Melatonin inhibits proliferation and viability and promotes apoptosis in colorectal cancer cells via upregulation of the microRNA-34a/449a cluster
Abstract
Colorectal cancer (CRC) has a significant burden on healthcare systems worldwide, and is associated with high morbidity and mortality rates in patients. In 2020, the estimated new cases of colon cancer in the United States are 78,300 in men and 69,650 in women.
Thus, developing effective and novel alternative agents and adjuvants with reduced side effects is important to reduce the lethality of the disease and improve the quality of life of patients.
Melatonin, a pineal hormone that possesses numerous physiological functions, including anti‑inflammatory and antitumor activities, can be found in various tissues, including the gastrointestinal tract.
Melatonin exerts anticarcinogenic effects via various mechanisms; however, the identified underlying molecular mechanisms do not explain the full breadth of anti‑CRC effects mediated by melatonin.
MicroRNAs (miRs) serve critical roles in tumorigenesis, however, whether melatonin can inhibit CRC by regulating miRs is not completely understood.
In the present study, the roles and mechanism underlying melatonin in CRC were investigated. The proliferation of human CRC cells was tested by CCK8, EDU and colony formation assay. The apoptosis of cancer cells was detected by flow cytometry and western blotting. A xenograft mouse model was constructed and the proliferation and apoptosis of tumor tissue was detected by Ki‑67 and TUNEL staining assay respectively. Reverse transcription‑quantitative PCR and western blotting were performed to measure the regulation of miRs on mRNA, and the dual‑luciferase report analysis experiment was used to verify the direct target genes of miRs.
Compared with the control group, melatonin inhibited viability and proliferation, and induced apoptosis in CRC cells.
Additionally, the effect of melatonin in a xenograft mouse model was assessed.
Compared with the control group, melatonin significantly enhanced the expression levels of the miR‑34a/449a cluster, reduced CRC cell proliferation and viability, and increased CRC cell apoptosis.
Finally, the dual‑luciferase reporter assay indicated that Bcl‑2 and Notch1 were the target mRNAs of the miR‑34a/449a cluster.
To the best of our knowledge, the present study was the first to suggest that melatonin inhibited proliferation and viability, and promoted apoptosis in CRC cells via upregulating the expression of the miR‑34a/449a cluster in vitro and in vivo. Therefore, melatonin may serve as a potential therapeutic for CRC.
See also:
- Official Web Site: The Di Bella Method;
- Melatonin use in cancer patients have started in 1974, when melatonin prepared according to Prof. Di Bella’s formulation [...]. For 11 days was administered to the patient, admitted to the general medical ward at the Maggiore-Pizzardi Hospital in Bologna, very slowly (over approx. 8 hours) and intravenously administered 1000 mg of melatonin for 11 days. During the course of each day, the patient was intravenously administered 4 saline drips of 500 ml, each containing ten 25 mg bottles of freeze-dried melatonin, lasting 2 hours, totaling 1000 mg per day. No other drug of any kind was administered in order to ascertain the effect of the MLT without interference [...]. From Melatonin with adenosine solubilized in water and stabilized with glycine for oncological treatment - technical preparation, effectivity and clinical findings;
- About Melatonin - In vitro, review and in vivo publications;
- Publication: Melatonin anticancer effects: Review (from Di Bella's Foundation);
- Publication: Key aspects of melatonin physiology: 30 years of research (from Di Bella's Foundation);
- The Di Bella Method (A Fixed Part - Calcium, 2 grams per day, orally);
- Oesophageal squamocellular carcinoma: a complete and objective response;
- Pancreatic Adenocarcinoma: clinical records on 17 patients treated with Di Bella's Method;
- Complete objective response to biological therapy of plurifocal breast carcinoma;
- Pleural Mesothelioma: clinical records on 11 patients treated with Di Bella's Method;
- Malignant pleural mesothelioma, stage T3-T4. Consideration of a case study;
- Neuroblastoma: Complete objective response to biological treatment;
- Large B-cells Non-Hodgkin's Lymphoma, Stage IV-AE: a Case Report;
- Non-Hodgkin's Lymphoma, Stage III-B-E: a Case Report.
Melatonin inhibits proliferation and viability and promotes apoptosis in colorectal cancer cells via upregulation of the microRNA-34a/449a cluster - Supplementary File