Antitumor potential of ivermectin against T-cell lymphoma-bearing hosts

Abstract

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.

Keywords: Antitumor; Apoptosis; Cell cycle arrest; Ivermectin; T cell Lymphoma.