Shukla Alok, Sharma Arpit, Gupta Shivani, Mishra Abha, Singh Amit
Biomolecular Engineering Laboratory, School of Biochemical Engineering, Indian Institute of Technology (BHU), Varanasi, 221005, India.
Department of Pharmacology, Institute of Medical Science, Banaras Hindu University, Varanasi, 221005, India.
Med Oncol. 2025 Apr 21;42(5):169. doi: 10.1007/s12032-025-02726-0.
Ivermectin, a broad-spectrum antiparasitic agent from the ivermectin family, has shown promising anticancer potential. Originally developed for veterinary and human use against parasitic infections, ivermectin demonstrated significant antitumor effects in our study against tumor cells (Dalton's lymphoma cells). A dose-dependent decrease in tumor cell viability was observed following 24-h treatment with ivermectin, with an IC₅₀ value calculated at 10.55 µg/mL. In comparison, the standard anticancer drug cisplatin exhibited a slightly higher cytotoxic potency, with an IC₅₀ of 8.32 µg/mL under the same treatment duration. Flow cytometric analysis revealed that ivermectin induced cell cycle arrest in the G0-G1 phase. Apoptotic tumor cell death was confirmed via Annexin V/PI staining, further supported by nuclear condensation, a hallmark of apoptosis, visualized through both confocal microscopy and flow cytometry. The apoptosis was determined to be mitochondrial-dependent, as evidenced by a decline in mitochondrial membrane potential (ΔΨm) observed through JC-1 assay. The treatment increased DAPI-positive cells and exhibited severe chromatin condensation. Additionally, cell death was validated using Acridine Orange and Propidium Iodide staining, which highlighted increased cell membrane rupture and death through apoptosis and necrosis. Mitochondrial dependent apoptosis further supported by increased ROS production upon ivermectin treatment. Moreover, In vivo, ivermectin treatment led to a substantial reduction in tumor size in tumor-bearing mice, along with normalization of spleen size, body weight, and improvement histopathology of liver. These findings collectively support the therapeutic potential of ivermectin as a repurposed anticancer agent, acting through multiple mechanisms including cell cycle arrest, ROS generation, mitochondrial dysfunction, and apoptosis.
伊维菌素是一种来自伊维菌素家族的广谱抗寄生虫药物，已显示出有前景的抗癌潜力。伊维菌素最初开发用于兽医和人类对抗寄生虫感染，在我们针对肿瘤细胞（道尔顿淋巴瘤细胞）的研究中显示出显著的抗肿瘤作用。用伊维菌素处理24小时后，观察到肿瘤细胞活力呈剂量依赖性下降，计算得出的IC₅₀值为10.55μg/mL。相比之下，标准抗癌药物顺铂在相同处理持续时间下表现出略高的细胞毒性效力，IC₅₀为8.32μg/mL。流式细胞术分析显示，伊维菌素诱导细胞周期停滞在G0-G1期。通过膜联蛋白V/PI染色证实了凋亡性肿瘤细胞死亡，共聚焦显微镜和流式细胞术观察到的核浓缩（凋亡的标志）进一步支持了这一结果。通过JC-1检测观察到线粒体膜电位（ΔΨm）下降，证明凋亡是线粒体依赖性的。该处理增加了DAPI阳性细胞并表现出严重的染色质浓缩。此外，使用吖啶橙和碘化丙啶染色验证了细胞死亡，突出显示通过凋亡和坏死增加了细胞膜破裂和死亡。伊维菌素处理后ROS产生增加进一步支持了线粒体依赖性凋亡。此外，在体内，伊维菌素处理导致荷瘤小鼠的肿瘤大小大幅减小，同时脾脏大小、体重恢复正常，肝脏组织病理学得到改善。这些发现共同支持了伊维菌素作为一种重新利用的抗癌药物的治疗潜力，其作用机制包括细胞周期停滞、ROS生成、线粒体功能障碍和凋亡。
