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

View Article: PubMed Central - PubMed

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Potentiation of the anticancer effects of paclitaxel by alectinib in the KBv200 cell xenograft nude mice model. The tumor growth curve was drawn to monitor the tumor volume with time after implantation. The data shown are expressed as the mean±s.d. of the tumor volume for each group (n=9) (a). The tumor xenografts were excised, and the tumors were photographed on the 21st day after implantation (b). The body weights of the experimental animals were measured every 2 days, and the average percentage change was calculated after treatment (c). The average tumor weight of each group was calculated after the tumors were excised from the mice (d). The data are shown as the mean±s.d. for each group, **P<0.01.
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fig2: Potentiation of the anticancer effects of paclitaxel by alectinib in the KBv200 cell xenograft nude mice model. The tumor growth curve was drawn to monitor the tumor volume with time after implantation. The data shown are expressed as the mean±s.d. of the tumor volume for each group (n=9) (a). The tumor xenografts were excised, and the tumors were photographed on the 21st day after implantation (b). The body weights of the experimental animals were measured every 2 days, and the average percentage change was calculated after treatment (c). The average tumor weight of each group was calculated after the tumors were excised from the mice (d). The data are shown as the mean±s.d. for each group, **P<0.01.

Mentions: To investigate whether alectinib could enhance the efficacy of anticancer drugs in vivo, we established a ABCB1-overexpressing multidrug-resistant KBv200 cell xenograft model in nude mice. Paclitaxel has been one of the most commonly used conventional chemotherapeutic agents for oral cancers in the clinic.42 Therefore, we performed KBv200 cell xenografts using paclitaxel. The xenograft growth inhibitions in the alectinib, paclitaxel or combined treatment groups were 1.36%, 11.32% or 48.33%, respectively. There was no significant difference in tumor size among animals treated with saline, alectinib or paclitaxel alone. However, the combination of alectinib and paclitaxel induced a significant greater inhibitory effect on xenograft growth compared with the animals treated with only saline, paclitaxel or alectinib (P<0.01; Figure 2a–c). These data suggest that alectinib can enhance the efficacy of conventional substrate chemotherapeutical agents in ABCB1-overexpressing cell xenografts in vivo. Importantly, at the tested doses, no mortality and a significant decrease in body weight were associated with the combination treatment (Figure 2d), suggesting that the combination regimen did not cause increased toxicity.


Alectinib (CH5424802) antagonizes ABCB1- and ABCG2-mediated multidrug resistance in vitro , in vivo and ex vivo
Potentiation of the anticancer effects of paclitaxel by alectinib in the KBv200 cell xenograft nude mice model. The tumor growth curve was drawn to monitor the tumor volume with time after implantation. The data shown are expressed as the mean±s.d. of the tumor volume for each group (n=9) (a). The tumor xenografts were excised, and the tumors were photographed on the 21st day after implantation (b). The body weights of the experimental animals were measured every 2 days, and the average percentage change was calculated after treatment (c). The average tumor weight of each group was calculated after the tumors were excised from the mice (d). The data are shown as the mean±s.d. for each group, **P<0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382559&req=5

fig2: Potentiation of the anticancer effects of paclitaxel by alectinib in the KBv200 cell xenograft nude mice model. The tumor growth curve was drawn to monitor the tumor volume with time after implantation. The data shown are expressed as the mean±s.d. of the tumor volume for each group (n=9) (a). The tumor xenografts were excised, and the tumors were photographed on the 21st day after implantation (b). The body weights of the experimental animals were measured every 2 days, and the average percentage change was calculated after treatment (c). The average tumor weight of each group was calculated after the tumors were excised from the mice (d). The data are shown as the mean±s.d. for each group, **P<0.01.
Mentions: To investigate whether alectinib could enhance the efficacy of anticancer drugs in vivo, we established a ABCB1-overexpressing multidrug-resistant KBv200 cell xenograft model in nude mice. Paclitaxel has been one of the most commonly used conventional chemotherapeutic agents for oral cancers in the clinic.42 Therefore, we performed KBv200 cell xenografts using paclitaxel. The xenograft growth inhibitions in the alectinib, paclitaxel or combined treatment groups were 1.36%, 11.32% or 48.33%, respectively. There was no significant difference in tumor size among animals treated with saline, alectinib or paclitaxel alone. However, the combination of alectinib and paclitaxel induced a significant greater inhibitory effect on xenograft growth compared with the animals treated with only saline, paclitaxel or alectinib (P<0.01; Figure 2a–c). These data suggest that alectinib can enhance the efficacy of conventional substrate chemotherapeutical agents in ABCB1-overexpressing cell xenografts in vivo. Importantly, at the tested doses, no mortality and a significant decrease in body weight were associated with the combination treatment (Figure 2d), suggesting that the combination regimen did not cause increased toxicity.

View Article: PubMed Central - PubMed

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus