Resveratrol synergistically augments anti-tumor effect of 5-FU in vitro and in vivo by increasing S-phase arrest and tumor apoptosis.
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.
Department of Pharmaceutics, School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, P. R. China The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of Pharmacology and Toxicology for New Drugs, Department of Pharmacology, Hebei Medical University, Shijiazhuang 050017, P. R. China.
Jiening
J
Dun
The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of Pharmacology and Toxicology for New Drugs, Department of Pharmacology, Hebei Medical University, Shijiazhuang 050017, P. R. China.
Xueyan
X
Chen
The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of Pharmacology and Toxicology for New Drugs, Department of Pharmacology, Hebei Medical University, Shijiazhuang 050017, P. R. China.
Haixia
H
Gao
Shijiazhuang First Hospital, Shijiazhuang 050017, P. R. China.
Yan
Y
Zhang
Maternity and Child care center of Qinhuangdao, Qinhuangdao 066000, P. R. China.
Huajun
H
Zhang
The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of Pharmacology and Toxicology for New Drugs, Department of Pharmacology, Hebei Medical University, Shijiazhuang 050017, P. R. China zhangyjlm@163.com.
Yongjian
Y
Zhang
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D000077185:Resveratrol; D016196:S Phase / Q000187:drug effects* / Q000502:physiology; D012878:Skin Neoplasms / Q000188:drug therapy*; D013267:Stilbenes / Q000494:pharmacology* / Q000627:therapeutic use
D000964:Antimetabolites, Antineoplastic; D013267:Stilbenes; D000077185:Resveratrol; D005472:Fluorouracil
5-fluorouracil; Resveratrol; S-phase arrest; synergistic effect; two-stage mouse skin carcinogenesis