Mitomycin C enhanced the antitumor efficacy of Rocaglamide in colorectal cancer.

Rocaglamide (ROC), a natural phytochemical isolated from Aglaia species, is a translational inhibitor of de novo c-FLIP synthesis, which relieves the inhibition of c-FLIP dimerization with procasoase-8 and downstream activation. Unfortunately, a lot of cancer cells, especially colorectal cancer cells (CRC), exhibit marked resistance to Rocaglamide-induced cell death. Research has demonstrated that mitomycin C (MMC) has broad-spectrum anti-tumor activity that it can synergize with a wide range of clinical drugs to inhibit tumor growth. The current study investigated whether MMC combined with ROC could sensitize CRC cells with different ROC resistance to apoptosis. HCT116 and HT29, two different CRC cells, were treated with ROC and/or MMC, and the induction of apoptosis, inhibition of cell migration and invasion, arrest of cell cycle, induction of reactive oxygen species, and effects on Bcl-2 family signaling pathway were investigated. The results showed that low concentration of MMC combined with ROC significantly promoted HCT116 and HT29 cell apoptosis and inhibited cell proliferation by downregulating the expression of Bcl-2 and c-FLIP, upregulating the expression of Bax, activating the caspase cascade (involving the mitochondrial apoptosis pathway), arresting cell cycle in G1 phase, and increasing the level of reactive oxygen species (ROS). In addition, the viability and morphology of MRC-5 cells were not significantly affected by the combined treatment with ROC and MMC, indicating its safety. Therefore, it is concluded that the combination treatment of ROC and MMC is a highly effective tumor therapy and may offer a promising therapeutic strategy for the treatment of CRC.