Afatinib Decreases P‐Glycoprotein Expression to Promote Adriamycin Toxicity of A549T Cells

• Published in: Journal of cellular biochemistry Vol. 119; no. 1; pp. 414 - 423
• Main Authors: Zhang, Yan, Wang, Chang‐yuan, Duan, Ying‐jie, Huo, Xiao‐kui, Meng, Qiang, Liu, Zhi‐hao, Sun, Hui‐jun, Ma, Xiao‐dong, Liu, Ke‐xin
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.01.2018
• Subjects: 1-Phosphatidylinositol 3-kinase; A549 Cells; AFATINIB ADRIAMYCIN; AKT protein; Anticancer properties; Antitumor activity; APOPTOSIS; ATP Binding Cassette Transporter, Sub-Family B - biosynthesis; AUTOPHAGY; Caspase; Caspase-3; Cell survival; Chemotherapy; Doxorubicin - pharmacology; Drugs; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Glycoproteins; Humans; Inhibition; Inhibitors; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; MDR; Molecular modelling; mRNA; Multidrug resistance; Neoplasm Proteins - biosynthesis; P-Glycoprotein; Phagocytosis; Poly(ADP-ribose) polymerase; P‐GP; Quinazolines - pharmacology; Toxicity; APOPTOSIS; AFATINIB ADRIAMYCIN; MDR; P-GP; AUTOPHAGY
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.26194

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. MDR is one of the main reasons for the failure of lung cancer therapy. AFT increased anti‐proliferation activity of ADR in A549T cells through downregulating of P‐gp via inhibiting the activation of PI3K/AKT signaling pathway and promoting ADR‐induced apoptosis and autophagy. These findings provide an evidence that combination of AFT and ADR may achieve a better therapeutic effect to lung cancer in clinic.