Glioblastoma: Role of Mitochondria N-acetylserotonin/Melatonin Ratio in Mediating Effects of miR-451 and Aryl Hydrocarbon Receptor and in Coordinating Wider Biochemical Changes

Abstract

A wide array of different factors and processes have been linked to the biochemical underpinnings of glioblastoma multiforme (GBM) and glioblastoma stem cells (GSC), with no clear framework in which these may be integrated.

Consequently, treatment of GBM/GSC is generally regarded as very poor.

This article provides a framework that is based on alterations in the regulation of the melatonergic pathways within mitochondria of GBM/GSC.

It is proposed that the presence of high levels of mitochondria-synthesized melatonin is toxic to GBM/GSC, with a number of processes in GBM/GSC acting to limit melatonin's synthesis in mitochondria.

One such factor is the aryl hydrocarbon receptor, which increases cytochrome P450 (CYP)1b1 in mitochondria, leading to the 'backward' conversion of melatonin to N-acetylserotonin (NAS). N-acetylserotonin has some similar, but some important differential effects compared with melatonin, including its activation of the tyrosine receptor kinase B (TrkB) receptor. TrkB activation is important to GBM/GSC survival and proliferation. A plethora of significant, but previously disparate, data on GBM/GSC can then be integrated within this framework, including miR-451, AMP-activated protein kinase (AMPK)/mTOR, 14-3-3 proteins, sirtuins, tryptophan 2,3-dioxygenase, and the kynurenine pathways.

Such a conceptualization provides a framework for the development of more effective treatment for this poorly managed condition.

About this publication.

See also:

- Official Web Site: The Di Bella Method;

- 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;

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

- The Di Bella Method (A Fixed Part - Calcium, 2 grams per day, orally);

- The Di Bella Method (A Variable Part - Omega 3 Essential/Unsaturated Fatty Acids. From 1.5 grams up to 3.0 grams per day orally);

- 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;

- 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;

- 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;

- Observations on the Report of a case of pulmonary adenocarcinoma with lymph node, hepatic and osseus metastasis;

- Neuroblastoma: Complete objective response to biological treatment;

- Oesophageal squamocellular carcinoma: a complete and objective response;

- The Di Bella Method (DBM) in the treatment of prostate cancer: a preliminary retrospective study of 16 patients and a review of the literature;

- 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.