Abstract
Selenium (Se)-containing molecules exert antioxidant properties and modulate targets associated with tumor growth, metastasis, angiogenesis, and drug resistance. Prevention clinical trials with low-dose supplementation of different types of Se molecules have yielded conflicting results. Utilizing several xenograft models, we earlier reported that the enhanced antitumor activity of various chemotherapeutic agents by selenomethione and Se-methylselenocysteine in several human tumor xenografts is highly dose- and schedule-dependent. Further, Se pretreament offered selective protection of normal tissues from drug-induced toxicity, thereby allowing higher dosing than maximum tolerated doses.These enhanced therapeutic effects were associated with inhibition of hypoxia-inducible factor 1- and 2-alpha (HIF1α, HIF2α) protein, nuclear factor (erythyroid-derived 2)-like 2 (Nrf2) and pair-related homeobox-1 (Prx1) transcription factors, downregulation of oncogenic- and upregulation of tumor suppressor miRNAs. This review provides: 1) a brief update of clinical prevention trials with Se; 2) advances in the use of specific types, doses, and schedules of Se that selectively modulate antitumor activity and toxicity of anti-cancer drugs; 3) identification of targets selectively modulated by Se; 4) plasma and tumor tissue Se levels achieved after oral administration of Se in xenograft models and cancer patients; 5) development of a phase 1 clinical trial with escalating doses of orally administered selenomethionine in sequential combination with axitinib to patients with advanced clear cell renal cell carcinoma; and 6) clinical prospects for future therapeutic use of Se in combination with anticancer drugs.
Highlights
The human tumor microenvironment of nonmalignant cells and stroma is molecularly and immunologically heterogeneous
Treatment with therapeutic doses of MSC alone of colorectal and head and neck xenografts expressing lower incidence of HIFs resulted in a pronounced inhibition of HIF1α and sensitizes cancer cells to treatment with a variety of anticancer drugs [8, 16]
Significant levels of vascular endothelial growth factor (VEGF) remained stably expressed even though HIF1α and HIF2α were inhibited by MSC. These results suggest that VEGF levels are differentially regulated by HIF1α and HIF2α, and a complete inhibition of VEGF may require administration of a combination of agents that inhibit VEGF regulated by HIF1α and those that target VEGF-regulated by HIF-independent mechanisms
Summary
The human tumor microenvironment of nonmalignant cells and stroma is molecularly and immunologically heterogeneous. That the pleiotropic role of MSC and SLM in modulating multiple targets would be essential for the selective and effective sensitization of tumor cells to subsequent treatment with anticancer drugs.
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