Selective Synergy of Ivermectin Combined With Recombinant Methioninase Against Colon-Cancer Cells in Contrast to Normal Fibroblasts

Abstract

Background/aim: Recent studies have shown that ivermectin, developed as an anti-parasitic drug, has efficacy against several cancer types. Methionine restriction, including the use of recombinant methioninase (rMETase), has been developed to target methionine addiction, a fundamental hallmark of cancer, termed the Hoffman effect. Metastatic colorectal cancer (CRC) is a recalcitrant disease that requires novel and disruptive treatment approaches. The present study aimed to determine the efficacy of ivermectin in combination with rMETase on a CRC cell line compared to normal fibroblasts.

Materials and methods: The human CRC cell line HCT-116 and normal human fibroblasts Hs27 were seeded at a density of 1,000 cells per well in 96-well plates and cultured overnight at 37°C. After treatment with ivermectin (0.5 μM to 128 μM) or rMETase (0.0625 U/ml to 8 U/ml) for 72 h, cell viability was assessed using the WST-8 reagent to determine the half-maximal inhibitory concentration (IC₅₀) values for ivermectin and rMETase on both cell lines. Using these IC₅₀ values, cell-viability assays for ivermectin alone, rMETase alone, and the combination of ivermectin and rMETase were performed on both cell lines to determine their synergy.

Results: The IC₅₀ value for ivermectin alone was 4.81 μM and rMETase alone was 0.61 U/ml against HCT-116 colon-cancer cells. The IC₅₀ value for ivermectin alone was 8.67 μM and rMETase alone was 0.67 U/ml against Hs27 normal fibroblasts. In HCT-116 cells, treatment with the combination of ivermectin and rMETase resulted in greater reduction of cell proliferation, compared to treatment with each drug alone; however, no synergy was observed against Hs27 cells.

Conclusion: rMETase and ivermectin showed selective synergistic anti-cancer efficacy against colon-cancer cells, indicating the clinical potential of the combination for metastatic CRC.

Keywords: Hoffman effect; Ivermectin; colorectal cancer; combination; methionine addiction; normal fibroblasts; recombinant methioninase (rMETase); synergy.