雷公藤氯内酯醇T4可能通过AEG-1调控肺癌多药耐药细胞自噬和耐药的机制研究

Tumor multidrug resistance is the main reason for the failure of chemotherapy of lung cancer.More and more studies have shown that killing tumor cells by non-apoptotic pathway or downregulating MDR1 gene may circumvent tumor resistance. Autophagy is a new kind of programmed cell death mode.The current studies show that excessive autophagic death can result in the death of tumor cells. Moreover,two important signal pathways of autophagy PI3K/Akt and AMPK-mTOR are associated with tumor multidrug resistance.Recently, some scholars have found that AEG-1 not only can induce protect autophagy of tumor cells by AMPK-mTOR pathway, but also can induce tumor multidrug resistance by upregulating MDR1 gene via PI3K/Akt pathway. Tripterygium extracts tripchlorolide T4 has low toxicity and high pharmacological activity. Our previous study showed that T4 can downregulate AEG-1, induce A549 and A549/DDP cells autophagy. In this study, multidrug-resistant lung adenocarcinoma cell line A549 and A549/DDP and nude mice xenograft tumor models were used to examined the role of T4 and AEG-1 in regulating autophagy and multidrug resistance in lung cancer and its mechanisms.This study will provide a theoretical basis for T4 in the treatment of multidrug-resistant lung adenocarcinoma.

多药耐药是导致肺癌化疗失败的主要原因之一。许多研究表明通过非凋亡途径杀灭肿瘤细胞或下调MDR1基因表达可能规避肿瘤耐药。自噬是一种新的程序性细胞死亡方式，研究发现，诱导过度激活自噬可以杀灭肿瘤细胞。此外，自噬相关的PI3K/Akt和AMPK-mTOR两条重要信号通路与肿瘤的MDR1基因表达及耐药有关。最近研究发现AEG-1不仅通过AMPK-mTOR介导肿瘤细胞保护性自噬，还能通过PI3K/Akt上调肿瘤的MDR1基因表达，产生耐药性。雷公藤氯内酯醇T4具有毒性低药理活性高的特点。我们的前期研究发现T4能下调AEG-1的表达，诱导肺腺癌细胞A549及多药耐药细胞A549/DDP产生自噬性细胞死亡。本研究以A549及A549/DDP细胞和裸鼠皮下移植瘤为模型，观察T4通过AEG-1对肺癌自噬和耐药的影响，并探讨上述两条信号通路在其中的作用。本研究将为T4在多药耐药肺腺癌的治疗提供理论依据。

肺癌是目前世界上死亡率最高的疾病之一，研究新型的药物对肺癌的治疗起关键作用。雷公藤内酯(T4)是从雷公藤甲素中提取或经雷公藤甲素的羟基酰化和氯化得到的一种减毒单体，活性高于雷公藤甲素，毒性低于雷公藤甲素。研究发现，雷公藤内酯可诱导肺癌细胞自噬，但其机制尚未阐明。在我们的研究中，我们讨论了雷公藤内酯是否通过抑制PI3K/Akt/mTOR信号通路，提高A549/DDP细胞的顺铂敏感性，从而诱导A549和A549/DDP肺癌细胞自噬。