Inhibition of cystathionine β-synthase promotes apoptosis and reduces cell proliferation in chronic myeloid leukemia

Wang, Dan; Yang, Huan; Zhang, Yun; Hu, Rong; Hu, Dongjie; Wang, Qunxian; Liu, Yannan; Liu, Mingjing; Meng, Zijun; Zhou, Weihui; Song, Weihong

doi:10.1038/s41392-020-00410-5

Cited by 27 publications

(17 citation statements)

References 68 publications

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“…For CML, similar to our analysis, several studies have shown that levels of glutamate, serine, which is a precursor of cysteine, and alanine are increased by CML (153)(154)(155). Consistent with these NEAAs playing an important role in CML, restriction of serine (156,157) and its derivatives glycine (156), or cysteine (158,159) decreases CML proliferation, supporting that targeting these NEAA pathways may be a potential target for CML.…”

Section: Restriction Of Other Neaas Derived From Glutamate Decrease Myeloid Leukemia Proliferationsupporting

confidence: 87%

Amino Acid Metabolic Vulnerabilities in Acute and Chronic Myeloid Leukemias

et al. 2021

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Amino acid (AA) metabolism plays an important role in many cellular processes including energy production, immune function, and purine and pyrimidine synthesis. Cancer cells therefore require increased AA uptake and undergo metabolic reprogramming to satisfy the energy demand associated with their rapid proliferation. Like many other cancers, myeloid leukemias are vulnerable to specific therapeutic strategies targeting metabolic dependencies. Herein, our review provides a comprehensive overview and TCGA data analysis of biosynthetic enzymes required for non-essential AA synthesis and their dysregulation in myeloid leukemias. Furthermore, we discuss the role of the general control nonderepressible 2 (GCN2) and-mammalian target of rapamycin (mTOR) pathways of AA sensing on metabolic vulnerability and drug resistance.

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Section: Restriction Of Other Neaas Derived From Glutamate Decrease Myeloid Leukemia Proliferationsupporting

confidence: 87%

Amino Acid Metabolic Vulnerabilities in Acute and Chronic Myeloid Leukemias

et al. 2021

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“…tumorigenic; thus the inhibition of CBS activity in K562 and mononuclear cells isolated from the bone marrows of CML patients using the CBS-inhibitor aminooxy acetic acid (AOAA) lead to an overall reduction in proliferation and the induction of apoptosis in these cells (21).…”

Section: Essential Amino Acids Methioninementioning

confidence: 99%

Targeting Amino Acid Metabolic Vulnerabilities in Myeloid Malignancies

et al. 2021

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Tumor cells require a higher supply of nutrients for growth and proliferation than normal cells. It is well established that metabolic reprograming in cancers for increased nutrient supply exposes a host of targetable vulnerabilities. In this article we review the documented changes in expression patterns of amino acid metabolic enzymes and transporters in myeloid malignancies and the growing list of small molecules and therapeutic strategies used to disrupt amino acid metabolic circuits within the cell. Pharmacological inhibition of amino acid metabolism is effective in inducing cell death in leukemic stem cells and primary blasts, as well as in reducing tumor burden in in vivo murine models of human disease. Thus targeting amino acid metabolism provides a host of potential translational opportunities for exploitation to improve the outcomes for patients with myeloid malignancies.

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“…Previously, the effect of endogenous H 2 S inhibition by employing AOAA and PAG on xenograft tumor growth has been reported in human chronic myeloid leukemia and astrocytoma. They observed dramatically decreased tumor growth in the treated animals compared to control [64,65]. Our study showed that PAG, AOAA, and L-Asp significantly inhibited BC xenograft tumor growth, and the combined group showed stronger preventive effects on tumor growth.…”

Section: Discussionmentioning

confidence: 51%

Pharmacological Inhibition of Endogenous Hydrogen Sulfide Attenuates Breast Cancer Progression

Khan

Wang

et al. 2022

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Hydrogen sulfide (H2S), a gaseous signaling molecule, is associated with the development of various malignancies via modulating various cellular signaling cascades. Published research has established the fact that inhibition of endogenous H2S production or exposure of H2S donors is an effective approach against cancer progression. However, the effect of pharmacological inhibition of endogenous H2S-producing enzymes (cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MPST)) on the growth of breast cancer (BC) remains unknown. In the present study, DL-propargylglycine (PAG, inhibitor of CSE), aminooxyacetic acid (AOAA, inhibitor of CBS), and L-aspartic acid (L-Asp, inhibitor of 3-MPST) were used to determine the role of endogenous H2S in the growth of BC by in vitro and in vivo experiments. An in silico study was also performed to confirm the results. Corresponding to each enzyme in separate groups, we treated BC cells (MCF-7 and MDA-MB-231) with 10 mM of PAG, AOAA, and L-Asp for 24 h. Findings reveal that the combined dose (PAG + AOAA + L-Asp) group showed exclusive inhibitory effects on BC cells’ viability, proliferation, migration, and invasion compared to the control group. Further, treated cells exhibited increased apoptosis and a reduced level of phospho (p)-extracellular signal-regulated protein kinases such as p-AKT, p-PI3K, and p-mTOR. Moreover, the combined group exhibited potent inhibitory effects on the growth of BC xenograft tumors in nude mice, without obvious toxicity. The molecular docking results were consistent with the wet lab experiments and enhanced the reliability of the drugs. In conclusion, our results demonstrate that the inhibition of endogenous H2S production can significantly inhibit the growth of human breast cancer cells via the AKT/PI3K/mTOR pathway and suggest that endogenous H2S may act as a promising therapeutic target in human BC cells. Our study also empowers the rationale to design novel H2S-based anti-tumor drugs to cure BC.

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Inhibition of cystathionine β-synthase promotes apoptosis and reduces cell proliferation in chronic myeloid leukemia

Cited by 27 publications

References 68 publications

Amino Acid Metabolic Vulnerabilities in Acute and Chronic Myeloid Leukemias

Amino Acid Metabolic Vulnerabilities in Acute and Chronic Myeloid Leukemias

Targeting Amino Acid Metabolic Vulnerabilities in Myeloid Malignancies

Pharmacological Inhibition of Endogenous Hydrogen Sulfide Attenuates Breast Cancer Progression

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