Dietary Supplement Selenium and HIF-1alpha Regulation in Cancer

Roswell Park Cancer Institute Corp, Buffalo NY

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Abstract

DESCRIPTION (provided by applicant): The chemopreventive effects of the essential dietary trace element Selenium (Se) is known to impact cancer incidence and mortality, however its antiangiogenic role makes it a possible novel and ideal chemomodulator candidate. Unlike other antiangiogenic agents, Se is well-tolerated at a relatively high daily dose of 7200 <g in human. Se induced chemomodulation was found to be neither species nor tumor or drug specific and was evident in different tumor xenografts with different classes of anti-cancer drugs. While the chemotherapeutic armamentarium is currenlty quite wide in scope of action and target, its use is limited by dose limiting toxicitiy and poor tumor uptake that is primarily an outcome of: a) a faulty tumor delivery system constituted mainly of immature, chaotic vasculature, and, b) tumor morphologic heterogeneity arising due to presence of avascular, hypoxic tumor differentiated regions - a hallmark of more resistant phenotypes. Despite presence of such physical barriers, Se was found to significantly modulate the therapeutic efficacy in such tumors. Further Se, due to its additional chemo protective properties on healthy host tissues, allows dose escalation to higher than the maximum tolerated dose enabling to further enhance therapeutic efficacy. Tumor vasculature lack smooth muscles and are chaotic with faulty, intermittent, unstable blood flow that confers a high intratumoral interstitial fluid pressure(IFP) hindering therapeutic efficacy. Preliminary data indicates that Se down regulates reactive oxygen species (ROS) resulting in degradation of hypoxia-inducible factor-1alpha (HIF-11) that induces tumor vascular normalization, lowering of IFP and a consequent increase in tumor specific drug delivery. HIF-11, by its transcriptional activation regulates more than 70 genes, play a key role in tumor angiogenesis, progression, metastasis and survival. The current proposal will investigate the commonality of Se in enhancing tumor specific drug delivery as a result of vascular normalization in six different human tumor xenografts from three different cancer sites through HIF-11 degradation as a consequence of down regulation of ROS. If successful, the results will have therapeutic implications for many human diseases besides cancer where HIF-11 play a key role and will help understand the role of Se-induced HIF-11 degradation in disease free maintenance of life across an individual's life span. PUBLIC HEALTH RELEVANCE: The commonality of the antiangiogenic and vascular maturation activity of dietary supplement selenium (Se) through HIF-1 degradation via modulation of reactive oxygen species will be investigated in two histologically distinct human tumor xenografts from three different cancer sites - lungs, head and neck, and, colon, for understanding its'synergistic interaction with conventional cancer chemotherapy where often natural supplements are contraindicated. Successful completion of the studies proposed will establish the role of Se in inhibiting HIF-11 in cancer and other disease for a disease free maintenance of life across the life span of an individual.