Alectinib (CH5424802) antagonizes ABCB1- and ABCG2-mediated multidrug resistance in vitro, in vivo and ex vivo

• Published in: Experimental & molecular medicine Vol. 49; no. 3; p. e303
• Main Authors: Yang, Ke, Chen, Yifan, To, Kenneth Kin Wah, Wang, Fang, Li, Delan, Chen, Likun, Fu, Liwu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.03.2017; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/31; 13/95; 38/109; 38/77; 631/154/152; 631/67/1059/99; 82/80; 96/109; 96/31; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; ATP Binding Cassette Transporter, Subfamily G, Member 2 - metabolism; Biomedical and Life Sciences; Biomedicine; Carbazoles - pharmacology; Carbazoles - therapeutic use; Drug Resistance, Neoplasm; HEK293 Cells; Humans; MCF-7 Cells; Medical Biochemistry; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Medicine; Original; original-article; Piperidines - pharmacology; Piperidines - therapeutic use; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Stem Cells
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/emm.2016.168

Alectinib, an inhibitor of anaplastic lymphoma kinase (ALK), was approved by the Food and Drug Administration (FDA) for the treatment of patients with ALK-positive non-small cell lung cancer (NSCLC). Here we investigated the reversal effect of alectinib on multidrug resistance (MDR) induced by ATP-binding cassette (ABC) transporters, which is the primary cause of chemotherapy failure. We provide the first evidence that alectinib increases the sensitivity of ABCB1- and ABCG2-overexpressing cells to chemotherapeutic agents in vitro and in vivo . Mechanistically, alectinib increased the intracellular accumulation of ABCB1/ABCG2 substrates such as doxorubicin (DOX) and Rhodamine 123 (Rho 123) by inhibiting the efflux function of the transporters in ABCB1- or ABCG2-overexpressing cells but not in their parental sensitive cells. Furthermore, alectinib stimulated ATPase activity and competed with substrates of ABCB1 or ABCG2 and competed with [125I] iodoarylazidoprazosin (IAAP) photolabeling bound to ABCB1 or ABCG2 but neither altered the expression and localization of ABCB1 or ABCG2 nor the phosphorylation levels of AKT and ERK. Alectinib also enhanced the cytotoxicity of DOX and the intracellular accumulation of Rho 123 in ABCB1-overexpressing primary leukemia cells. These findings suggest that alectinib combined with traditional chemotherapy may be beneficial to patients with ABCB1- or ABCG2-mediated MDR. Cancer: A possible weapon against drug resistance The drug alectinib shows potential for reversing the resistance of some cancer cells to multiple chemotherapy drugs. “Multidrug resistance” (MDR), in which cancer cells simultaneously become resistant to several unrelated anti-cancer drugs often emerges during a course of chemotherapy. Alectinib is already used to inhibit some enzymes implicated in cancer. Liwu Fu at Sun Yat-Sen University, Guangzhou, China, and colleagues found that alectinib increases the sensitivity of some cancer cells to drugs they had developed resistance against. The effect was demonstrated in cultured human cancer cells and in cancers in mice. The study suggests that alectinib acts by inhibiting the activity of proteins involved in pumping chemotherapy agents out of cells, and which are known to be involved in MDR. Alectinib should be investigated for its potential to counteract MDR in human cancers.