Ardjmand Daniel, Kubota Yutaro, Sato Motokazu, Han Qinghong, Mizuta Kohei, Morinaga Sei, Hoffman Robert M
AntiCancer Inc., San Diego, CA, U.S.A.
Department of Surgery, University of California San Diego, San Diego, CA, U.S.A.
Anticancer Res. 2024 Mar;44(3):929-933. doi: 10.21873/anticanres.16887.
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.
The half-maximal inhibitory concentrations (IC) 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 IC of each drug, we determined the efficacy of rapamycin and rMETase combined on both HCT-116 and Hs-27.
Hs-27 normal fibroblasts were more sensitive to rapamycin than HCT-116 colon-cancer cells (IC=0.37 nM and IC=1.38 nM, respectively). HCT-116 cells were more sensitive to rMETase than Hs-27 cells (IC 0.39 U/ml and IC 0.96 U/ml, respectively). The treatment of Hs-27 cells with the combination of rapamycin (IC=0.37 nM) and rMETase (IC=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 (IC=1.38 nM) and rMETase (IC=0.39 U/ml) was able to decrease cancer-cell viability significantly more than either single-drug treatment.
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.
背景/目的：雷帕霉素和重组蛋氨酸酶（rMETase）均已显示出对癌细胞的靶向作用。雷帕霉素通过抑制mTOR蛋白激酶来阻止癌细胞生长。rMETase通过降解蛋氨酸来靶向癌细胞对蛋氨酸的依赖，并且已证明可提高化疗药物的疗效。在本研究中，我们旨在确定雷帕霉素和rMETase联合用于体外抗结肠癌细胞系时与正常成纤维细胞相比是否存在协同作用。
使用CCK-8细胞活力测定法测定雷帕霉素单独和rMETase单独对HCT-116人结肠癌细胞系和Hs-27人成纤维细胞的半数最大抑制浓度（IC）。计算每种药物的IC后，我们确定了雷帕霉素和rMETase联合对HCT-116和Hs-27的疗效。
Hs-27正常成纤维细胞对雷帕霉素比HCT-116结肠癌细胞更敏感（IC分别为0.37 nM和1.38 nM）。HCT-116细胞对rMETase比Hs-27细胞更敏感（IC分别为0.39 U/ml和0.96 U/ml）。用雷帕霉素（IC = 0.37 nM）和rMETase（IC = 0.96 U/ml）联合处理Hs-27细胞，与单独使用这两种药物相比，其对Hs-27细胞活力的影响无显著差异。然而，用雷帕霉素（IC = 1.38 nM）和rMETase（IC = 0.39 U/ml）联合处理HCT-116细胞比单一药物处理能更显著地降低癌细胞活力。
雷帕霉素和rMETase在体外联合用于抗结肠癌细胞而非正常成纤维细胞时具有癌症特异性协同作用，表明这些药物联合可作为一种有效的靶向癌症治疗方法。
