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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-\u03b3-lyase (CSE), cystathionine-\u03b2-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\u2019 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.<\/jats:p>","DOI":"10.3390\/molecules27134049","type":"journal-article","created":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T22:43:00Z","timestamp":1656024180000},"page":"4049","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Pharmacological Inhibition of Endogenous Hydrogen Sulfide Attenuates Breast Cancer Progression"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4380-233X","authenticated-orcid":false,"given":"Nazeer Hussain","family":"Khan","sequence":"first","affiliation":[{"name":"Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China"},{"name":"School of Life Sciences, Henan University, Kaifeng 475004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Wang","sequence":"additional","affiliation":[{"name":"Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6325-1267","authenticated-orcid":false,"given":"Wenkang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery, The First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5487-641X","authenticated-orcid":false,"given":"Muhammad","family":"Shahid","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi 43600, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6798-2991","authenticated-orcid":false,"given":"Saadullah","family":"Khattak","sequence":"additional","affiliation":[{"name":"Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China"},{"name":"School of Life Sciences, Henan University, Kaifeng 475004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4448-5276","authenticated-orcid":false,"given":"Ebenezeri Erasto","family":"Ngowi","sequence":"additional","affiliation":[{"name":"Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China"},{"name":"Department of Biological Sciences, Faculty of Science, Dar es Salaam University College of Education, Dar es Salaam 11101, Tanzania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1363-7935","authenticated-orcid":false,"given":"Muhammad","family":"Sarfraz","sequence":"additional","affiliation":[{"name":"Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China"},{"name":"Faculty of Pharmacy, The University of Lahore, Lahore 54590, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Ying","family":"Ji","sequence":"additional","affiliation":[{"name":"Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China"},{"name":"Kaifeng Key Laboratory of Infection and Biological Safety, College of Medicine, Henan University, Kaifeng 475004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Yang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China"},{"name":"Department of General Thoracic Surgery, Hami Central Hospital, Hami 839000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Dong","family":"Wu","sequence":"additional","affiliation":[{"name":"Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China"},{"name":"School of Stomatology, Henan University, Kaifeng 475004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,23]]},"reference":[{"key":"ref_1","unstructured":"Fleege, N.M., and Cobain, E.F. 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