Role of cystathionine β-synthase in human breast Cancer

Sen, Suvajit; Kawahara, Brian; Gupta, Divya; Tsai, Rebecca; Khachatryan, Marine; Roy‐Chowdhuri, Sinchita; Bose, Shikha; Yoon, Alfred P.; Faull, Kym F.; Farias‐Eisner, Robin; Chaudhuri, Gautam

doi:10.1016/j.freeradbiomed.2015.05.024

Cited by 135 publications

(150 citation statements)

References 32 publications

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“…Interestingly, a similar effect was noted in MCF7 breast cancer cells after incubation for 5 d in cocultures with activated macrophages in vitro: MCF7 cells with CBS silencing shifted a significant proportion of cells in the G0/G1 phase (7).…”

Section: Discussionsupporting

confidence: 66%

“…Several lines of studies show that exogenously administered or endogenously produced H 2 S can induce pro-proliferative signaling pathways (including MAP kinases, Akt, ERK1 activation) (5)(6)(7)(35)(36)(37)(38)(39)(40)(41)(42)(43). By inhibiting colon cancer cell H 2 S production, YD0171 may suppress these signaling processes, although this remains to be directly investigated in future studies.…”

Section: Discussionmentioning

confidence: 99%

“…Full-length recombinant human CBS was produced as described (7). H 2 S production by CBS was measured in vitro using the 7-azido-4-methylcoumarin (AzMC) method (14) in a 96-well plate format.…”

Section: Measurement Of H 2 S Production By Recombinant Human Cbsmentioning

confidence: 99%

“…The prototypical CBS inhibitor aminooxyacetic acid (AOAA) suppresses the proliferation of colon cancer cells in vitro and reduces tumor growth in vivo (1,2). CBS and H 2 S have also been implicated in the pathogenesis of ovarian and breast cancer (6,7).…”

Section: Synthesis and Chemical Characterization Of Yd0171mentioning

confidence: 99%

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Cystathionine-β-Synthase Inhibition for Colon Cancer: Enhancement of the Efficacy of Aminooxyacetic Acid via the Prodrug Approach

Chao

Zatarain

Ding

et al. 2016

Mol Med

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Colon cancer cells contain high levels of cystathionine-β-synthase (CBS). Its product, hydrogen sulfide (H 2 S), promotes the growth and proliferation of colorectal tumor cells. To improve the antitumor efficacy of the prototypical CBS inhibitor aminooxyacetic acid (AOAA), we have designed and synthesized YD0171, a methyl ester derivative of AOAA. The antiproliferative effect of YD0171 exceeded the antiproliferative potency of AOAA in HCT116 human colon cancer cells. The esterase inhibitor paraoxon prevented the cellular inhibition of CBS activity by YD0171. YD0171 suppressed mitochondrial respiration and glycolytic function and induced G0/G1 arrest, but did not induce tumor cell apoptosis or necrosis. Metabolomic analysis in HCT116 cells showed that YD0171 affects multiple pathways of cell metabolism. The efficacy of YD0171 as an inhibitor of tumor growth was also tested in nude mice bearing subcutaneous HCT116 cancer cell xenografts. Animals were treated via subcutaneous injection of vehicle or AOAA (0.1, 0.5 or 1 mg/kg/d) for 3 wks. Tumor growth was significantly reduced by 9 mg/kg/d AOAA, but not at the lower doses. YD0171 was more potent: tumor volume was significantly inhibited at 0.5 and 1 mg/kg/d. Thus, the in vivo efficacy of YD0171 is nine times higher than that of AOAA. YD0171 (1 mg/kg/d) attenuated tumor growth and metastasis formation in the intracecal HCT116 tumor model. YD0171 (3 mg/kg/d) also reduced tumor growth in patient-derived tumor xenograft bearing athymic mice. YD0171 (3 mg/kg/d) induced the regression of established HCT116 tumors in vivo. A 5-d safety study in mice demonstrated that YD0171 at 20 mg/kg/d (given in two divided doses) does not increase plasma markers of organ injury, nor does it induce histological alterations in the liver or kidney. YD0171 caused a slight elevation in plasma homocysteine levels. In conclusion, the prodrug approach improves the pharmacological profile of AOAA; YD0171 represents a prototype for CBS inhibitory anticancer prodrugs. By targeting colorectal cancer bioenergetics, an emerging important hallmark of cancer, the approach exemplified herein may offer direct translational opportunities.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Measurement Of H 2 S Production By Recombinant Human Cbsmentioning

confidence: 99%

Section: Synthesis and Chemical Characterization Of Yd0171mentioning

confidence: 99%

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Cystathionine-β-Synthase Inhibition for Colon Cancer: Enhancement of the Efficacy of Aminooxyacetic Acid via the Prodrug Approach

