Louvain centre for Toxicology and Applied Pharmacology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.
Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
Sci Rep. 2016 Jul 12;6:29559. doi: 10.1038/srep29559.
Overexpression of ABCB1 (also called P-glycoprotein) confers resistance to multiple anticancer drugs, including tyrosine kinase inhibitors (TKIs). Several ABCB1 single nucleotide polymorphisms affect the transporter activity. The most common ABCB1 variants are 1236C > T, 2677G > T, 3435C > T and have been associated with clinical response to imatinib in chronic myelogenous leukaemia (CML) in some studies. We evaluated the impact of these polymorphisms on the anti-proliferative effect and the intracellular accumulation of TKIs (imatinib, nilotinib, dasatinib and ponatinib) in transfected HEK293 and K562 cells. ABCB1 overexpression increased the resistance of cells to doxorubicin, vinblastine and TKIs. Imatinib anti-proliferative effect and accumulation were decreased to a larger extent in cells expressing the ABCB1 wild-type protein compared with the 1236T-2677T-3435T variant relatively to control cells. By contrast, ABCB1 polymorphisms influenced the activity of nilotinib, dasatinib and ponatinib to a much lesser extent. In conclusion, our data suggest that wild-type ABCB1 exports imatinib more efficiently than the 1236T-2677T-3435T variant protein, providing a molecular basis for the reported association between ABCB1 polymorphisms and the response to imatinib in CML. Our results also point to a weaker impact of ABCB1 polymorphisms on the activity of nilotinib, dasatinib and ponatinib.
ABCB1（也称为 P-糖蛋白）的过度表达导致对多种抗癌药物（包括酪氨酸激酶抑制剂[TKI]）产生耐药性。几种 ABCB1 单核苷酸多态性影响转运体的活性。最常见的 ABCB1 变体是 1236C>T、2677G>T、3435C>T，在一些研究中与慢性髓系白血病（CML）中对伊马替尼的临床反应相关。我们评估了这些多态性对转染的 HEK293 和 K562 细胞中 TKI（伊马替尼、尼罗替尼、达沙替尼和泊那替尼）的增殖抑制作用和细胞内积累的影响。ABCB1 过表达增加了细胞对多柔比星、长春新碱和 TKI 的耐药性。与对照细胞相比，表达 ABCB1 野生型蛋白的细胞中伊马替尼的增殖抑制作用和积累减少程度更大，而 1236T-2677T-3435T 变体相对较少。相比之下，ABCB1 多态性对尼罗替尼、达沙替尼和泊那替尼的活性影响要小得多。总之，我们的数据表明，野生型 ABCB1 比 1236T-2677T-3435T 变体蛋白更有效地将伊马替尼输出，为报道的 ABCB1 多态性与 CML 中对伊马替尼的反应之间的关联提供了分子基础。我们的结果还表明，ABCB1 多态性对尼罗替尼、达沙替尼和泊那替尼的活性影响较弱。
