damage, is indispensable for ferroptosis execution. Pharmacological inhibition or genetic ablation of ATM significantly antagonizes ferroptosis. Besides, ATM ablation-induced ferroptotic resistance is largely independent of its downstream target TRP53, as cells defective in both and are still more insensitive to ferroptotic inducers than the single knockout cells. Mechanistically, ATM dominates the intracellular labile free iron by phosphorylating NCOA4, facilitating NCOA4-ferritin interaction and therefore sustaining ferritinophagy, a selective type of macroautophagy/autophagy specifically degrading ferritin for iron recycling. Our results thus uncover a novel regulatory circuit of ferroptosis comprising ATM-NCOA4 in orchestrating ferritinophagy and iron bioavailability. AMPK: AMP-activated protein kinase; ATM: ataxia telangiectasia mutated; BSO: buthionine sulphoximine; CDKN1A: cyclin-dependent kinase inhibitor 1A (P21); CQ: chloroquine; DFO: deferoxamine; DFP: deferiprone; Fer: ferrostatin-1; FTH1: ferritin heavy polypeptide 1; GPX4: glutathione peroxidase 4; GSH: glutathione; MEF: mouse embryonic fibroblast; NCOA4: nuclear receptor coactivator 4; PFTα: pifithrin-α; PTGS2: prostaglandin-endoperoxide synthase 2; Slc7a11: solute carrier family 7 member 11; Sul: sulfasalazine; TFRC: transferrin receptor; TRP53: transformation related protein 53.
Topics: Animals; Mice; Ferroptosis; Autophagy; Fibroblasts; Transcription Factors; Ferritins; Iron; Buthionine Sulfoximine
PubMed: 36752571
DOI: 10.1080/15548627.2023.2170960 -
American Journal of Hypertension Jun 2012Oxidative stress contributes to the development of several cardiovascular diseases, including diabetes, renal insufficiency, and arterial hypertension. Animal studies... (Review)
Review
Oxidative stress contributes to the development of several cardiovascular diseases, including diabetes, renal insufficiency, and arterial hypertension. Animal studies have evidenced the association between higher blood pressure (BP) and increased oxidative stress, and treatment with antioxidants has been shown to reduce BP, while BP reduction due to antihypertensive drugs is associated with reduced oxidative stress. In 2000, it was first reported that oxidative stress and arterial hypertension were produced in normal Sprague-Dawley rats by oral administration of buthionine sulfoximine (BSO), which induces glutathione (GSH) depletion, indicating that oxidative stress may induce hypertension. The contribution of several potential pathogenic factors has been evaluated in the BSO rat model, the prototype of oxidative stress-induced hypertension, including vascular reactivity, endothelium-derived factors, renin-angiotensin system activity, TXA(2)-PGH(2) production, sodium sensitivity, renal dopamine-induced natriuresis, and sympathetic tone. This review summarizes the main factors implicated in the pathogenesis of BSO-induced hypertension and the alterations associated with GSH depletion that are related to renal function or BP control.
Topics: Animals; Antioxidants; Blood Pressure; Buthionine Sulfoximine; Cardiovascular System; Disease Models, Animal; Glutathione; Hypertension; Kidney; Mice; Oxidative Stress; Rats; Rats, Sprague-Dawley
PubMed: 22223042
DOI: 10.1038/ajh.2011.240 -
ACS Nano Jul 2023Radiotherapy (RT) is one of the important clinical treatments for local control of triple-negative breast cancer (TNBC), but radioresistance still exists. Ferroptosis...
