Resveratrol synergistically augments anti-tumor effect of 5-FU in vitro and in vivo by increasing S-phase arrest and tumor apoptosis

Abstract

Many studies have shown that natural dietary agents, in combination with chemical agents, can improve the therapeutic response of cancers to chemotherapy and reduce the associated side-effects. In the present study, we investigated the therapeutic potential and mechanisms of anticancer effects for the combination of 5-fluorouracil (5-FU) and resveratrol (Res). In these studies, we employed the cancer cell lines TE-1 and A431 and an animal model of skin cancer. The presented results provide the first evidence that Res can enhance the anti-tumor potency of 5-FU by inducing S-phase arrest. The combination of Res and 5-FU demonstrates synergistic efficacy, causing tumor regression in a two-stage model of mouse skin carcinogenesis induced by DMBA and TPA. There was clear evidence of Res augmenting the growth inhibitory effect of 5-FU on the TE-1 and A431 cancer cells in vitro. In the in vivo studies, the tumor regression rate in the combination group increased significantly after four weeks of treatment (P < 0.01). The combination of 5-FU and Res significantly increased the percentage of apoptotic cells and the level of activated caspase-3, cleaved PARP and p53 proteins as well as increased the Bax/Bcl-2 ratio. In conclusion, the 5-FU/Res combination enabled a more effective inhibition of cell growth and the induction of apoptosis in cancer cells than 5-FU alone. The results of this study suggest that chemotherapy using natural dietary agents with chemical agents represents a superior cancer treatment option.

Inhibition of autophagosome-lysosome fusion by ginsenoside Ro via the ESR2-NCF1-ROS pathway sensitizes esophageal cancer cells to 5-fluorouracil-induced cell death via the CHEK1-mediated DNA damage checkpoint

“…43 Consistently, we found that ECA-109 and TE-1 cells are more resistant to 5-Fu than other chemosensitive esophageal cancer cells such as OE19 and OE33 cells (Fig. S3A) [44][45][46] and that 5-Fu induces prosurvival autophagy, and caspase-independent and autophagy-associated cell death (Fig. 5D and 6C).…”

“…S3A), which was consistent with previous reports. 44,45 Unexpectedly, these cells were more 5-Fu-resistant than other chemosensitive cells such as OE19 (IC 50 = 3.03 μg/ml) and OE33 (IC 50 = 1.24 μg/ml), 46 implying that ECA-109 and TE-1 cells were 5-Fu-resistant. A recent study showed that 5-Fu-induced cell death in chemoresistant esophageal cancer cells is apoptosis-independent, and that autophagy exerts a protective effect.…”

Resveratrol inhibits the hydrogen dioxide-induced apoptosis via Sirt 1 activation in osteoblast cells

“…The agent was shown to induce apoptosis in such cancer cells as skin cancer cells, 35) colon cancer cells, 36) and neuroblastoma Cells, 37) whereas was indicated to exert the protective role against apoptosis in the human tenocytes, 38) in endothelial cells 39) and in other types of cells, 40) particularly, under the pressure of oxidative stress. [40][41][42] And in this study, we confirmed the protective role of RSV and the Sirt 1 activation against the H 2 O 2 -induced apoptosis in MC3T3-E1 osteoblast cells.…”

Mango mistletoe Dendrophthoe pentandra leaf extract acts synergistically with 5-Fluorouracil to induce apoptosis and increase p21 expression in human cervical adenocarcinoma HeLa cells by reducing survivin expression

“…Our findings consistent with Priyadarsini et al (2010) that 5-FU works by causing the G1/S arrest and induces apoptosis by inhibiting the biosynthesis process. MMDP containing quercetin suppresses the viability of HeLa cells in G2/M phase and induces apoptosis through mitochondrial pathways (Priyadarsini et al, 2010;Dun et al, 2015). The presence of p21 interferes with CDK-cyclin interactions, thereby, inhibiting progression of the cell cycle (Wang et al, 2011).…”