Targeting autophagy augments the activity of DHA-E3 to overcome p-gp mediated multi-drug resistance
Targeting autophagy augments the activity of DHA-E3 to overcome p-gp mediated multi-drug resistance
复制标题
靶向自噬增强 DHA-E3 的活性以克服 p-gp 介导的多药耐药性
DOI：
10.1016/j.biopha.2016.10.063
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发表时间：
2016
影响因子：
7.5
通讯作者：
Yuan HQ
中科院分区：
文献类型：
--
作者：
Xi Guangmin;Wang Ming;Liu Yongqing;Wang Wei;Yuan Huiqing;Sun Bing;Lou Hongxiang;Xi Guangmin;Shaikh Abdul Sami;Yuan HQ
多药耐药（MDR）是化疗成功的主要障碍。寻找有效的MDR调节剂，并将其与抗癌药物治疗相结合，已成为一种很有前途的抗MDR策略。在我们前期的研究中，我们发现DHA的人工合成衍生物DHA-E3具有调节P-糖蛋白（P-gp）功能和逆转肿瘤细胞MDR的能力。本研究进一步评价DHA-E3在体外对MDR的逆转作用，并探讨其作用机制。结果表明，DHA-E3能显著增强长春新碱（VCR）和阿霉素（ADR）对高表达P-gp的KB/VCR和A02细胞的细胞毒作用。机制研究发现，DHA-E3通过直接抑制P-gp的药物转运活性，增加ADR和罗丹明-123的细胞内积累。在本研究中，我们发现DHA-E3不仅逆转MDR，而且诱导MDR癌细胞的自噬。为了确定DHA-E3诱导的自噬是否是一种适应性生存反应或导致细胞死亡，我们使用自噬抑制剂3-MA或靶向Beclin 1的siRNA操纵自噬活性。我们发现，DHA-E3的逆转活性在3-MA的存在下或阻断Beclin 1的表达时显著加剧。这些结果表明，DHA-E3能够逆转MDR，诱导自噬是一种防御机制，抑制该过程可能是增强逆转剂逆转活性的有效策略。
Multidrug resistance (MDR) is a major obstacle for successful chemotherapy treatment. Searching for effective MDR modulators and combining them with anticancer drug therapies has been a promising strategy against clinical MDR. In our previous study, we have found that DHA-E3, a synthetic derivative of DHA, has the ability to modulate the function of P-glycoprotein (P-gp) and reverse MDR in cancer cells. In this study, we further evaluated the reversal effect of DHA-E3 on MDR and explored its mechanism of action in vitro. Our findings showed that DHA-E3 significantly potentiated the cytotoxicity of vincristine(VCR) and adriamycin(ADR) in the P-gp over-expressing KB/VCR and A02 cells. The mechanistic study found that DHA-E3 increased the intracellular accumulation of ADR and rhodamine-123 by directly inhibiting the drug-transport activity of P-gp. In the present study, we found that DHA-E3 not only reversed MDR, but also induced autophagy in MDR cancer cells. To determine whether DHA-E3-induced autophagy is an adaptive survival response or contributes to cell death, we manipulated autophagic activity using autophagy inhibitor 3-MA or siRNA targeting Beclin1. We found that the reversal activity of DHA-E3 was significantly exacerbated in the presence of 3-MA or blocking the expression of Beclin1. These results suggest that DHA-E3 is capable of reversing MDR, induction of autophagy represents a defense mechanism and inhibiting this process may be an effective strategy to augment the reversal activity of reversal agents.