Radiotherapy (RT) is one of the important clinical treatments for local control of triple-negative breast cancer (TNBC), but radioresistance still exists. Ferroptosis has been recognized as a natural barrier for cancer progression and represents a significant role of RT-mediated anticancer effects, while the simultaneous activation of ferroptosis defensive system during RT limits the synergistic effect between RT and ferroptosis. Herein, we engineered a tumor microenvironment (TME) degradable nanohybrid with a dual radiosensitization manner to combine ferroptosis induction and high- effect based on metal-organic frameworks for ferroptosis-augmented RT of TNBC. The encapsulated l-buthionine-sulfoximine (BSO) could inhibit glutathione (GSH) biosynthesis for glutathione peroxidase 4 (GPX4) inactivation to break down the ferroptosis defensive system, and the delivered ferrous ions could act as a powerful ferroptosis executor triggering the Fenton reaction; the combination of them induces potent ferroptosis, which could synergize with the surface decorated Gold (Au) NPs-mediated radiosensitization to improve RT efficacy. antitumor results revealed that the nanohybrid could significantly improve the therapeutic efficacy and antimetastasis efficiency based on the combinational mechanism between ferroptosis and RT. This work thus demonstrated that combining RT with efficient ferroptosis induction through nanotechnology was a feasible and promising strategy for TNBC treatment.
Topics: Humans; Triple Negative Breast Neoplasms; Ferroptosis; Anesthetics, Local; Buthionine Sulfoximine; Fibrinolytic Agents; Glutathione; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37256771
DOI: 10.1021/acsnano.3c00048 -
Journal of Biological Inorganic... Apr 2022Two ternary copper(II) complexes with 2,2'-biquinoline (BQ) and with sulfonamides: sulfamethazine (SMT) or sulfaquinoxaline (SDQ) whose formulae are Cu(SMT)(BQ)Cl and...
Enhanced antitumor effect of L-buthionine sulfoximine or ionizing radiation by copper complexes with 2,2´-biquinoline and sulfonamides on A549 2D and 3D lung cancer cell models.
Two ternary copper(II) complexes with 2,2'-biquinoline (BQ) and with sulfonamides: sulfamethazine (SMT) or sulfaquinoxaline (SDQ) whose formulae are Cu(SMT)(BQ)Cl and Cu(SDQ)(BQ)Cl·CHOH, in what follows SMTCu and SDQCu, respectively, induced oxidative stress by increasing ROS level from 1.0 μM and the reduction potential of the couple GSSG/GSH. The co-treatment with L-buthionine sulfoximine (BSO), which inhibits the production of GSH, enhanced the effect of copper complexes on tumor cell viability and on oxidative damage. Both complexes generated DNA strand breaks given by-at least partially-the oxidation of pyrimidine bases, which caused the arrest of the cell cycle in the G2/M phase. These phenomena triggered processes of apoptosis proven by activation of caspase 3 and externalization of phosphatidylserine and loss of cell integrity from 1.0 μM. The combination with BSO induced a marked increase in the apoptotic population. On the other hand, an improved cell proliferation effect was observed when combining SDQCu with a radiation dose of 2 Gy from 1.0 μM or with 6 Gy from 1.5 μM. Finally, studies in multicellular spheroids demonstrated that even though copper(II) complexes did not inhibit cell invasion in collagen gels up to 48 h of treatment at the higher concentrations, multicellular resistance outperformed several drugs currently used in cancer treatment. Overall, our results reveal an antitumor effect of both complexes in monolayer and multicellular spheroids and an improvement with the addition of BSO. However, only SDQCu was the best adjuvant of ionizing radiation treatment.
Topics: Apoptosis; Buthionine Sulfoximine; Copper; Glutathione; Humans; Lung; Lung Neoplasms; Quinolines; Radiation, Ionizing; Sulfonamides
PubMed: 35247094
DOI: 10.1007/s00775-022-01933-8 -
Archives of Pharmacal Research Nov 2019In this study, we investigated the synergistic effect of L-buthionine sulfoximine (BSO) on the chlorin e6 (Ce6)-based photodynamic therapy (PDT) of cancer cells. Among...
