Pharmacological Inhibition of Endogenous Hydrogen Sulfide Attenuates Breast Cancer Progression

Abstract

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.

Pan-cancer analysis of the angiotensin II receptor-associated protein as a prognostic and immunological gene predicting immunotherapy responses in pan-cancer

“…Previous studies reported that AKT and mTOR proteins function by phosphorylation (Wang et al, 2022;Zhu et al, 2022), and AGTRAP can promote phosphorylation of AKT and mTOR, initiating the AKT/mTOR axis. Accumulating evidence has demonstrated the functions of p-AKT and p-mTOR in promoting the progression of breast cancer and gastric cancer (Xu et al, 2021;Khan et al, 2022). Our study reveals that a novel biomarker, AGTRAP, can regulate the AKT/mTOR axis.…”

Novel Regulatory Roles of Hydrogen Sulfide in Health and Disease

“…Moreover, in a study utilizing a patient-derived xenograft model, our own group has demonstrated that those colon cancers that express higher levels of CBS, when implanted onto nude mice, proliferate faster and respond better to pharmacological CBS inhibition than those colon cancers that express low levels of CBS [ 27 ]. These observations—together with several other lines of recently emerging data regarding the importance of H 2 S overproduction in various cancers [ 28 , 29 , 30 ]—may help with the future clinical translation of the CBS inhibition concept for the experimental therapy of cancer.…”

Hydrogen sulfide responsive nanoplatforms: Novel gas responsive drug delivery carriers for biomedical applications

“…However, endogenous H 2 S shows high expression only in some tumor cells, and its concentration can reach 3.4 mM [81] . Some scholars have revealed changes in the expression and role of the enzymes (CSE and CBS) that help to produce H 2 S during a development of cancer [82] , such as colon [83] , gastric [84] , prostate [85] , breast [86] , liver [87] , and mouth [88] , as summarized in Table 1 . The cancer can generate H 2 S only through CES [89] , or CBS [90] , [91] .…”

“… Cancer type Cell line H 2 S producting enzyme Ref. CBS CES Colon HT29 ↑ ↑ [85] Gastric SGC-7901 ↑ ↑ [86] Prostate PC3 ↑ ↑ [87] Breast MCF-7 ↑ ↑ [88] Liver HepG2 ↑ ↑ [89] Mouth OSCC ↑ ↑ [90] Melanoma A375 N/A ↑ [91] Leukemia HL-60 ↑ N/A [92] Ovarian OV202 ↑ N/A [93] Gliomas C6 N/A N/A [94] N/A: Not test; ↑: upregulation; CSE: cysteine γ-lyase; CBS: cysteine β-synthetase. …”