Melatonin synergistically enhances docetaxel induced endoplasmic reticulum stress to promote apoptosis by suppressing NF-κB activation in cervical cancer

Published on Sunday, 03 December 2023

Abstract

Cervical cancer is the fourth most common malignancy in women globally. Although chemotherapy significantly improves the survival of cervical cancer patients, the development of drug resistance is inevitable.

In the present study, our study showed that melatonin suppressed the proliferation, cell survival, colony formation, and the ability of adhering to fibronectin in cervical cancer cells.

Our data suggested that docetaxel insensitivity was caused by NF-κB pathway activation, and followed by reducing endoplasmic reticulum stress and apoptosis.

We showed that melatonin functioned as an oncostatic agent via inhibition of NF-κB signaling in cervical cancer cells. Interestingly, melatonin not only reduced the basal and inducible NF-κB pathway activation, but also prevented docetaxel induced NF-κB pathway activation by stabilizing IκBα protein.

Importantly, inhibition of NF-κB pathway activation by melatonin abrogated the protective effect of NF-κB activation on docetaxel provoked endoplasmic reticulum stress, and further enhanced endoplasmic reticulum stress and apoptosis to produce synergistic oncostatic effects in cervical cancer cells.

In summary, we revealed that melatonin was a novel agent to enhance docetaxel sensitivity by abolishing NF-κB activation and aggravating endoplasmic reticulum stress.

Our results might provide a rationale for the clinical application of melatonin to overcome docetaxel resistance in cervical cancer patients.

NOTE: This publication cites (Ref. N.15): Di Bella G., Mascia F., Gualano L., Di Bella L. - Melatonin anticancer effect: review. Int J Mol Sci. 2013;14:2410–2430.

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- 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 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 Method (A Fixed Part - Somatostatin, Octreotide, Sandostatin LAR, analogues and/or derivatives);

- Somatostatin in oncology, the overlooked evidences - In vitro, review and in vivo publications;

- Publication, 2018 Jul: Over-Expression of GH/GHR in Breast Cancer and Oncosuppressor Role of Somatostatin as a Physiological Inhibitor (from Di Bella's Foundation);

- Publication, 2018 Sep: The over-expression of GH/GHR in tumour tissues with respect to healthy ones confirms its oncogenic role and the consequent oncosuppressor role of its physiological inhibitor, somatostatin: a review of the literature (from Di Bella's Foundation);

- Publication, 2019 Aug: The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity (from Di Bella's Foundation);

- Publication, 2019 Sep: Effects of Somatostatin and Vitamin C on the Fatty Acid Profile of Breast Cancer Cell Membranes (from Di Bella's Foundation);

- Publication, 2019 Sep: Effects of somatostatin, curcumin, and quercetin on the fatty acid profile of breast cancer cell membranes (from Di Bella's Foundation);

- Publication, 2020 Sep: Two neuroendocrine G protein-coupled receptor molecules, somatostatin and melatonin: Physiology of signal transduction and therapeutic perspectives (from Di Bella's Foundation);