In this study, we investigated the synergistic effect of L-buthionine sulfoximine (BSO) on the chlorin e6 (Ce6)-based photodynamic therapy (PDT) of cancer cells. Among various cancer cells, HCT116 cells have highest intracellular L-glutathione (GSH) level and SNU478 cells showed the lowest GSH level. BSO alone showed negligible intrinsic cytotoxicity against CCD986sk cells. Since HCT116 and SNU478 cells showed the highest and the lowest intracellular GSH levels, respectively, those were used to test synergistic effect on the Ce6-based PDT. In the absence of light, BSO and Ce6 combination did not practically increase reactive oxygen species (ROS) in either of HCT116 or SNU478 cells, while light irradiation increased ROS level dose-dependently. 10 μM BSO treatment significantly depleted total GSH level in cancer cells, i.e. total GSH level decreased to one-fourth of the control in HCT116 cells while it decreased to two-fifth of the control treatment at SNU478 cell. BSO showed synergistic effect on the ROS production in HCT116 cells while it has practically no benefits in ROS production of SNU478 cells. No synergistic effect was observed in viability of SNU478 cells because BSO itself was cytotoxic to SNU478 cells. However, BSO had negligible cytotoxicity against HCT116 cells and showed synergistic anticancer effect in combination with Ce6-based PDT. Furthermore, the addition of glutathione reduced ethyl ester (GSH-OEt), recovered intracellular GSH level, and cell viability with reduced the intracellular ROS level. We suggest that synergistic effect of BSO in the Ce6-based PDT should be considered with intrinsic intracellular GSH level of cancer cells.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Buthionine Sulfoximine; Cell Survival; Chlorophyllides; Drug Screening Assays, Antitumor; Drug Synergism; Glutathione; HCT116 Cells; Humans; Mice; Photochemotherapy; Porphyrins; Reactive Oxygen Species
PubMed: 31482490
DOI: 10.1007/s12272-019-01179-0 -
PloS One 2017Acquisition of anoikis resistance is a prerequisite for metastasis in hepatocellular carcinoma (HCC). However, little is known about how energy metabolism and...
BACKGROUND & AIMS
Acquisition of anoikis resistance is a prerequisite for metastasis in hepatocellular carcinoma (HCC). However, little is known about how energy metabolism and antioxidant systems are altered in anoikis-resistant (AR) HCC cells. We evaluated anti-tumor effects of a combination treatment of 3-bromopyruvate (3-BP) and buthionine sulfoximine (BSO) in AR HCC cells.
METHODS
We compared glycolysis, reactive oxygen species (ROS) production, and chemoresistance among Huh-BAT, HepG2 HCC cells, and the corresponding AR cells. Expression of hexokinase II, gamma-glutamylcysteine synthetase (rGCS), and epithelial-mesenchymal transition (EMT) markers in AR cells was assessed. Anti-tumor effects of a combination treatment of 3-BP and BSO were evaluated in AR cells and an HCC xenograft mouse model.
RESULTS
AR HCC cells showed significantly higher chemoresistance, glycolysis and lower ROS production than attached cells. Expression of hexokinase II, rGCS, and EMT markers was higher in AR HCC cells than attached cells. A combination treatment of 3-BP/BSO effectively suppressed proliferation of AR HCC cells through apoptosis by blocking glycolysis and enhancing ROS levels. In xenograft mouse models, tumor growth derived from AR HCC cells was significantly suppressed in the group treated with 3-BP/BSO compared to the group treated with 3-BP or sorafenib.
CONCLUSIONS
These results demonstrated that a combination treatment of 3-BP/BSO had a synergistic anti-tumor effect in an AR HCC model. This strategy may be an effective adjuvant therapy for patients with sorafenib-resistant HCC.
Topics: Anoikis; Antineoplastic Agents; Buthionine Sulfoximine; Carcinoma, Hepatocellular; Epithelial-Mesenchymal Transition; Hep G2 Cells; Humans; Liver Neoplasms; Niacinamide; Phenylurea Compounds; Pyruvates; Reactive Oxygen Species; Sorafenib
PubMed: 28362858
DOI: 10.1371/journal.pone.0174271