Modulation of the tumor microenvironment by zerumbone and 5-fluorouracil in colorectal cancer by target in cancer-associated fibroblasts.

BACKGROUND: This research aimed at the evaluation of the incremental effect(s) of combination therapy on colorectal cancer-associated fibroblasts (CAFs) in vivo and in vitro models of CRC. Drug resistance decreases the effectiveness of treatment for colorectal cancer (CRC) patients. CAFs, the main cells in the tumor stroma, contribute essentially to cancer drug resistance. Zerumbone (ZER) has been used for its anti-tumorigenic feature in various cancers. Also, 5-fluorouracil (5-FU) resistance is widely reported in advanced CRC patients. The possible impacts of combination therapy (or polytherapy is therapy that uses more than one medication or modality) with the use of herbs combined with chemical medicines may lead to improvement in patients' responses. METHODS: According to the research design, the influence of 5-FU and ZER on the viability of the CT-26 cell line was examined through the MTT assay, and the size and dimension of the tumors were measured after 21 days of therapy in CRC BALB/c mice, and then the CAF cells were separated from the tissues of the tumors. Genes' mRNA expression and also the level of the proteins of the genes of interest (Survivin, Vimentin, & β -catenin) were evaluated using qRT-PCR and Western blotting on CT-26 and mouse-isolated CAF cells. RESULTS AND CONCLUSIONS: We showed that ZER and 5-FU significantly increased our gene expression in the CT-26 cell line and isolated CAFs in the level of protein and mRNA in comparison to the controls (ZER-treated, untreated, & 5-FU-treated). Moreover, evaluating the size of the tumor in ZER and 5-FU-treated groups demonstrated a remarkable decline, which exhibited higher prominence in the group of combination therapy. A combination of natural and chemical drugs can largely enhance the effectiveness of cancer therapy.