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发病率和死亡率，但其抗血管生成作用使其成为可能的新型理想化学调节剂候选物。与其他抗血管生成剂不同，硒在人体中以7200 μ g的相对高的日剂量耐受良好。硒诱导的化学调节被发现既不是物种也不是肿瘤或药物特异性的，并且在具有不同类别的抗癌药物的不同肿瘤异种移植物中是明显的。虽然化疗设备目前在作用范围和靶点方面相当广泛，但其使用受到剂量限制毒性和肿瘤摄取不良的限制，这主要是以下因素的结果：a）主要由不成熟、混乱的脉管系统构成的有缺陷的肿瘤递送系统，和B）由于无血管、缺氧的肿瘤分化区域的存在而产生的肿瘤形态异质性-更耐药表型的标志。尽管存在这样的物理屏障，但发现Se显著调节此类肿瘤的治疗功效。此外，由于Se对健康宿主组织的额外化学保护性质，其允许剂量递增至高于最大耐受剂量，从而能够进一步增强治疗功效。肿瘤血管系统缺乏平滑肌，并且混乱，血流有缺陷，间歇性，不稳定，导致肿瘤内间质液压力（IFP）高，阻碍治疗效果。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）的降解，诱导肿瘤血管正常化，降低IFP和肿瘤特异性药物输送的增加。HIF-11通过其转录激活调节70多个基因，在肿瘤血管生成、进展、转移和存活中起关键作用。目前的建议将调查硒在增强肿瘤特异性药物递送的共性，作为血管正常化的结果，在六个不同的人类肿瘤异种移植物从三个不同的癌症部位通过HIF-11降解的结果，ROS的下调。如果成功的话，这些结果将对许多人类疾病产生治疗意义，除了癌症，其中HIF-11发挥关键作用，并将有助于了解Se诱导的HIF-11降解在个体寿命内无疾病维持生命中的作用。公共卫生相关性：膳食补充剂硒（Se）通过调节活性氧通过HIF-1降解的抗血管生成和血管成熟活性的共性将在来自三个不同癌症部位-肺、头颈部和结肠的两种组织学上不同的人类肿瘤异种移植物中进行研究，以了解其与常规癌症化疗的协同作用，其中通常天然补充剂是禁忌的。这些研究的成功完成将确立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维持无疾病的生命。

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.