Laboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, 1-5 Beichenxilu Rd., Chaoyang, Beijing, 100101, China.
University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China.
J Exp Clin Cancer Res. 2019 Jun 18;38(1):265. doi: 10.1186/s13046-019-1251-7.
Discovery and development of novel drugs that are capable of overcoming drug resistance in tumor cells are urgently needed clinically. In this study, we sought to explore whether ivermectin (IVM), a macrolide antiparasitic agent, could overcome the resistance of cancer cells to the therapeutic drugs.
We used two solid tumor cell lines (HCT-8 colorectal cancer cells and MCF-7 breast cancer cells) and one hematologic tumor cell line (K562 chronic myeloid leukemia cells), which are resistant to the chemotherapeutic drugs vincristine and adriamycin respectively, and two xenograft mice models, including the solid tumor model in nude mice with the resistant HCT-8 cells and the leukemia model in NOD/SCID mice with the resistant K562 cells to investigate the reversal effect of IVM on the resistance in vitro and in vivo. MTT assay was used to investigate the effect of IVM on cancer cells growth in vitro. Flow cytometry, immunohistochemistry, and immunofluorescence were performed to investigate the reversal effect of IVM in vivo. Western blotting, qPCR, luciferase reporter assay and ChIP assay were used to detect the molecular mechanism of the reversal effect. Octet RED96 system and Co-IP were used to determine the interactions between IVM and EGFR.
Our results indicated that ivermectin at its very low dose, which did not induce obvious cytotoxicity, drastically reversed the resistance of the tumor cells to the chemotherapeutic drugs both in vitro and in vivo. Mechanistically, ivermectin reversed the resistance mainly by reducing the expression of P-glycoprotein (P-gp) via inhibiting the epidermal growth factor receptor (EGFR), not by directly inhibiting P-gp activity. Ivermectin bound with the extracellular domain of EGFR, which inhibited the activation of EGFR and its downstream signaling cascade ERK/Akt/NF-κB. The inhibition of the transcriptional factor NF-κB led to the reduced P-gp transcription.
These findings demonstrated that ivermectin significantly enhanced the anti-cancer efficacy of chemotherapeutic drugs to tumor cells, especially in the drug-resistant cells. Thus, ivermectin, a FDA-approved antiparasitic drug, could potentially be used in combination with chemotherapeutic agents to treat cancers and in particular, the drug-resistant cancers.
临床上急需发现和开发能够克服肿瘤细胞耐药性的新型药物。在这项研究中，我们试图探索伊维菌素（IVM）能否克服癌细胞对治疗药物的耐药性。
我们使用两种实体瘤细胞系（HCT-8 结肠癌细胞和 MCF-7 乳腺癌细胞）和一种血液瘤细胞系（K562 慢性髓性白血病细胞），它们分别对化疗药物长春新碱和阿霉素耐药，以及两种异种移植小鼠模型，包括耐 HCT-8 细胞的裸鼠实体瘤模型和耐 K562 细胞的 NOD/SCID 小鼠白血病模型，研究 IVM 对体内外耐药性的逆转作用。MTT 法检测 IVM 对体外癌细胞生长的影响。流式细胞术、免疫组化和免疫荧光法检测 IVM 的体内逆转作用。Western blot、qPCR、荧光素酶报告基因检测和 ChIP 检测用于检测逆转作用的分子机制。Octet RED96 系统和 Co-IP 用于确定 IVM 与 EGFR 之间的相互作用。
我们的结果表明，伊维菌素在非常低的剂量下，不会引起明显的细胞毒性，就能在体外和体内显著逆转肿瘤细胞对化疗药物的耐药性。从机制上讲，伊维菌素主要通过抑制表皮生长因子受体（EGFR）来降低 P-糖蛋白（P-gp）的表达，从而逆转耐药性，而不是直接抑制 P-gp 活性。伊维菌素与 EGFR 的细胞外结构域结合，抑制 EGFR 的激活及其下游信号级联 ERK/Akt/NF-κB。转录因子 NF-κB 的抑制导致 P-gp 转录减少。
这些发现表明，伊维菌素显著增强了化疗药物对肿瘤细胞的抗癌疗效，特别是在耐药细胞中。因此，伊维菌素，一种 FDA 批准的抗寄生虫药物，可能与化疗药物联合用于治疗癌症，特别是耐药性癌症。
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