Afatinib Decreases P‐Glycoprotein Expression to Promote Adriamycin Toxicity of A549T Cells |
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Authors: | Yan Zhang Chang‐yuan Wang Ying‐jie Duan Xiao‐kui Huo Qiang Meng Zhi‐hao Liu Hui‐jun Sun Xiao‐dong Ma Ke‐xin Liu |
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Institution: | 1. Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China;2. Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, China;3. General Hospital of Fuxin Mining (Group) Co., Ltd, Fuxin, China |
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Abstract: | We investigated the reversal effect of afatinib (AFT) on activity of adriamycin (ADR) in A549T cells and clarified the related molecular mechanisms. A549T cells overexpressing P‐glycoprotein (P‐gp) were resistant to anticancer drug ADR. AFT significantly increased the antitumor activity of ADR in A549T cells. AFT increased the intracellular concentration of ADR by inhibiting the function and expression of P‐gp at mRNA and protein levels in A549T cells. Additionally, the reversal effect of AFT on P‐gp mediated multidrug resistance (MDR) might be related to the inhibition of PI3K/Akt pathway. Cotreatment with AFT and ADR could enhance ADR‐induced apoptosis and autophagy in A549T cells. Meanwhile, the co‐treatment significantly induced cell apoptosis and autophagy accompanied by increased expression of cleaved caspase‐3, PARP, LC3B‐II, and beclin 1. Apoptosis inhibitors had no significant effect on cell activity, while autophagy inhibitors decreased cell viability, suggesting that autophagy may be a self protective mechanism of cell survival in the absence of chemotherapy drugs. Interestingly, when combined with AFT and ADR, inhibition of apoptosis and/or autophagy could enhance cell viability. These results indicated that in addition to inhibit P‐gp, ADR‐induced apoptosis, and autophagy promoted by AFT contributed to the antiproliferation effect of combined AFT and ADR on A549T cells. These findings provide evidence that AFT combined ADR may achieve a better therapeutic effect to lung cancer in clinic. J. Cell. Biochem. 119: 414–423, 2018. © 2017 Wiley Periodicals, Inc. |
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Keywords: | MDR AFATINIB ADRIAMYCIN P‐GP APOPTOSIS AUTOPHAGY |
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