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A selective low-dose cisplatin strategy enabled by melatonin and cannabinoids for targeting osteosarcoma and chondrosarcoma

Published on Thursday, 27 August 2026

Abstract

Therapeutic management of osteosarcoma and chondrosarcoma is limited by cisplatin (CP)-associated systemic toxicity and acquired chemoresistance. Strategies enabling effective dose reduction while maintaining antitumor activity are urgently required.

This study investigated whether melatonin (MEL) and cannabinoids (CBD, THC) enhance CP efficacy through synergistic, multi-target mechanisms in osteosarcoma (MG63, Saos2) and chondrosarcoma (SW1353) cells, with normal fibroblast (FL) and osteoblast (HC) cells as controls.

Cytotoxicity and antiproliferative effects were evaluated using MTT and LDH assays.

Drug interactions were quantified via combination index (CI) and dose-reduction index (DRI) analyses.

Apoptotic mechanisms were assessed by Casp3, Casp8, Casp9, and Bax gene expression, DNA fragmentation, DAPI nuclear staining, and Rhodamine-123-based mitochondrial membrane potential analysis.

Anti-migratory and anti-invasive effects were examined using wound-healing and invasion assays.

Molecular docking was performed to predict interactions with COX-2, MMPs, ADAMTS-5, and MAPK pathway proteins.

Combination regimens, particularly THC + CP + MEL, and CP + MEL, demonstrated strong synergism (CI < 1) in SW1353 and Saos2 cells, enabling up to a 2.77 - 4.38-fold reduction in CP dose.

Synergistic treatments significantly upregulated apoptotic markers and induced selective DNA fragmentation, chromatin condensation, and mitochondrial depolarization in cancer cells, while normal cells showed minimal alterations. Cannabinoids markedly suppressed migration and invasion, effects further enhanced in combination treatments. Docking analyses supported high-affinity multi-target interactions consistent with the observed biological responses.

Collectively, melatonin enhances cannabinoid-mediated chemosensitization to cisplatin through selective, pro-apoptotic and anti-invasive mechanisms, supporting a low-dose, multi-target combinatorial strategy for bone sarcoma therapy.

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About this publication.

The Di Bella's Method: Use of Melatonin (since 1974), pseudo-Metronomic Chemotherapy Cyclophosphamide and/or Hydroxyurea, Vitamin D, Somatostatin/Octreotide analogues and/or derivatives (since 1977), Retinoids (40mg per day Beta-Carotene, 10mg per day ATRA and 10mg per day Axerophthol palmitate), with prolactin inhibitors Cabergoline and/or Bromocriptine (together with others chemical compounds) in Fibro/Osteo-Sarcoma (the dosage and administration schedule must be individualised for each patient):

- 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: the dosage and administration schedule must be individualised for each patient - 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;