Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
Toxicol Appl Pharmacol. 2024 Mar;484:116866. doi: 10.1016/j.taap.2024.116866. Epub 2024 Feb 15.
ABC transporter-mediated multidrug resistance (MDR) remains a major obstacle for cancer pharmacological treatment. Some tyrosine kinase inhibitors (TKIs) have been shown to reverse MDR. The present study was designed to evaluate for the first time whether foretinib, a multitargeted TKI, can circumvent ABCB1 and ABCG2-mediated MDR in treatment-resistant cancer models.
Accumulation of fluorescent substrates of ABCB1 and ABCG2 in ABCB1-overexpressing MES-SA/DX5 and ABCG2-overexpressing MCF-7/MX and their parenteral cells was evaluated by flow cytometry. The growth inhibitory activity of single and combination therapy of foretinib and chemotherapeutic drugs on MDR cells was examined by MTT assay. Analysis of combined interaction effects was performed using CalcuSyn software.
It was firstly proved that foretinib increased the intracellular accumulation of rhodamine 123 and mitoxantrone in MES-SA/DX5 and MCF-7/MX cancer cells, with accumulation ratios of 12 and 2.2 at 25 μM concentration, respectively. However, it did not affect the accumulation of fluorescent substrates in the parental cells. Moreover, foretinib synergistically improved the cytotoxic effects of doxorubicin and mitoxantrone. The means of combination index (CI) values at fraction affected (Fa) values of 0.5, 0.75, and 0.9 were 0.64 ± 0.08 and 0.47 ± 0.09, in MES-SA/DX5 and MCF-7/MX cancer cells, respectively. In silico analysis also suggested that the drug-binding domain of ABCB1 and ABCG2 transporters could be considered as potential target for foretinib.
Overall, our results suggest that foretinib can target MDR-linked ABCB1 and ABCG2 transporters in clinical cancer therapy.
ABC 转运蛋白介导的多药耐药（MDR）仍然是癌症药物治疗的主要障碍。一些酪氨酸激酶抑制剂（TKIs）已被证明可以逆转 MDR。本研究旨在首次评估多靶点 TKI 福替尼是否可以在耐药性癌症模型中绕过 ABCB1 和 ABCG2 介导的 MDR。
通过流式细胞术评估 ABCB1 过表达的 MES-SA/DX5 和 ABCG2 过表达的 MCF-7/MX 及其亲本细胞中 ABCB1 和 ABCG2 荧光底物的积累。MTT 法检测福替尼单药及联合化疗药物对 MDR 细胞的生长抑制活性。使用 CalcuSyn 软件分析联合作用的相互影响。
首次证明福替尼增加了 rhodamine 123 和米托蒽醌在 MES-SA/DX5 和 MCF-7/MX 癌细胞中的细胞内积累，在 25 μM 浓度下分别为 12 和 2.2 的积累比。然而，它并不影响荧光底物在亲本细胞中的积累。此外，福替尼协同增强了多柔比星和米托蒽醌的细胞毒性作用。在 Fa 值为 0.5、0.75 和 0.9 时，组合指数（CI）值的平均值分别为 0.64±0.08 和 0.47±0.09，在 MES-SA/DX5 和 MCF-7/MX 癌细胞中。计算机分析还表明，ABCB1 和 ABCG2 转运蛋白的药物结合域可被视为福替尼的潜在靶标。
总的来说，我们的研究结果表明福替尼可以作为临床癌症治疗中针对 MDR 相关 ABCB1 和 ABCG2 转运蛋白的药物。
