Melatonin-mediated downregulation of thymidylate synthase as a novel mechanism for overcoming 5-fluorouracil associated chemoresistance in colorectal cancer cells

Abstract

Background: 5-fluorouracil (5-FU) has been established as the first-line chemotherapy for advanced colorectal cancer (CRC); however, acquired chemoresistance is often the cause of poor therapeutic response. Melatonin is a molecule which is associated with circadian rhythms. Although antitumor effects of melatonin have been shown, the underlying mechanism(s) for its activity and its effect, if any, in chemoresistant CRC has not been studied. We aimed to investigate antitumor effects of melatonin, and more specifically its effect on molecular mechanisms in 5-FU resistant CRC cells.

Methods: The cell growth was assessed in CRC cells, patient-derived organoids, and 5-FU resistant CRC cells after treatments with melatonin. In addition, the expression of thymidylate synthase (TYMS), and miRNAs which are targeting TYMS were examined.

Results: We observed that melatonin inhibited the cell growth in 5-FU resistant CRC cells. Additionally, we found that melatonin significantly promoted apoptosis. Furthermore, a combination of melatonin and 5-FU markedly enhanced 5-FU mediated cytotoxicity in 5-FU resistant cells. In addition, melatonin significantly decreased the expression of TYMS. Interestingly, this effect was manifested through the simultaneous increase in the expression of miR-215-5p, for which, TYMS serves as the direct downstream target for this miRNA.

Conclusion: Melatonin facilitates overcoming 5-FU resistance through downregulation of TYMS. Melatonin may serve as a potential therapeutic option on its own, or in conjunction with 5-FU, in the treatment of patients with advanced or chemoresistant CRC.

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See also:

- Official Web Site: The Di Bella Method;

- About Melatonin - In vitro, review and in vivo publications;

- The Di Bella Method (A Fixed Part - Melatonin tablets. From 30-40mg/day up to 200mg/day orally in patients with advanced stage of cancer disease and/or patients without respond to traditional treatments);

- Melatonin with adenosine solubilized in water and stabilized with glycine for oncological treatment - technical preparation, effectivity and clinical findings;

- The Di Bella Method (A Fixed Part - Cyclophosphamide 50mg tablets and/or Hydroxyurea 500mg tablets, one or two per day);

- Congenital fibrosarcoma in complete remission with Somatostatin, Retinoids, Vitamin D3, Vitamin E, Vitamin C, Melatonin, Calcium, Chondroitin sulfate associated with low doses of Cyclophosphamide in a 14-year Follow Up;

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- The Di Bella Method DBM improved survival objective response and performance status in a retrospective observational clinical study on 23 tumours of the head and neck;

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- The Synergism of Somatostatin, Melatonin, Vitamins Prolactin and Estrogen Inhibitors Increased Survival, Objective Response and Performance Status In 297 Cases of Breast Cancer;

- Complete objective response, stable for 5 years, with the Di Bella Method, of multiple-metastatic carcinoma of the breast;

- Evaluation of the safety and efficacy of the first-line treatment with somatostatin combined with melatonin, retinoids, vitamin D3, and low doses of cyclophosphamide in 20 cases of breast cancer: a preliminary report;

- The Di Bella Method (DBM) improved survival, objective response and performance status in a retrospective observational clinical study on 122 cases of breast cancer;

- Complete objective response to biological therapy of plurifocal breast carcinoma.