{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T17:56:02Z","timestamp":1772819762487,"version":"3.50.1"},"reference-count":100,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2018,10,29]],"date-time":"2018-10-29T00:00:00Z","timestamp":1540771200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P30CA016056"],"award-info":[{"award-number":["P30CA016056"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Durable 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\u2013Lindau tumor suppressor gene function, a stable expression of hypoxia-inducible factors 1\u03b1 and 2\u03b1 (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.<\/jats:p>","DOI":"10.3390\/ijms19113378","type":"journal-article","created":{"date-parts":[[2018,10,29]],"date-time":"2018-10-29T11:10:41Z","timestamp":1540811441000},"page":"3378","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["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\u2014Bench-to-Bedside Therapy"],"prefix":"10.3390","volume":"19","author":[{"given":"Youcef M.","family":"Rustum","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA"},{"name":"Roswell Park Comprehensive Cancer Center, Department of Pharmacology &amp; Therapeutics, Buffalo, NY 14263, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sreenivasulu","family":"Chintala","sequence":"additional","affiliation":[{"name":"Neurological Surgery, Indiana University, Indianapolis, IN 46202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Farukh A.","family":"Durrani","sequence":"additional","affiliation":[{"name":"Roswell Park Comprehensive Cancer Center, Department of Cell Stress Biology, Buffalo, NY 14263, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arup","family":"Bhattacharya","sequence":"additional","affiliation":[{"name":"Roswell Park Comprehensive Cancer Center, Department of Pharmacology &amp; Therapeutics, Buffalo, NY 14263, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1038\/nrclinonc.2016.224","article-title":"Renal-cell carcinoma in 2016: Advances in treatment\u2014Jostling for pole position","volume":"14","author":"Albiges","year":"2017","journal-title":"Nat. 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