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Inhibition of endogenous hydrogen sulfide production in clear-cell renal cell carcinoma cell lines and xenografts restricts their growth, survival and angiogenic potential.

ABSTRACT: Clear cell renal cell carcinoma (ccRCC) is characterized by Von Hippel-Lindau (VHL)-deficiency, resulting in pseudohypoxic, angiogenic and glycolytic tumours. Hydrogen sulfide (H2S) is an endogenously-produced gasotransmitter that accumulates under hypoxia and has been shown to be pro-angiogenic and cytoprotective in cancer. It was hypothesized that H2S levels are elevated in VHL-deficient ccRCC, contributing to survival, metabolism and angiogenesis. Using the H2S-specific probe MeRhoAz, it was found that H2S levels were higher in VHL-deficient ccRCC cell lines compared to cells with wild-type VHL. Inhibition of H2S-producing enzymes could reduce the proliferation, metabolism and survival of ccRCC cell lines, as determined by live-cell imaging, XTT/ATP assay, and flow cytometry respectively. Using the chorioallantoic membrane angiogenesis model, it was found that systemic inhibition of endogenous H2S production was able to decrease vascularization of VHL-deficient ccRCC xenografts. Endogenous H2S production is an attractive new target in ccRCC due to its involvement in multiple aspects of disease.

SUBMITTER: Sonke E

PROVIDER: S-EPMC4876030 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Inhibition of endogenous hydrogen sulfide production in clear-cell renal cell carcinoma cell lines and xenografts restricts their growth, survival and angiogenic potential.

Sonke Eric E Verrydt Megan M Postenka Carl O CO Pardhan Siddika S Willie Chantalle J CJ Mazzola Clarisse R CR Hammers Matthew D MD Pluth Michael D MD Lobb Ian I Power Nicholas E NE Chambers Ann F AF Leong Hon S HS Sener Alp A

Nitric oxide : biology and chemistry 20150609

Clear cell renal cell carcinoma (ccRCC) is characterized by Von Hippel-Lindau (VHL)-deficiency, resulting in pseudohypoxic, angiogenic and glycolytic tumours. Hydrogen sulfide (H2S) is an endogenously-produced gasotransmitter that accumulates under hypoxia and has been shown to be pro-angiogenic and cytoprotective in cancer. It was hypothesized that H2S levels are elevated in VHL-deficient ccRCC, contributing to survival, metabolism and angiogenesis. Using the H2S-specific probe MeRhoAz, it was ...[more]

PMID: 26068241

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Project description:BackgroundParallel development of preclinical models that recapitulate treatment response observed in patients is central to the advancement of personalized medicine.ObjectiveTo evaluate the use of biopsy specimens to develop patient-derived xenografts and the use of corresponding cell lines from renal cell carcinoma (RCC) tumors for the assessment of histopathology, genomics, and treatment response.Design, setting, and participantsA total of 74 tumor specimens from 66 patients with RCC were implanted into immunocompromised NOD-SCID IL2Rg-/- mice. Four cell lines generated from patients' specimens with clear cell pathology were used for comparative studies.Outcome measurements and statistical analysisPreclinical models were established and assessed. Engraftment rates were analyzed using chi-square testing. Analysis of variance (two-way analysis of variance) was conducted to assess tumor growth.Results and limitationsOverall, 33 RCC mouse xenograft models were generated with an overall engraftment rate of 45% (33 of 74). Tumor biopsies engrafted comparably with surgically resected tumors (58% vs 41%; p=0.3). Xenograft tumors and their original tumors showed high fidelity in regard to histology, mutation status, copy number change, and targeted therapy response. Engraftment rates from metastatic tumors were higher but not more significant than primary tumors (54% vs 34%; p=0.091). Our engraftment rate using metastases or biopsies was comparable with recent reports using resected primary tumors. In stark contrast to corresponding cell lines, all tested xenografts recapitulated patients' clinical response to sunitinib.ConclusionsPatient-derived xenograft models can be effectively established from tumor biopsies. Preclinical xenograft models but not matched cell lines reflected clinical responses to sunitinib.Patient summaryMatched patient-derived clear cell renal cell carcinoma xenografts and cell lines from responsive and refractory patients treated with sunitinib were established and evaluated for pharmacologic response to anti-vascular endothelial growth factor treatment. Both models accurately reflected the genetic characteristics of original tumors, but only xenografts recapitulated drug responses observed in patients. These models could serve as a powerful platform for precision medicine.

Project description: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 endogenous hydrogen sulfide production in clear-cell renal cell carcinoma cell lines and xenografts restricts their growth, survival and angiogenic potential.

Publications

Inhibition of endogenous hydrogen sulfide production in clear-cell renal cell carcinoma cell lines and xenografts restricts their growth, survival and angiogenic potential.

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