Melatonin suppression of aerobic glycolysis (Warburg effect), survival signalling and metastasis in human leiomyosarcoma

J Pineal Res. 2016 Mar;60(2):167-77. doi: 10.1111/jpi.12298. Epub  2015 Dec 23.
Melatonin suppression of aerobic glycolysis (Warburg effect), survival signalling and metastasis in human leiomyosarcoma.

1Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.
2Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA.
3Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, LA, USA.
4Department of Surgery, Tulane University School of Medicine, New Orleans, LA, USA.

Abstract

Leiomyosarcoma (LMS) represents a highly malignant, rare soft tissue sarcoma with high rates of morbidity and mortality. Previously, we demonstrated that tissue-isolated human LMS xenografts perfused in situ are highly sensitive to the direct anticancer effects of physiological nocturnal blood levels of melatonin which inhibited tumour cell proliferative activity, linoleic acid (LA) uptake and metabolism to 13-hydroxyoctadecadienoic acid (13-HODE). Here, we show the effects of low pharmacological blood concentrations of melatonin following oral ingestion of a melatonin supplement by healthy adult human female subjects on tumour proliferative activity, aerobic glycolysis (Warburg effect) and LA metabolic signalling in tissue-isolated LMS xenografts perfused in situ with this blood. Melatonin markedly suppressed aerobic glycolysis and induced a complete inhibition of tumour LA uptake, 13-HODE release, as well as significant reductions in tumour cAMP levels, DNA content and [(3) H]-thymidine incorporation into DNA. Furthermore, melatonin completely suppressed the phospho-activation of ERK 1/2, AKT, GSK3β and NF-kB (p65). The addition of S20928, a nonselective melatonin antagonist, reversed these melatonin inhibitory effects. Moreover, in in vitro cell culture studies, physiological concentrations of melatonin repressed cell proliferation and cell invasion. These results demonstrate that nocturnal melatonin directly inhibited tumour growth and invasion of human LMS via suppression of the Warburg effect, LA uptake and other related signalling mechanisms. An understanding of these novel signalling pathway(s) and their association with aerobic glycolysis and LA metabolism in human LMS may lead to new circadian-based therapies for the prevention and treatment of LMS and potentially other mesenchymally derived solid tumours.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

KEYWORDS:
Warburg effect; leiomyosarcoma; melatonin; metastasis; signalling pathways

PMID:

26607298

Phase I study and preclinical efficacy evaluation of the mTOR inhibitor sirolimus plus gemcitabine in patients with advanced solid tumours.

Br J Cancer. 2014 Jul 8. doi: 10.1038/bjc.2014.370. [Epub ahead of print]
Phase I study and preclinical efficacy evaluation of the mTOR inhibitor sirolimus plus gemcitabine in patients with advanced solid tumours.

Abstract

Background:We conducted a phase I study in patients with advanced solid tumours to identify the recommended dose, assess pharmacokinetics (PK), pharmacodynamic activity and preclinical antitumour efficacy of the combination of sirolimus and gemcitabine.Methods:Nineteen patients were treated with sirolimus 2 or 5 mg daily and gemcitabine 800 or 1000 mg m-2 on days 1 and 8. Dose escalation depended on dose-limiting toxicity (DLT) rate during the first 3-week period. Paired skin biopsies were evaluated for phosphorylated S6 (pS6) as marker of mTOR (mammalian target of rapamycin) inhibition. Pharmacokinetics and preclinical evaluation of efficacy using two different sarcoma cell lines and leiomyosarcoma xenografts were also conducted.Results:Three DLTs were observed: grade 3 transaminitis, grade 3 thrombocytopenia and grade 4 thrombocytopenia. Common treatment-related adverse events included anaemia, neutropenia, thrombocytopenia and transaminitis. Pharmacodynamic analyses demonstrated mTOR inhibition with sirolimus 5 mg and PK showed no influence of sirolimus concentrations on gemcitabine clearance. In vitro and in vivo studies suggested mTOR pathway hyperactivation by gemcitabine that was reversed by sirolimus. Tumour growth in leiomyosarcoma xenografts was dramatically inhibited by the treatment.Conclusions:Recommended dose was sirolimus 5 mg per 24 h plus gemcitabine 800 mg m-2. Antitumour activity in preclinical sarcoma models and mTOR signalling inhibition were observed. A phase II study is currently ongoing.British Journal of Cancer advance online publication, 8 July 2014; doi:10.1038/bjc.2014.370 www.bjcancer.com.

PMID:25003665      [PubMed – as supplied by publisher]

Medical treatment of soft tissue sarcomas based on the histological subtype

Magy Onkol. 2014 Mar;58(1):53-8. Epub  2014 Feb 1.
[Medical treatment of soft tissue sarcomas based on the histological subtype].
[Article in Hungarian]

Onkológiai Osztály, MH-Egészségügyi Központ, Budapest, Hungary. zspapai@gmail.com.

Abstract
in  English, Hungarian

The medical treatment of adult soft tissue sarcomas is more and more dictated by the histological subtype, this applies to both cytotoxics and target therapies. Doxorubicin and ifosfamid Doxorubicin are the two drugs used either in monotherapy or combination with the best established response rates in adult soft tissue sarcomas for several years. In addition to these compounds there is evidence of efficacy of new drugs such as taxanes in angiosarcoma, gemcitabine+taxanes combination in leiomyosarcomas, trabectedin in leiomyosarcomas and liposarcomas with an extremely high activity in myxoid liposarcoma. With regard to target therapy pazopanib seems especially active in leiomyosarcomas and synoviosarcomas, but totally inactive in liposarcomas, sunitinib and cediranib in alveolar soft part sarcomas, sunitinib and bevacizumab+temozolamide combination in solitary fibrous tumors, and sorafenib in angiosarcomas. mTOR inhibitors are active in PEComas (perivascular epitheloid cell tumors) and crizotinib in ALK rearranged inflammatory myofibroblastic tumors. The efficacy of imatinib and sunitinib in GIST tumors are established, and that of imatinib in dermatofibrosarcoma as well.

PMID:24712007      [PubMed – indexed for MEDLINE    Free full text