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- 학술저널
- 저자정보
- 발행연도
- 2017.1
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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.
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참고문헌 (24)
참고문헌 신청
[학술지
Dai CL / 2008 / Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G memb
Dean M / 2001 / The human ATP-binding cassette(ABC)transporter superfamily / J Lipid Res 42 : 1007 ~ 1017
Deng W / 2013 / Tandutinib(MLN518)reverses multidrug resistance by inhibiting the efflux activity of the multidrug resistance protein 7(ABCC10) / Oncol Rep 29 : 2479 ~ 2485
Diamond EL / 2016 / Alectinib approved for ALK+ lung cancer / Cancer Discov 6 : 115 ~
Dai CL / 2008 / Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G memb
Dean M / 2001 / The human ATP-binding cassette(ABC)transporter superfamily / J Lipid Res 42 : 1007 ~ 1017
Deng W / 2013 / Tandutinib(MLN518)reverses multidrug resistance by inhibiting the efflux activity of the multidrug resistance protein 7(ABCC10) / Oncol Rep 29 : 2479 ~ 2485
Diamond EL / 2016 / Alectinib approved for ALK+ lung cancer / Cancer Discov 6 : 115 ~
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