Hayashi Anna, Kamio Koichiro, Miyanaga Akihiko, Yoshida Keisuke, Noro Rintaro, Matsuda Kuniko, Tozuka Takehiro, Omori Miwako, Hirao Mariko, Fukuizumi Aya, Hisakane Kakeru, Takeuchi Susumu, Matsumoto Masaru, Kasahara Kazuo, Amano Takanori, Honda Kazufumi, Seike Masahiro
Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan;
Anticancer Res. 2024 Dec;44(12):5271-5282. doi: 10.21873/anticanres.17355.
BACKGROUND/AIM: Chemoresistance to paclitaxel (PTX) significantly ameliorates therapeutic efficacy in patients with non-small cell lung cancer (NSCLC), especially in advanced stages, deteriorating the progression free and overall survival rates. One of the critical mechanisms contributing to drug resistance is the excretion of PTX from target cells via efflux pumps. Ivermectin was developed as a bactericidal agent against parasites; however, it has recently been shown to inhibit the proliferation of human cancer cells. Hence, we aimed to evaluate the therapeutic potential of ivermectin in combination with PTX and investigate the molecular mechanisms by which ivermectin overcomes PTX resistance.
We assessed the antitumor effects of ivermectin in A549 cells treated with or without PTX. We also established PTX-resistant cells using this cell line and explored the underlying mechanisms. Additionally, we evaluated whether ivermectin attenuates PTX-resistance with the retrieval of drug sensitivity.
Combined treatment of A549 cells with PTX and ivermectin inhibited cell growth. These cells acquired chemoresistance upon long-term exposure to gradually increasing PTX concentrations, which was accompanied by ABCB1 mRNA up-regulation, and subsequent overproduction of P-glycoprotein (P-gp). Consistent with this, P-gp over-expression resulted in a PTX-resistant phenotype. Notably, the simultaneous ivermectin treatment during the gradual exposure completely abolished P-gp expression, leading to an increased intracellular PTX concentration and sustained PTX sensitivity. Ivermectin was found to regulate P-gp expression via the EGFR/ERK/Akt/NF-[Formula: see text]B pathway.
Combined treatment of PTX-resistant A549 cells with ivermectin and PTX may circumvent PTX resistance caused by P-gp induction, highlighting a novel therapeutic avenue for drug repurposing.
背景/目的：对紫杉醇（PTX）的化疗耐药性显著降低了非小细胞肺癌（NSCLC）患者的治疗效果，尤其是在晚期患者中，这使得无进展生存率和总生存率恶化。导致耐药的关键机制之一是PTX通过外排泵从靶细胞中排出。伊维菌素最初是作为一种抗寄生虫的杀菌剂开发的；然而，最近的研究表明它能抑制人类癌细胞的增殖。因此，我们旨在评估伊维菌素与PTX联合使用的治疗潜力，并研究伊维菌素克服PTX耐药性的分子机制。
我们评估了伊维菌素在接受或未接受PTX处理的A549细胞中的抗肿瘤作用。我们还使用该细胞系建立了PTX耐药细胞，并探索其潜在机制。此外，我们评估了伊维菌素是否通过恢复药物敏感性来减轻PTX耐药性。
PTX与伊维菌素联合处理A549细胞可抑制细胞生长。这些细胞在长期暴露于逐渐增加的PTX浓度后获得了化疗耐药性，这伴随着ABCB1 mRNA上调以及随后P-糖蛋白（P-gp）的过量产生。与此一致，P-gp的过表达导致了PTX耐药表型。值得注意的是，在逐渐暴露过程中同时使用伊维菌素处理完全消除了P-gp的表达，导致细胞内PTX浓度增加并持续保持PTX敏感性。发现伊维菌素通过EGFR/ERK/Akt/NF-κB途径调节P-gp的表达。
伊维菌素与PTX联合处理PTX耐药的A549细胞可能规避由P-gp诱导引起的PTX耐药性，为药物重新利用开辟了一条新的治疗途径。
