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The Sensitization of Melatonin in Osteosarcoma Cells by Suppression of Anti-Apoptotic Proteins

Published on Friday, 25 July 2025

Abstract

Background: Investigation of anti-cancer agents with desirable selective toxicity is critical for cancer therapy. The use of natural adjuvants can be a promising option in reducing the toxicity of the anti-cancer agent. The aim of this study was to investigate the potential application of melatonin (MLT) as a natural adjuvant molecule along with doxorubicin (DOX) to induce cytotoxicity in osteosarcoma (OS) cells.

Methods: Human OS cell lines included Saos-2, MG-63, and Human Bone Marrow Mesenchymal Stem Cells (hBM-MSCs) were treated with free DOX, free MLT, DOX-loaded NPs (DOX-NPs), MLT-loaded NPs (MLT-NPs), combination of DOX and MLT (DOX-MLT) and combination of DOX and MLT-loaded NPs (DOX-MLT-NPs) in separated cell culture. Cell proliferation of experiments were evaluated by MTT assay after 24 h. Total protein levels were determined by enzyme immunoassay ELISA.

Results: Herein, we found the combination of MLT with DOX, especially formulated in nano-form, is resulted in a significant reduction in the protein levels of both X-linked Inhibitor of Apoptosis (XIAP) and Survivin (p < 0.0001). Indeed, there was a significant decrease in the expression of XIAP and Survivin when MLT is combined with DOX compared to the individual treatments.

Conclusion: Our findings indicated the synergism of the antitumor effect could be due to the down-regulation of XIAP and Survivin in the levels of protein.

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About this publication.

The Di Bella's Method: Use of Melatonin and pseudo-Metronomic Chemotherapy Cyclophosphamide and/or Hydroxyurea (together with others chemical compounds) in Osteo/Fibro Sarcoma:

- A retrospective observational study on cases of Osteosarcomas treated with a multitherapy: The rationale and effectiveness;

- A Retrospective Observational Study on Cases of Sarcoma Treated with the Di Bella Method: Rationale and Effectiveness;

- 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;

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

- 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 - Cyclophosphamide 50mg tablets and/or Hydroxyurea 500mg tablets, one or two per day);

The Di Bella's Method: Use of Melatonin since 1974 and pseudo-Metronomic Chemotherapy Cyclophosphamide and/or Hydroxyurea - together with others chemical compounds - in several Oncological Pathologies:

- A retrospective observational clinical study of triple negative breast cancer cases treated with Di Bella Method: A preliminary data;

- 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;

- A retrospective observational study on cases of anaplastic brain tumors treated with the Di Bella Method: A rationale and effectiveness;

- Recurrent Glioblastoma Multiforme (grade IV – WHO 2007): a case of complete objective response achieved by means of the concomitant administration of Somatostatin and Octreotide – Retinoids – Vitamin E – Vitamin D3 – Vitamin C – Melatonin – D2 R agonists (Di Bella Method – DBM) associated with Temozolomide;

- 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;

- Chronic Lymphocytic Leukemia: Long-Lasting Remission with Combination of Cyclophosphamide, Somatostatin, Bromocriptine, Retinoids, Melatonin, and ACTH;

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in advanced non-small-cell lung cancer patients with low performance status;

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in chemotherapy-pretreated patients with advanced lung adenocarcinoma and low performance status;