The Combination of Recombinant Methioninase and Low-dose Chloroquine Selectively Eradicates Colon-Cancer Cells Without Apparent Toxicity on Co-cultured Normal Fibroblasts.

BACKGROUND/AIM: Methionine addiction is a metabolic hallmark of cancer. Recombinant methioninase (rMETase) targets methionine addiction and effectively depletes methionine. rMETase has shown synergy with chemotherapeutic agents on numerous types of cancer cells. Chloroquine (CQ), an anti-autophagy agent, has demonstrated anti-cancer efficacy in pre-clinical studies. The present study aimed to evaluate the cancer selectivity and synergistic efficacy of rMETase and CQ in a co-culture model of colon-cancer cells and normal fibroblasts.

MATERIALS AND

METHODS

HCT116 human colon-cancer cells and Hs-27 human normal fibroblasts were co-cultured in Dulbecco's Modified Eagle's Medium (DMEM) and treated with rMETase (0.1-0.5 U/ml) alone, CQ (10-60 μM) alone, or rMETase at various concentrations in combination with CQ (20 μM). Cell morphology and viability were monitored for six days using phase-contrast microscopy (Olympus IX71). The effects of each treatment on the cancer cells and normal fibroblasts were compared.

RESULTS

rMETase treatment selectively reduced HCT116 viability in a dose-dependent manner while sparing normal fibroblasts. In contrast, high-concentrations of CQ decreased the viability of both cell types, with strong cytotoxicity at ≥40 μM. Combination treatment with rMETase and low-dose CQ (20 μM) produced greater selective efficacy against the cancer cells than rMETase alone, eliminating the cancer cells and without significant inhibition of fibroblast viability.

CONCLUSION

rMETase has selective efficacy against cancer cells in the presence of normal cells, and its efficacy is significantly enhanced selectively on the cancer cells by CQ. The results of the present study suggest the potential for future clinical application of the combination of rMETase and CQ for cancer treatment.