title: Afatinib reverses multidrug resistance in ovarian cancer via dually inhibiting ATP binding cassette subfamily B member 1.
abstract: ABCB1-mediated multidrug resistance (MDR) remains a major obstacle to successful chemotherapy in ovarian cancer. Herein, afatinib at nontoxic concentrations significantly reversed ABCB1-mediated MDR in ovarian cancer cells in vitro (p < 0.05). Combining paclitaxel and afatinib caused tumor regressions and tumor necrosis in A2780T xenografts in vivo. More interestingly, unlike reversible TKIs, afatinib had a distinctive dual-mode action. Afatinib not only inhibited the efflux function of ABCB1, but also attenuated its expression transcriptionally via down-regulation of PI3K/AKT and MAPK/p38-dependent activation of NF-κB. Furthermore, apart from a substrate binding domain, afatinib could also bind to an ATP binding domain of ABCB1 through forming hydrogen bonds with Gly533, Gly534, Lys536 and Ala560 sites. Importantly, mutations in these four binding sites of ABCB1 and the tyrosine kinase domain of EGFR were not correlated with the reversal activity of afatinib on MDR. Given that afatinib is a clinically approved drug, our results suggest combining afatinib with chemotherapeutic drugs in ovarian cancer. This study can facilitate the rediscovery of superior MDR reversal agents from molecular targeted drugs to provide a more effective and safer way of resensitizing MDR.
authors: Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors: Sheng-qi
authors: SQ
authors: Wang
authors: Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors: Shi-ting
authors: ST
authors: Liu
authors: Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors: Bo-xin
authors: BX
authors: Zhao
authors: Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors: Fu-heng
authors: FH
authors: Yang
authors: Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors: Ya-tian
authors: YT
authors: Wang
authors: Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors: Qian-Ying
authors: QY
authors: Liang
authors: GCP Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors: Ya-bin
authors: YB
authors: Sun
authors: Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors: Yuan
authors: Y
authors: Liu
authors: Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors: Zhi-hua
authors: ZH
authors: Song
authors: Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors: Yun
authors: Y
authors: Cai
authors: Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors: Guo-feng
authors: GF
authors: Li
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000077716:Afatinib; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D016328:NF-kappa B; D011799:Quinazolines; D000077716:Afatinib; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases
keywords: ABCB1; afatinib; multidrug resistance; ovarian cancer; tyrosine kinase inhibitor