Ceritinib Enhances the Efficacy of Substrate Chemotherapeutic Agent in Human ABCB1-Overexpressing Leukemia Cells In Vitro, In Vivo and Ex-Vivo

Abstract

Background/Aims: Multidrug resistance (MDR) triggered by ATP binding cassette (ABC) transporters, such as ABCB1, ABCC1, and ABCG2, is a key obstacle for successful cancer chemotherapy. There is currently no FDA-approved MDR modulator that can be used in clinic. Ceritinib, a selective ALK inhibitor, has been approved as the second-line treatment for ALK-positive non-small cell lung cancer. Here, we examined the role of ceritinib in leukemia associated MDR in therapy. Methods: The cell proliferation was detected by MTT assay. The flow cytometry was used to detect the expression of cell surface protein and to detect the accumulation and efflux of rhodamine 123 (Rh123) or doxorubicin (Dox) in cells. The RT-PCR and Western blot were performed to detect the gene expression and protein expression levels, respectively. Results: We found that ceritinib enhanced the efficacy of substrate chemotherapeutic agent in ABCB1-overexpressing K562/adr leukemia cells both in vitro and in vivo models, but neither in sensitive parental K562 leukemia cells nor in ABCC1-overexpressing HL-60/adr leukemia cells. Mechanistically, ceritinib significantly increased the intracellular accumulation of Rh123 or Dox but did neither alter ABCB1 expressions at both protein and mRNA levels nor block the phosphorylations of AKT and ERK1/2 at the concentration of MDR reversal. Importantly, ceritinib also increased the intracellular accumulation of Dox and enhanced the efficacy of Dox in primary leukemia cells in ex-vivo. Conclusion: Our results suggested that ceritinib enhanced the efficacy of substrate chemotherapeutic agent on inhibition of leukemia cell growth in vitro, in vivo and ex-vivo, which linked to block ABCB1 function, pumping out its substrate conventional chemotherapeutic agent, thereby increasing the intracellular accumulation. These suggest the combination of ceritinib and substrate chemotherapeutic drugs maybe an effective treatment of resistant leukemia patients with ABCB1-mediated MDR.

Olmutinib Reverses Doxorubicin Resistance in ETS1-Overexpressing Leukemia Cells

“…To determine whether ETS1 and ABCB1 were involved in Dox resistance in leukemia, we assessed their protein and mRNA expression in the K562/ADR cell line. Consistent with the database and previous studies [ 15 , 16 ], results showed that EST1 and ABCB1 were significantly up-regulated in Dox-resistant leukemia cells ( Figure 1 ), indicating the stimulative effect of ETS1 and ABCB1 on Dox resistance in leukemia.…”

<p>Pharmacokinetic-Based Drug–Drug Interactions with Anaplastic Lymphoma Kinase Inhibitors: A Review</p>

“…16,56 Ceritinib may have the potential to increase the plasma concentrations of co-administered drugs that are transported by P-gp and BCRP. 56,57 Caution should be exercised with the concomitant use of P-gp and BCRP substrates. 16 Alectinib Alectinib is not a substrate for P-gp, BCRP, or OATP1B1/ 3, but M4 is a substrate for P-gp.…”

Sitravatinib, a Tyrosine Kinase Inhibitor, Inhibits the Transport Function of ABCG2 and Restores Sensitivity to Chemotherapy-Resistant Cancer Cells in vitro

“…However, high toxicity and drug-drug interactions remain to be a challenge (39). To date, many researchers using in vivo and ex vivo models have demonstrated that TKIs have ability to restore the sensitivity of substrate antineoplastic drugs of ABC transporters for effective chemotherapy (40)(41)(42)(43). Most recently, Chen et al conducted a phase I clinical evaluation in a population of patients to reveal that cyclosporine A (CsA), a competitive ABCB1 inhibitor, could combat drug resistance caused by brentuximab vedotin in relapsed/refractory Hodgkin lymphoma with tolerable and feasible profile (44).…”