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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
Journal article   Open access   Peer reviewed

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

Youcef M Rustum, Sreenivasulu Chintala, Farukh A Durrani and Arup Bhattacharya
International journal of molecular sciences, Vol.19(11), p.3378
10/29/2018
DOI: 10.3390/ijms19113378
PMCID: PMC6275006
PMID: 30380599
url
https://doi.org/10.3390/ijms19113378View
Published (Version of record) Open Access

Abstract

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⁻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.
 Animals Antineoplastic Agents - therapeutic use Antineoplastic Combined Chemotherapy Protocols - therapeutic use Basic Helix-Loop-Helix Transcription Factors - genetics Carcinoma, Renal Cell - blood supply Carcinoma, Renal Cell - drug therapy Carcinoma, Renal Cell - genetics Carcinoma, Renal Cell - pathology Cell Line, Tumor Female Fluorouracil - therapeutic use Gene Expression Regulation, Neoplastic - drug effects Humans Hypoxia-Inducible Factor 1, alpha Subunit - genetics Kidney Neoplasms - blood supply Kidney Neoplasms - drug therapy Kidney Neoplasms - genetics Kidney Neoplasms - pathology Mice, Nude MicroRNAs - genetics Selenocysteine - analogs & derivatives Selenocysteine - therapeutic use Selenomethionine - therapeutic use Topotecan - therapeutic use

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