A systematic review of the therapeutic effects of resveratrol in combination with 5-fluorouracil during colorectal cancer treatment: with a special focus on the oxidant, apoptotic, and anti-inflammatory activities

Abstract

Purpose: 5-fluorouracil (5-FU), an effective chemotherapy drug, is commonly applied for colorectal cancer treatment. Nevertheless, its toxicity to normal tissues and the development of tumor resistance are the main obstacles to successful cancer chemotherapy and hence, its clinical application is limited. The use of resveratrol can increase 5-FU-induced cytotoxicity and mitigate the unwanted adverse effects. This study aimed to review the potential therapeutic effects of resveratrol in combination with 5-FU against colorectal cancer.

Methods: According to the PRISMA guideline, a comprehensive systematic search was carried out for the identification of relevant literature in four electronic databases of PubMed, Web of Science, Embase, and Scopus up to May 2021 using a pre-defined set of keywords in their titles and abstracts. We screened 282 studies in accordance with our inclusion and exclusion criteria. Thirteen articles were finally included in this systematic review.

Results: The in vitro findings showed that proliferation inhibition of colorectal cancer cells in the groups treated by 5-FU was remarkably higher than the untreated groups and the co-administration of resveratrol remarkably increased cytotoxicity induced by 5-FU. The in vivo results demonstrated a decrease in tumor growth of mice treated by 5-FU than the untreated group and a dramatic decrease was observed following combined treatment of resveratrol and 5-FU. It was also found that 5-FU alone and combined with resveratrol could regulate the cell cycle profile of colorectal cancer cells. Moreover, this chemotherapeutic agent induced the biochemical and histopathological changes in the cancerous cells/tissues and these alterations were synergized by resveratrol co-administration (for most of the cases), except for the inflammatory mediators.

Conclusion: The results obtained from this systematic review demonstrated that co-administration of resveratrol could sensitize the colorectal cancer cells to 5-FU treatment via various mechanisms, including regulation of cell cycle distribution, oxidant, apoptosis, anti-inflammatory effects.

Keywords: 5-fluorouracil; Chemotherapy; Colorectal cancer; Resveratrol; Systemic review.

Fig. 1

Chemical structure of resveratrol

Fig. 2

Flow diagram of PRISMA applied in the current systematic study for selection process

Fig. 3

The molecular mechanisms of resveratrol co-treatment during colorectal cancer treatment by 5-fluorouracil (5-FU) chemotherapeutic agent. Resveratrol exerts the synergistic anti-tumoral effects through increments in oxidant and apoptosis activities, and reduction in inflammatory effects. ↑↑synergistically increased by 5-FU plus resveratrol compared to 5-FU alone; ↑↑synergistically decreased by 5-FU plus resveratrol compared to 5-FU alone; ↓decreased by 5-FU plus resveratrol compared to 5-FU alone; Bcl-xL, B-cell lymphoma-extra large; BAX, Bcl-2-associated X protein; GPx, glutathione peroxidase; IL-6, interleukin 6; IKK, IκBα kinase; LPO, lipid peroxidation; ROS, reactive oxygen species; NF-κB, nuclear factor-kappa B; COX-2, cyclooxygenase-2; TNF-α, tumor necrosis factor alpha.; MMP-9, matrix metalloproteinase-9