Inhibition of Glutathione Synthesis with Propargylglycine Enhances N-Acetylmethionine Protection and Methylation in Bromobenzene-Treated Syrian Hamsters

Lertratanangkoon, K.; Scimeca, Joseph M.; Wei, Jingna

doi:10.1093/jn/129.3.649

Cited by 12 publications

(9 citation statements)

References 30 publications

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“…2F) in Huh7 cells. PPG, an irreversible inhibitor of cystathionase, (24) was used to inhibit the synthesis of MTs in previous reports. PPG also inhibited sorafenib-induced NRF2 transcriptional activity ( Fig.…”

Section: Nrf2 Is Required For Sorafenib-induced Mt-1g Expressionmentioning

confidence: 99%

Metallothionein‐1G facilitates sorafenib resistance through inhibition of ferroptosis

et al. 2016

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Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide and currently has the fastest rising incidence of all cancers. Sorafenib was originally identified as an inhibitor of multiple oncogenic kinases and remains the only approved systemic therapy for advanced HCC. However, acquired resistance to sorafenib has been found in HCC patients, which results in poor prognosis. Here, we showed that metallothionein (MT)-1G is a critical regulator and promising therapeutic target of sorafenib resistance in human HCC cells. The mRNA and protein expression of MT-1G is remarkably induced by sorafenib, but not other clinically-relevant kinase inhibitors (e.g., erlotinib, gefitinib, tivantinib, vemurafenib, selumetinib, imatinib, masitinib, and ponatinib). Activation of transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), but not p53 and hypoxia-inducible factor 1-alpha (HIF1α), is essential for induction of MT-1G expression following sorafenib treatment. Importantly, genetic and pharmacological inhibition of MT-1G enhances the anticancer activity of sorafenib in vitro and in tumor xenograft models. The molecular mechanisms underlying the action of MT-1G in sorafenib resistance involves the inhibition of ferroptosis, a novel form of regulated cell death. Knockdown of MT-1G by RNAi increases glutathione depletion and lipid peroxidation, which contributes to sorafenib-induced ferroptosis. Conclusion These findings demonstrate a novel molecular mechanism of sorafenib resistance and also suggest that MT-1G is a new regulator of ferroptosis in HCC cells.

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Section: Nrf2 Is Required For Sorafenib-induced Mt-1g Expressionmentioning

confidence: 99%

Metallothionein‐1G facilitates sorafenib resistance through inhibition of ferroptosis

et al. 2016

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“…Therefore, we applied dosages (0.44 mmol/kg; i.e., 50 mg/kg for DL-propargylglycine and 31 mg/kg for hydroxylamine) similar to those previously used in mammals and fish [DL-propargylglycine: 10 mg/kg intra-arterial in fish (50), 10 -50 mg/kg iv and 25-227 mg/kg ip in mammals (5,8,35,41,42,56,82,83,85); hydroxylamine: 0.25-1 mmol/kg ip and 0.02-0.44 mmol/kg iv in mammals (56,73)]. It is also important that sufficient time be allowed for the injected antagonists to inhibit effectively.…”

Section: Experimental Protocolsmentioning

confidence: 99%

Vasoactivity of hydrogen sulfide in normoxic and anoxic turtles (Trachemys scripta)

Stecyk

Skovgaard

Nilsson

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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of hydrogen sulfide in normoxic and anoxic turtles (Trachemys scripta). Am J Physiol Regul Integr Comp Physiol 298: R1225-R1239, 2010. First published February 17, 2010 doi:10.1152/ajpregu.00521.2009.-Systemic vascular resistance (Rsys) of freshwater turtles increases substantially during anoxia, but the underlying mechanisms are not fully understood. We investigated whether hydrogen sulfide (H2S), an endogenously produced metabolite believed to be an O 2 sensor/ transducer of vasomotor tone, contributes to the increased R sys of anoxic red-eared slider turtles (Trachemys scripta). Vascular infusion of the H 2S donor NaHS in anesthetized turtles at 21°C and fully recovered normoxic turtles at 5°C and 21°C revealed H 2S to be a potent vasoconstrictor of the systemic circulation. Likewise, wire myography of isolated turtle mesenteric and pulmonary arteries demonstrated H 2S to mediate an anoxia-induced constriction. Intriguingly, however, NaHS did not exert vasoconstrictory effects during anoxia (6 h at 21°C; 14 days at 5°C) when plasma H 2S concentration, estimated from the colorimetric measurement of plasma acid-labile sulfide concentration, likely increased by ϳ3-and 4-fold during anoxia at 21°C, and 5°C, respectively. Yet, blockade of endogenous H 2S production by DL-propargylglycine or hydroxylamine (0.44 mmol/kg) partially reversed the decreased systemic conductance (G sys) exhibited by 5°C anoxic turtles. These findings suggest that the signal transduction pathway of H 2S-mediated vasoactivity is either maximally activated in the systemic circulation of anoxic turtles and/or that it is oxygen dependent. red-eared slider; anoxia; temperature; cardiovascular; systemic resistance; pulmonary resistance; blood pressure; heart NORTH AMERICAN FRESHWATER turtles of the genera Trachemys, Chrysemys, and Chelydra exhibit a remarkable ability to survive a prolonged lack of oxygen (anoxia). At high temperatures (20 -25°C), these turtles successfully recover after 24 h of anoxia, but they can survive weeks to months without oxygen at the low temperatures, at which these animals overwinter (3-5°C) (57, 71). The exceptional anoxia tolerance is achieved through a profound reduction of whole animal metabolic rate, which slows metabolic fuel use and the rate of waste accumulation (21, 30) and the ability to use bone and shell as buffers to ameliorate the catastrophic acidosis that otherwise would accompany the sustained anaerobic metabolism (29,53).The large reduction in metabolism is attended by a pronounced lowering of cardiovascular performance during anoxia, where heart rate (f H ) and systemic blood flow (Q sys ) are drastically reduced and where pulmonary blood flow (Q pul ) virtually ceases (16,23,25,(65)(66)(67). While systemic blood pressure (P sys ) also decreases during anoxia, the reduction in Q sys is considerably larger, indicating a substantial (3-to 5-fold) increase in systemic peripheral resistance (R sys ). At high temperatures, the rise in R sys is largely due to increased ␣-adrenergic tone (54, 65), but ...

