Dietary Supplement Selenium and HIF-1alpha Regulation in Cancer

描述(申请人提供)：必需的膳食微量元素硒(Se)的化学预防作用已知会影响癌症的发病率和死亡率，但其抗血管生成作用使其可能成为一种新的和理想的化学调节剂候选药物。与其他抗血管生成药物不同，硒在人体内的耐受性较好，日剂量相对较高，为7200&lt；g。Se诱导的化学调节既不是物种的，也不是肿瘤的，也不是药物特异性的，在不同种类的抗癌药物对不同的肿瘤移植瘤有明显的诱导作用。虽然目前化疗药物的作用范围和靶点相当广泛，但其使用受到剂量限制毒性和肿瘤摄取不足的限制，这主要是以下结果的结果：a)主要由不成熟、混乱的血管系统组成的错误的肿瘤输送系统，以及b)由于存在无血管、缺氧的肿瘤分化区域而导致的肿瘤形态异质性--更多耐药表型的标志。尽管存在这样的物理障碍，但人们发现硒显著调节了此类肿瘤的治疗效果。此外，由于Se对健康宿主组织具有额外的化学保护特性，允许剂量上升到高于最大耐受剂量，从而进一步提高治疗效果。肿瘤血管缺乏平滑的肌肉，血流不稳定、间歇性差，导致高的肿瘤间质内液体压(IFP)，阻碍了治疗效果。初步数据表明，Se下调活性氧(ROS)，导致缺氧诱导因子-1α(HIF-11)的降解，从而诱导肿瘤血管正常化，降低IFP，从而增加肿瘤特异性药物输送。HIF-11通过其转录激活调控70多个基因，在肿瘤血管生成、进展、转移和生存中发挥关键作用。目前的提案将研究Se在增强肿瘤特异性药物输送方面的共性，这是由于ROS下调导致来自三个不同肿瘤部位的六种不同人类肿瘤移植瘤的血管正常化，通过HIF-11的降解导致的。如果成功，这一结果将对除癌症外的许多人类疾病具有治疗意义，在这些疾病中，HIF-11发挥着关键作用，并将有助于理解Se诱导的HIF-11降解在维持一个人一生中无病生命方面的作用。与公共卫生相关：膳食补充剂硒(Se)通过调节活性氧簇而降解HIF-1，从而抑制血管生成和血管成熟的活性的共同性将在两个组织学上不同的人类肿瘤移植瘤中进行研究--肺、头和颈部，以及结肠癌--以了解其与传统癌症化疗的协同作用，在这些癌症化疗中，天然补充剂通常是禁忌的。拟议研究的成功完成将确定硒在抑制癌症和其他疾病中的HIF-11方面的作用，从而在一个人的整个生命周期中保持生命的无病。

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.