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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

A schematic model illustrating the reversal of MDR by alectinib. When the primary tumors were treated with chemotherapeutic agents, the sensitive cancer cells were killed, but the MDR cancer cells simultaneously became resistant to structurally and mechanistically distinct classes of anticancer drugs. Overexpressing ABCB1 or ABCG2 in the MDR cells resulted in an efflux of drugs across the membrane. In the presence of alectinib, the intracellular accumulation of conventional anticancer drugs was increased in the ABCB1- or ABCG2-overexpressing cells, resulting in sensitization of the MDR cells. The reversal of MDR by alectinib was mediated by inhibition of ABCB1/ABCG2 transport function and by enhanced intracellular accumulation of anticancer substrate drugs.
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fig8: A schematic model illustrating the reversal of MDR by alectinib. When the primary tumors were treated with chemotherapeutic agents, the sensitive cancer cells were killed, but the MDR cancer cells simultaneously became resistant to structurally and mechanistically distinct classes of anticancer drugs. Overexpressing ABCB1 or ABCG2 in the MDR cells resulted in an efflux of drugs across the membrane. In the presence of alectinib, the intracellular accumulation of conventional anticancer drugs was increased in the ABCB1- or ABCG2-overexpressing cells, resulting in sensitization of the MDR cells. The reversal of MDR by alectinib was mediated by inhibition of ABCB1/ABCG2 transport function and by enhanced intracellular accumulation of anticancer substrate drugs.

Mentions: It has been reported that ABCB1 is expressed in both AML and CML.45, 46 To investigate whether alectinib could reverse ABCB1-mediated MDR in ex vivo, bone marrow samples were collected from resistant patients with AML or CML. Four of the eleven patient samples exhibited high expression of ABCB1 (Figure 7a). We then examined the effect of alectinib on the intracellular accumulation of Rho 123 in these ABCB1-overexpressing primary leukemia blast samples using flow cytometric analysis. As shown in Figure 7b and c, alectinib significantly increased the intracellular accumulation of Rho 123. In addition, we used MTT assays to assess the sensitization effect of alectinib in these samples. The result revealed that 1.5 μM alectinib significantly increased the sensitivity of all four samples to DOX, which exhibited similar efficiency to 10 μM VRP (Figure 7d). These results suggest that alectinib is able to sensitize ABCB1-overexpressing primary leukemia cells to conventional anticancer drugs, and thus, it might be useful in combination regimens to combat ABCB1-mediated MDR in the clinic. The schematic model illustrating the reversal of MDR by alectinib was showed in Figure 8.


Alectinib (CH5424802) antagonizes ABCB1- and ABCG2-mediated multidrug resistance in vitro , in vivo and ex vivo
A schematic model illustrating the reversal of MDR by alectinib. When the primary tumors were treated with chemotherapeutic agents, the sensitive cancer cells were killed, but the MDR cancer cells simultaneously became resistant to structurally and mechanistically distinct classes of anticancer drugs. Overexpressing ABCB1 or ABCG2 in the MDR cells resulted in an efflux of drugs across the membrane. In the presence of alectinib, the intracellular accumulation of conventional anticancer drugs was increased in the ABCB1- or ABCG2-overexpressing cells, resulting in sensitization of the MDR cells. The reversal of MDR by alectinib was mediated by inhibition of ABCB1/ABCG2 transport function and by enhanced intracellular accumulation of anticancer substrate drugs.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig8: A schematic model illustrating the reversal of MDR by alectinib. When the primary tumors were treated with chemotherapeutic agents, the sensitive cancer cells were killed, but the MDR cancer cells simultaneously became resistant to structurally and mechanistically distinct classes of anticancer drugs. Overexpressing ABCB1 or ABCG2 in the MDR cells resulted in an efflux of drugs across the membrane. In the presence of alectinib, the intracellular accumulation of conventional anticancer drugs was increased in the ABCB1- or ABCG2-overexpressing cells, resulting in sensitization of the MDR cells. The reversal of MDR by alectinib was mediated by inhibition of ABCB1/ABCG2 transport function and by enhanced intracellular accumulation of anticancer substrate drugs.
Mentions: It has been reported that ABCB1 is expressed in both AML and CML.45, 46 To investigate whether alectinib could reverse ABCB1-mediated MDR in ex vivo, bone marrow samples were collected from resistant patients with AML or CML. Four of the eleven patient samples exhibited high expression of ABCB1 (Figure 7a). We then examined the effect of alectinib on the intracellular accumulation of Rho 123 in these ABCB1-overexpressing primary leukemia blast samples using flow cytometric analysis. As shown in Figure 7b and c, alectinib significantly increased the intracellular accumulation of Rho 123. In addition, we used MTT assays to assess the sensitization effect of alectinib in these samples. The result revealed that 1.5 μM alectinib significantly increased the sensitivity of all four samples to DOX, which exhibited similar efficiency to 10 μM VRP (Figure 7d). These results suggest that alectinib is able to sensitize ABCB1-overexpressing primary leukemia cells to conventional anticancer drugs, and thus, it might be useful in combination regimens to combat ABCB1-mediated MDR in the clinic. The schematic model illustrating the reversal of MDR by alectinib was showed in Figure 8.

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