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“…L -cysteine is a substrate for the endogenous production of H 2 S ( Salvi et al, 2016b ), mitochondria-targeted anethole dithiolethione (AP39), and (AP123) ( Gerő et al, 2016 ). Please see Table 1 for more information on common H 2 S donors as well as CBS and CSE inhibitors ( Lertratanangkoon et al, 1999 ; Lima et al, 2006 ; Szabó, 2007 ; Li et al, 2008 ; Kulkarni et al, 2009 ; Sun et al, 2009 ; Tyagi et al, 2009 ; Liu et al, 2010 , 2011 ; Wang et al, 2010 , 2016 ; Kodela et al, 2012 ; Predmore et al, 2012 ; Guo et al, 2013 ; Kondo et al, 2013 ; Lisjak et al, 2013 ; Luo et al, 2013 ; Martelli et al, 2013 , 2014 ; Barr et al, 2015 ; Fonseca et al, 2015 ; Iciek et al, 2015 , 2016 ; Liang D. et al, 2015 ; Polhemus et al, 2015 ; Tsai et al, 2015 ; Vannini et al, 2015 ; Chao et al, 2016 ; Qian et al, 2016 ; Salvi et al, 2016a ; Tain et al, 2016 ; Testai et al, 2016 ; Wu et al, 2016 ; Ali et al, 2018 ; Cao et al, 2018 ; Du et al, 2018 ; Ezeriņa et al, 2018 ; Liang et al, 2018 ; Lin S. et al, 2018 ; Ning et al, 2018 ; Powell et al, 2018 ; Qiu et al, 2018 ; Shimizu et al, 2018 ; Sone et al, 2018 ; Zhao et al, 2018 ; Zhou et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Hydrogen Sulfide (H2S)-Releasing Compounds: Therapeutic Potential in Cardiovascular Diseases

Zhang

Wang

et al. 2018

Front. Pharmacol.

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Cardiovascular disease is the main cause of death worldwide, but its pathogenesis is not yet clear. Hydrogen sulfide (H2S) is considered to be the third most important endogenous gasotransmitter in the organism after carbon monoxide and nitric oxide. It can be synthesized in mammalian tissues and can freely cross the cell membrane and exert many biological effects in various systems including cardiovascular system. More and more recent studies have supported the protective effects of endogenous H2S and exogenous H2S-releasing compounds (such as NaHS, Na2S, and GYY4137) in cardiovascular diseases, such as cardiac hypertrophy, heart failure, ischemia/reperfusion injury, and atherosclerosis. Here, we provided an up-to-date overview of the mechanistic actions of H2S as well as the therapeutic potential of various classes of H2S donors in treating cardiovascular diseases.

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Inhibition of Glutathione Synthesis with Propargylglycine Enhances N-Acetylmethionine Protection and Methylation in Bromobenzene-Treated Syrian Hamsters

Cited by 12 publications

References 30 publications

Metallothionein‐1G facilitates sorafenib resistance through inhibition of ferroptosis

Metallothionein‐1G facilitates sorafenib resistance through inhibition of ferroptosis

Vasoactivity of hydrogen sulfide in normoxic and anoxic turtles (Trachemys scripta)

Hydrogen Sulfide (H2S)-Releasing Compounds: Therapeutic Potential in Cardiovascular Diseases

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