Development of imatinib and dasatinib resistance: dynamics of expression of drug transportersABCB1, ABCC1, ABCG2, MVP, and SLC22A1

Abstract

About 20% of patients with chronic myeloid leukemia (CML) do not respond to treatment with imatinib either initially or because of acquired resistance. To study the development of CML drug resistance, an in vitro experimental system comprising cell lines with different resistance levels was established by exposing K562 cells to increasing concentrations of imatinib and dasatinib anticancer agents. The mRNA levels of BCR- ABL1 and of genes involved in drug transport or redistribution (ABCB1, ABCC1, ABCC3, ABCG2, MVP, and SLC22A1) were measured and the ABL1 kinase domain sequenced. Results excluded BCR- ABL1 overexpression and mutations as relevant resistance mechanisms. Most studied transporters were overexpressed in the majority of resistant cell lines. Their expression pattern was dynamic: varying with resistance level and chronic drug exposure. Studied efflux transporters may have an important role at the initial stages of resistance, but after prolonged exposure and for higher doses of drugs other mechanisms might take place.

Overexpression of lncRNA NEAT1 mitigates multidrug resistance by inhibiting ABCG2 in leukemia

“…It is well known that ABCG2 has important roles in MDR in leukemia (20,21). Therefore, to evaluate the effects of NEAT1 on the MDR of leukemic cells, the expression level of ABCG2 was detected by western blotting.…”

Transport of six tyrosine kinase inhibitors: active or passive?

“…However, Giannoudis et al [42] postulated that the uptake is likely passive diffusion because of the lipophilic properties of dasatinib. On the other hand, they state that the role of other uptake transporters could not be excluded [43]. In our hands there is a clear difference between 4 °C and 37 °C, indicating an active transport.…”

“…De Vries et al [45] also suggested the involvement of P-gp in the efflux of erlotinib. Giannoudis et al [42] and Gromicho et al [43] suggested that P-gp is also involved in dasatinib dependent efflux. The effect of hOCT inhibitors on sunitinib and crizotinib was similar, except for verapamil.…”

“…Nevertheless, Giannoudis et al [42] suggested that the uptake of dasatinib is not likely to be dependent on hOCT1 (on basolateral side). Also Gromicho et al [43] suggested that effective uptake of dasatinib is not likely to occur with the help of hOCT1. Forchap et al [47] concluded that dasatinib is not primarily transported by hOCT1.…”

Anticancer compounds from cyanobacterium Lyngbya species: a review

“…For example, imatinib and dasatinib are the most preferred synthetic drugs among many, against chronic myeloid leukemia (CML) and colorectal cancer. However, in the accelerated phase of CML and the advanced stage of colorectal cancer, the emerged drug-resistant cancer cells predominate, with eventual metastatic invasion of cancer to internal tissue, resulting in the transfer of patients to hospice (Hochhaus et al 2007;Gromicho et al 2011). Moreover, drug-resistant cancer cells need be addressed suitably to overcome the impasse in treatment; most established anticancer drugs cannot be replaced ordinarily, due to sporadic developments of resistant cancer stem cells.…”