Abstract
Objectives. Chemotherapy is considered to be essential in the treatment of patients with colorectal cancer (CRC), but drug resistance reduces its efficacy. Many patients with advanced CRC eventually show resistance to 5-fluorouracil (5-FU) therapy. Synergistic and potentiating effects of combination therapy, using herbal and chemical drugs, can improve patients’ response. Zerumbone (ZER), which is derived from ginger, has been studied for its growth inhibitory function in various types of cancer. Methods. The cytotoxic effects of ZER and 5-FU alone and their combination, on the SW48 and HCT-116 cells, were examined, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT). The mRNA and protein levels of β-catenin, survivin, and vimentin were measured in treated CRC cells, using qRT-PCR and western blot. Colony formation assay, scratch test, and flow cytometry were performed to detect the changes of proliferation, migration, and apoptosis. Key Findings. In HCT-116- and SW48-treated cells, the proliferation, the gene and protein expression levels of the markers, the migration, the colony formation, and the survival rates were all significantly reduced compared to the control groups, and the sharpest decline was observed in the 5-FU+ZER treatment groups. Conclusions. Combination therapy has shown promising results in CRC cells, especially in drug-resistant cells.
Highlights
colorectal cancer (CRC) is one of the most common diseases in industrialized countries and is currently the third most common cause of cancer-related deaths in males and the second most in females worldwide [1]. 5-FU is commonly used as a chemotherapeutic drug in cancer treatments and in combination with other drugs to treat many types of cancers including breast, anal, stomach, head, and neck cancer [2]
Epithelial-mesenchymal transition (EMT) is a very complex yet well-known process in cancer cells that is an essential stage in tumor metastasis and invasion [5, 6]
Zerumbone (z3902-50M),HPLC grade ≥ 98%purity, and dimethyl sulfoxide (DMSO) were purchased from SigmaAldrich; ZER was prepared in stock solution of 1 mM (MW 218.23 g/mol) using DMSO; the final concentration of DMSO for in vitro study was less than 0.01%; the different concentrations of ZER ranging from 0 to 100 μM were prepared from 1 mM stock
Summary
CRC is one of the most common diseases in industrialized countries and is currently the third most common cause of cancer-related deaths in males and the second most in females worldwide [1]. 5-FU is commonly used as a chemotherapeutic drug in cancer treatments and in combination with other drugs to treat many types of cancers including breast, anal, stomach, head, and neck cancer [2]. As drug resistance remains a major clinical problem for the clinical application of 5-FU and related chemotherapeutic drugs, investigating the molecular pathways and genes, responsible for therapeutic resistance to 5-FU in CRC, offers insights into mechanisms of cell survival, developing more responsive therapeutic targets [2, 4]. EMT is associated with several signaling pathways, including the transforming growth factor-β (TGF-β), Wnt, Hedgehog, and Notch pathways, and it can affect the involved genes such as β-catenin which is activated in the Wnt pathway [8]. The Wnt/β-catenin signaling pathway, called the canonical Wnt pathway, is a major regulating signaling pathway in BioMed Research International several cancers due to its effect on the transcription of the targeted genes [9]. Inhibition of Wnt/β-catenin signaling could increase sensitivity to chemotherapeutic agents in cancers [10]. β-Catenin is the main mediator of this pathway that is widely expressed in many tissues
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