Comparison of Cell-death Kinetics of Recombinant Methioninase (rMETase)-treated Cancer and Normal Cells: Only Cancer Cells Undergo Methionine-depletion Catastrophe at Low rMETase Concentrations.

Abstract

Background/aim: Methionine addiction, known as the Hoffman effect, makes cancer cells more sensitive to methionine restriction than normal cells. However, the long-term effects of methionine restriction on cancer and normal cells have not been thoroughly studied.

Materials and methods: HCT-116 human colorectal-cancer cells and Hs27 normal skin fibroblasts were treated with 0-8 U/ml of recombinant methioninase (rMETase) for 12 days. The cells were cultured in Dulbecco's modified Eagle's medium in 96-well tissue-culture plates.

Results: HCT-116 cells were sensitive to all concentrations of rMETase from 0.125 U/ml to 8 U/ml. After day-8 of treatment, HCT-116 cells were acutely sensitive to rMETase, especially at rMETase concentrations of 0.5 U/ml or higher. Normal Hs27 fibroblasts were much less sensitive to rMETase: In the range of 0.125 U/ml to 0.5 U/ml, rMETase had no effect on Hs27 cells. rMETase concentrations up to 2 U/ml had a slight initial effect on Hs27 cells, whereas at concentrations ranging from 4 U/ml to 8 U/ml, rMETase reduced Hs27 viability over the 12-day test period, with acute loss of viability observed after eight days of exposure.

Conclusion: Cancer cells were significantly more sensitive to rMETase than normal cells, with an acute loss of cell viability observed in cancer cells after eight days of treatment at concentrations of 0.5 U/ml or higher. These findings highlight the large difference in sensitivity between cancer and normal cells to rMETase and introduce the phenomenon of acute cell death in methionine restriction, which we term "methionine-depletion catastrophe".