• Statins and 5-fluorouracil Resistance: An Insight into Signaling Pathways
  • Elham Norouz Dolatabadi,1 Vahid Asghariazar,2 Maryam Darvish,3,* Kazem Nejati koshki,4
    1. Biotechnology department, Arak university of medical sciences, Arak, Iran
    2. Immunology research center, Ardabil university of medical sciences, Ardabil, Iran.
    3. Biotechnology department, Arak university of medical sciences, Arak, Iran
    4. Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran


  • Introduction: 5-Fluorouracil (5-FU) is part of a group of chemotherapy drugs that are widely used to treat cancer. 5-FU exerts its anticancer effects by inhibiting thymidylate synthase (TS) and incorporating its metabolites into RNA and DNA. Despite its anticancer effects, 5‐FU monotherapy was reported by Johnston and Kaye to have low response rates in the range of 10%‐20%. These limitations of 5‐FU‐based therapies are due to drug resistance. P53 protein as a tumor suppressor by inducing pro-apoptotic genes and decreasing anti-apoptotic genes leads to the onset of apoptosis and cell death. Although in vitro studies have shown that loss of p53 function decreases cell sensitivity to 5-FU by over-activating the Ras / PI-3K / PTEN / AKT / mTOR and Ras / Raf / MEK / ERK signaling pathways and finally increases 5-FU resistance. HMG-CoA inhibitors (statins), a class of drugs that reduce cholesterol, manage and prevent coronary heart disease. They are among the most commonly prescribed drugs worldwide. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), the rate-limiting enzyme in the mevalonate pathway. Mevalonate is involved in synthesizing isoprenyl proteins, dolichol, and ubiquinone that play several important roles in cellular functions. Mevalonate-derived prenyl groups, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), facilitate essential intracellular functions of various proteins such as Ras. Disruption of these processes in neoplastic cells by statins leads to the control of tumor onset, growth, and metastasis, which prevents the growth of cancer cells and leads to cell death and apoptosis. Preclinical data suggest statins exhibit pleiotropic antineoplastic effects in various tumors, but clinical studies have provided conflicting data as to whether statins influence the risk of cancer. The previous study showed that the combination of statins with other drugs, such as low-dose aspirin or safer non-steroidal anti-inflammatory medications, may be useful in preventing and treating different cancer.
  • Methods: PubMed, Embase and Google scholar databases were searched for related articles.
  • Results: Overuse of 5-fluorouracil to treat cancer causes drug resistance. Therapeutic combination of fluorouracil with statins can reduce this drug resistance
  • Conclusion: Evidence suggests that the use of statins could reduce drug resistance to different cancer. So they may be a suitable method for combination cancer treatment. This group of drugs can reduce the resistance to 5-Fluorouracil by regulating signaling pathways such as Ras / PI-3K / PTEN / AKT / mTOR and Ras / Raf / MEK / ERK in a different type of cancer.
  • Keywords: Statin; Cancer; Signaling Pathways; Drug resistance; 5-Fluorouracil