Dietary Supplement Selenium and HIF-1alpha Regulation in Cancer

描述（由申请人提供）：已知必需膳食微量元素硒（Se）的化学预防作用会影响癌症的发病率和死亡率，但其抗血管生成的作用使其可能成为一种新的理想的化学调节剂候选物。与其他抗血管生成药物不同，硒在人体内的较高日剂量为7200 <g时耐受性良好。硒诱导的化学调节既不具有物种特异性，也不具有肿瘤特异性或药物特异性，并且在不同种类抗癌药物的不同肿瘤异种移植物中都很明显。虽然目前化疗手段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良的限制，这主要是由于：a)主要由不成熟、混乱的血管系统组成的有缺陷的肿瘤传递系统，以及b)由于存在无血管、缺氧的肿瘤分化区而引起的肿瘤形态异质性-这是更耐药表型的标志。尽管存在这样的物理障碍，硒被发现可以显著调节这类肿瘤的治疗效果。此外，由于硒对健康宿主组织具有额外的化学保护特性，可以使剂量增加到高于最大耐受剂量，从而进一步增强治疗效果。肿瘤血管缺乏平滑肌，血流混乱，有缺陷，间歇性，不稳定，导致瘤内间质液压力（IFP）高，阻碍了治疗效果。初步数据表明，硒下调活性氧（ROS），导致缺氧诱导因子-1 α (HIF-11)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传递。HIF-11通过转录激活调控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。目前的提案将研究硒在增强肿瘤特异性药物递送中的共性，这是由于来自三个不同癌症部位的六种不同人类肿瘤异种移植物的血管正常化，通过HIF-11的降解，作为ROS下调的结果。如果成功，该结果将对除癌症之外的许多人类疾病具有治疗意义，其中HIF-11起着关键作用，并将有助于了解硒诱导的HIF-11降解在个体生命周期中无疾病维持生命中的作用。公共卫生相关性：将在来自三个不同癌症部位（肺、头颈和结肠）的两种组织学上不同的人类肿瘤异种移植物中研究膳食补充剂硒（Se）通过调节活性氧来降解HIF-1的抗血管生成和血管成熟活性的共性，以了解其与常规癌症化疗的协同作用，而常规癌症化疗通常是天然补充剂的禁忌。上述研究的成功完成将确定硒在癌症和其他疾病中抑制HIF-11的作用，从而在个体的整个生命周期中无病维持生命。

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.