Selective Synergy of Rapamycin Combined With Methioninase on Cancer Cells Compared to Normal Cells

Abstract

Background/aim: Rapamycin and recombinant methioninase (rMETase) have both shown efficacy to target cancer cells. Rapamycin prevents cancer-cell growth by inhibition of the mTOR protein kinase. rMETase, by degrading methionine, targets the methionine addiction of cancer and has been shown to improve the efficacy of chemotherapy drugs. In the present study, we aimed to determine if a synergy exists between rapamycin and rMETase when used in combination against a colorectal-carcinoma cell line, compared to normal fibroblasts, in vitro.

Materials and methods: The half-maximal inhibitory concentrations (IC₅₀) of rapamycin alone and rMETase alone against the HCT-116 human colorectal-cancer cell line and Hs-27 human fibroblasts were determined using the CCK-8 Cell Viability Assay. After calculating the IC₅₀ of each drug, we determined the efficacy of rapamycin and rMETase combined on both HCT-116 and Hs-27.

Results: Hs-27 normal fibroblasts were more sensitive to rapamycin than HCT-116 colon-cancer cells (IC₅₀=0.37 nM and IC₅₀=1.38 nM, respectively). HCT-116 cells were more sensitive to rMETase than Hs-27 cells (IC₅₀ 0.39 U/ml and IC₅₀ 0.96 U/ml, respectively). The treatment of Hs-27 cells with the combination of rapamycin (IC₅₀=0.37 nM) and rMETase (IC₅₀=0.96 U/ml) showed no significant difference in their effect on Hs-27 cell viability compared to the two drugs being used separately. However, the treatment of HCT-116 cells with the combination of rapamycin (IC₅₀=1.38 nM) and rMETase (IC₅₀=0.39 U/ml) was able to decrease cancer-cell viability significantly more than either single-drug treatment.

Conclusion: Rapamycin and rMETase, when used in combination against colorectal-cancer cells, but not normal fibroblasts, in vitro, have a cancer-specific synergistic effect, suggesting that the combination of these drugs can be used as an effective, targeted cancer therapy.

Keywords: HCT-116; Hoffman effect; Hs-27; IC50; Methioninase; SAM; SAMTOR; cancer cells; combination; mTOR; methionine addiction; normal cells; rMETase; rapamycin; synergy.