正钒酸钠抑制自噬增敏多柔比星抗肝癌作用机制研究

Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer worldwide. It is characterized with notoriously high chemoresistance and lack of effective systemic therapy. Despite extensive exploration for novel anti-cancer drugs and therapeutic options, little success has been achieved in improving the outcome of this lethal disease. Therefore, more effective therapeutic strategies for treatment of HCC are urgently needed. The transition metal vanadium is widely distributed in the environment and exhibits various biological and physiological effects in the human body. As a well known vanadium compounds, sodium orthovanadate(SOV) have shown numerous biological activities, including the inhibition of nonselective protein tyrosine phosphatases, activation of tyrosine kinases, mitogenic, neuroprotective and antidiabetic effects, but the effects of SOV in liver cancer has not yet been reported..Autophagy is now emerging as an important issue as apoptosis in response to drug therapy in cancer cells. Several anticancer drugs have been shown to regulate autophagy as well as apoptosis. Recently, some studies have shown that autophagy constitutes a potential target for cancer therapy and the induction of autophagy in response to therapeutics can be viewed as having a prodeath or a prosurvival role, which contributes to the anticancer efficacy of these drugs as well as drug resistance..In this study, for the first time, we explore the mechanism of SOV against human HCC cells in vitro and in vivo.furthermore, from the perspective of autophagy we decide to investigate that whether SOV could enhance the anti-HCC efficacy of doxorubicin both in vitro and in vivo.

探索新的药物治疗手段，提高肝癌药物治疗有效率，增敏化疗药物，成为目前肝癌研究的热点之一。抑制细胞增殖，促进细胞凋亡和自噬是抗肿瘤药物发挥抗肿瘤作用的重要机制，研究凋亡可能的通路,调控及相互关系对进一步认识治疗凋亡相关疾病有重要意义。近年来，自噬与肿瘤的关系研究更被广泛关注。适当的自噬可保护肿瘤细胞以应对缺氧、营养匮乏及清除自由基、损伤的线粒体等，抑制自噬可能会增加肿瘤细胞的凋亡。研究显示传统化疗药物多柔比星作用于肝癌后自噬增加可能是其耐药机制之一。正钒酸钠作为钒剂的代表性药物，近年来在缺血再灌注损伤、糖尿病、肿瘤领域展示出重要的治疗作用，但是正钒酸钠能否抑制肝癌细胞及其相关机制尚无人探讨。在前期，我们首次进行了正钒酸钠抑制肝癌的体内外研究。.本研究旨在联合正钒酸钠与多柔比星抑制肝癌，并且着重从凋亡和自噬的角度分析正钒酸钠联合多柔比星抗肿瘤机制。同时，从自噬角度探讨其对多柔比星的增敏作用。

肝癌是危害人类健康的重大疾病，探索新的药物治疗手段，提高药物治疗有效率，增敏化疗药物，成为目前肝癌研究的热点之一。抑制细胞增殖，促进细胞凋亡和自噬是抗肿瘤药物发挥抗肿瘤作用的重要机制，自噬与肿瘤的关系研究更被广泛关注。适当的自噬可保护肿瘤细胞以应对缺氧、营养匮乏及清除自由基、损伤的线粒体等，抑制自噬可能会增加肿瘤细胞的凋亡。研究显示传统化疗药物多柔比星作用于肝癌后自噬增加可能是其耐药机制之一。磷酸酯酶抑制剂正钒酸钠作为钒剂的代表性药物，近年来在缺血再灌注损伤、糖尿病、肿瘤领域展示出重要的治疗作用，但是，正钒酸钠能否抑制肝癌细胞及其相关机制尚无人探讨。.本研究探讨了磷酸酯酶抑制剂正钒酸钠对肝癌的作用及其机制，并且着重从凋亡和自噬的角度分析其抗肿瘤机制。同时，联合正钒酸钠与多柔比星作用于肝癌，从自噬角度探讨其对多柔比星的增敏作用，证实正钒酸钠可以增敏多柔比星的抗肝癌作用，为肝癌的药物治疗提供了一种新思路。