Non-Coding Micro RNAs and Hypoxia-Inducible Factors Are Selenium Targets for Development of a Mechanism-Based Combination Strategy in Clear-Cell Renal Cell Carcinoma—Bench-to-Bedside Therapy

dc.contributor.authorRustum, Youcef M.
dc.contributor.authorChintala, Sreenivasulu
dc.contributor.authorDurrani, Farukh A.
dc.contributor.authorBhattacharya, Arup
dc.contributor.departmentNeurological Surgery, School of Medicineen_US
dc.date.accessioned2019-06-06T18:31:08Z
dc.date.available2019-06-06T18:31:08Z
dc.date.issued2018-10-29
dc.description.abstractDurable response, inherent or acquired resistance, and dose-limiting toxicities continue to represent major barriers in the treatment of patients with advanced clear-cell renal cell carcinoma (ccRCC). The majority of ccRCC tumors are characterized by the loss of Von Hippel⁻Lindau tumor suppressor gene function, a stable expression of hypoxia-inducible factors 1α and 2α (HIFs), an altered expression of tumor-specific oncogenic microRNAs (miRNAs), a clear cytoplasm with dense lipid content, and overexpression of thymidine phosphorylase. The aim of this manuscript was to confirm that the downregulation of specific drug-resistant biomarkers deregulated in tumor cells by a defined dose and schedule of methylselenocysteine (MSC) or seleno-l-methionine (SLM) sensitizes tumor cells to mechanism-based drug combination. The inhibition of HIFs by selenium was necessary for optimal therapeutic benefit. Durable responses were achieved only when MSC was combined with sunitinib (a vascular endothelial growth factor receptor (VEGFR)-targeted biologic), topotecan (a topoisomerase 1 poison and HIF synthesis inhibitor), and S-1 (a 5-fluorouracil prodrug). The documented synergy was selenium dose- and schedule-dependent and associated with enhanced prolyl hydroxylase-dependent HIF degradation, stabilization of tumor vasculature, downregulation of 28 oncogenic miRNAs, as well as the upregulation of 12 tumor suppressor miRNAs. The preclinical results generated provided the rationale for the development of phase 1/2 clinical trials of SLM in sequential combination with axitinib in ccRCC patients refractory to standard therapies.en_US
dc.identifier.citationRustum, Y. M., Chintala, S., Durrani, F. A., & Bhattacharya, A. (2018). Non-Coding Micro RNAs and Hypoxia-Inducible Factors Are Selenium Targets for Development of a Mechanism-Based Combination Strategy in Clear-Cell Renal Cell Carcinoma-Bench-to-Bedside Therapy. International journal of molecular sciences, 19(11), 3378. doi:10.3390/ijms19113378en_US
dc.identifier.urihttps://hdl.handle.net/1805/19552
dc.language.isoen_USen_US
dc.publisherMDPIen_US
dc.relation.isversionof10.3390/ijms19113378en_US
dc.relation.journalInternational journal of molecular sciencesen_US
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 United States*
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/3.0/us*
dc.sourcePMCen_US
dc.subjectMethylselenocysteineen_US
dc.subjectSeleno-l-methionineen_US
dc.subjectClear-cell renal cell carcinoma microRNAsen_US
dc.subjectHypoxia-inducible factoren_US
dc.subjectAntitumor activityen_US
dc.titleNon-Coding Micro RNAs and Hypoxia-Inducible Factors Are Selenium Targets for Development of a Mechanism-Based Combination Strategy in Clear-Cell Renal Cell Carcinoma—Bench-to-Bedside Therapyen_US
dc.typeArticleen_US
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