Chao

Zatarain

Ding

et al. 2016

Mol Med

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“…Enzymatic conversion of homocysteine to cysteine significantly contributes to maintaining the cysteine level and subsequently also to synthesis of glutathione (Mosharov et al 2000). Hydrogen sulfide is a gaseous signaling molecule with impact on several cellular (Li et al 2011), physiological (Yang et al 2008) and pathophysiological functions (Szabo et al 2013;Sen et al 2015). In colon cancer cells, hydrogen sulfide supports cellular bioenergetics, tumor growth and proliferation, as well as promotes angiogenesis and vasorelaxation (Szabo et al 2013), while hydrogen sulfide released from human breast cancer cells prevents the suppressive effect of activation macrophage on their growth (Sen et al 2015).…”

Section: S-adenosylmethionine Metabolismmentioning

confidence: 99%

Role of S-adenosylmethionine cycle in carcinogenesis

Murín¹,

Vidomanová²,

Kowtharapu³

et al. 2017

gpb

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Abstract. Alterations in enzymatic activities underlying the cellular capacity to maintain functional S-adenosylmethionine (SAM) cycle are associated with modified levels of its constituents. Since SAM is the most prominent donor of methyl group for sustaining the methylation pattern of macromolecules by methyltransferases, its availability is an essential prerequisite for sustaining the methylation pattern of nucleic acids and proteins. In addition, increased intracellular concentrations of S-adenosylhomocysteine and homocysteine, another two constituents of SAM cycle, exerts an inhibitory effect on the enzymatic activity of methyltranferases. While methylation pattern of DNA and histones is considered as an important regulatory hallmark in epigenetically regulated gene expression, amended methylation of several cellular proteins, including transcription factors, affects their activity and stability. Indeed, varied DNA methylome is a common consequence of disturbed SAM cycle and is linked with molecular changes underlying the transformation of the cells that may underlay the carcinogenesis. Here we summarize the recent evidences about the impact of disturbed SAM cycle on carcinogenesis.

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Hydrogen Sulfide: An Emerging Precision Strategy for Gas Therapy

Ding

Chang

et al. 2021

Adv Healthcare Materials

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Advances in nanotechnology have enabled the rapid development of stimuli-responsive therapeutic nanomaterials for precision gas therapy. Hydrogen sulfide (H 2 S) is a significant gaseous signaling molecule with intrinsic biochemical properties, which exerts its various physiological effects under both normal and pathological conditions. Various nanomaterials with H 2 S-responsive properties, as new-generation therapeutic agents, are explored to guide therapeutic behaviors in biological milieu. The cross disciplinary of H 2 S is an emerging scientific hotspot that studies the chemical properties, biological mechanisms, and therapeutic effects of H 2 S. This review summarizes the state-of-art research on H 2 S-related nanomedicines. In particular, recent advances in H 2 S therapeutics for cancer, such as H 2 S-mediated gas therapy and H 2 S-related synergistic therapies (combined with chemotherapy, photodynamic therapy, photothermal therapy, and chemodynamic therapy) are highlighted. Versatile imaging techniques for real-time monitoring H 2 S during biological diagnosis are reviewed. Finally, the biosafety issues, current challenges, and potential possibilities in the evolution of H 2 S-based therapy that facilitate clinical translation to patients are discussed.

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Role of cystathionine β-synthase in human breast Cancer

Cited by 135 publications

References 32 publications

Cystathionine-β-Synthase Inhibition for Colon Cancer: Enhancement of the Efficacy of Aminooxyacetic Acid via the Prodrug Approach

Cystathionine-β-Synthase Inhibition for Colon Cancer: Enhancement of the Efficacy of Aminooxyacetic Acid via the Prodrug Approach

Role of S-adenosylmethionine cycle in carcinogenesis

Hydrogen Sulfide: An Emerging Precision Strategy for Gas Therapy

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