n-3 Polyunsaturated fatty acids enhance the antitumor effect of 5-fluorouracil by inhibiting bcl-2 and mutant-p53

Authors

  • Yao-Zong Tan,

    1. Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, Guangzhou, China
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    • These authors contributed equally to this work.
  • Wen-Ge Huang,

    1. Laboratory Animal Center of Sun Yat-Sen University, Guangzhou, China
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    • These authors contributed equally to this work.
  • Feng-Ying Chen,

    1. Laboratory Animal Center of Sun Yat-Sen University, Guangzhou, China
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  • Jie Li,

    1. Laboratory Animal Center of Sun Yat-Sen University, Guangzhou, China
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  • Jing-Ya Zhou,

    1. Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, Guangzhou, China
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  • Li-Jun Wang,

    1. Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, Guangzhou, China
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  • Li Chen,

    1. Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, Guangzhou, China
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  • Hui-Lian Zhu

    Corresponding author
    1. Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, Guangzhou, China
    • Correspondence: Prof. Hui-Lian Zhu, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, 74th Zhongshan Road II, Guangzhou 510080, China

      E-mail: zhuhl@mail.sysu.edu.cn

      Fax: +86 20 87330446

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Abstract

The study determined whether n-3 polyunsaturated fatty acids (n-3 PUFAs) enhance the chemotherapeutic ability of 5-fluorouracil (5-FU) to affect bcl-2 and mutant-p53 (mt-p53). Thirty-two BalbC/c mice bearing SW480 colorectal cancer (CRC) xenografts were randomly divided into four groups and fed with basic diet (5% of fat) and diets (20% of fat) with 0.69, 14.84, and 24.27% of n-3 PUFAs, while all mice received 5-FU injections (35 mg/kg) every 3 days. After 21 days' treatment, tumors were subjected to HE staining, TUNEL staining, and immunohistochemical analyses for bcl-2 and mt-p53, and serum n-3 PUFAs composition were determined by GC-FID. The proportion of serum n-3 PUFAs increased in the high (17.1%) and low (12.3%) n-3 groups (vs. 3.1% in control). The high n-3 group showed slower tumor growth (Δvolume: 370.3 mm3 vs. 556.9 mm3, p < 0.05), larger tumor necrosis areas with more loosely arranged cells, and greater tumor cell apoptosis (positive rate: 9.4% vs. 2.2%, p < 0.05) compared to the control. Both Bcl-2 and mt-p53 expressions were inversely and dose-dependently correlated to dietary n-3 PUFAs (all p < 0.05). n-3 PUFAs enhance the antitumor effect of 5-FU on SW480 xenografts probably through promoting tumor apoptosis via inhibiting bcl-2 and mt-p53.

Practical applications: n-3 PUFAs have distinct anti-cancer capacity and combination of n-3 PUFAs and 5-FU was considered as a potential approach for cancer chemotherapy, but the exact mechanism of the co-anticancer effect of n-3 PUFAs is still not clarified. Our present study demonstrated that n-3 PUFAs increase the apoptosis of CRC cells by inhibiting the expression of bcl-2 and mt-p53. These results highlight the pro-apoptosis effect of n-3 PUFAs and reveal the possible mechanism of this effect. The main strategy of chemotherapy regimens is to enhance the pro-apoptosis capacity of drugs against malignancy and n-3 PUFAs, as a kind of dietary nutrient, are easy to be obtained and cause no toxicity compared with other anti-cancer drugs. In this context, n-3 PUFAs may be developed as adjuvant anti-cancer agent combining with 5-FU or even other drugs.

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