期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 19, 期 11, 页码 -出版社
MDPI
DOI: 10.3390/ijms19113378
关键词
methylselenocysteine; seleno-L-methionine; clear-cell renal cell carcinoma microRNAs; hypoxia-inducible factor; antitumor activity
资金
- National cancer institute [P30CA016056]
- NATIONAL CANCER INSTITUTE [P30CA016056] Funding Source: NIH RePORTER
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 1 alpha and 2 alpha (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.
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