title: Differential effects of the glycolysis inhibitor 2-deoxy-D-glucose on the activity of pro-apoptotic agents in metastatic melanoma cells, and induction of a cytoprotective autophagic response.
abstract: 2-Deoxy-D-glucose (2DG) is a synthetic glucose analogue that inhibits glycolysis and blocks cancer cell growth. In this report, we evaluated the role of 2DG in the induction of cell death in human metastatic melanoma cells. We have also examined the effects of 2DG in combined treatments with four different pro-apoptotic agents: (i) Temozolomide (TMZ), a chemotherapic drug commonly used to treat metastatic melanoma, (ii) Pyrimethamine (Pyr), a pro-apoptotic antifolate drug recently reappraised in cancer therapy, (iii) Cisplatin (CisPt), a drug capable of directly binding to DNA ultimately triggering apoptosis of cancer cells and (iv) the kinase inhibitor Staurosporine (STS), a prototypical inducer of mitochondria-mediated apoptosis. We found that 2DG per se: (i) induced a cell cycle arrest in G(0) /G(1) , (ii) promoted autophagy, (iii) was ineffective in inducing apoptosis in association with the chemotherapic drug TMZ, whereas (iv) it was synergistic with CisPt and STS pro-apoptotic drugs through a mechanism involving changes of mitochondrial homeostasis. Conversely, (v) 2DG hindered the pro-apoptotic effects of Pyr via a mechanism involving either the block of cell cycle in G(0) /G(1)  or the modification of the free radical production of the cell, i.e., decreasing the production of reactive oxygen species (ROS) and increasing the production of reactive nitrogen species (RNS). Moreover, a clear-cut autophagic response involving endoplasmic reticulum remodelling was detectable. Since autophagic cytoprotection has been suggested to contribute to the induction of chemoresistance, these results could provide useful clues as concerns the use of 2DG as anticancer agent in combinatory protocols.
authors.affiliation: Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Giammarioli
authors.forename: Lucrezia
authors.initials: L
authors.lastname: Gambardella
authors.forename: Cristiana
authors.initials: C
authors.lastname: Barbati
authors.forename: Donatella
authors.initials: D
authors.lastname: Pietraforte
authors.forename: Antonella
authors.initials: A
authors.lastname: Tinari
authors.forename: Manuela
authors.initials: M
authors.lastname: Alberton
authors.forename: Lucio
authors.initials: L
authors.lastname: Gnessi
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: Maurizio
authors.initials: M
authors.lastname: Minetti
authors.forename: Walter
authors.initials: W
authors.lastname: Malorni
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D002453:Cell Cycle; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D008545:Melanoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism; D009362:Neoplasm Metastasis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D003847:Deoxyglucose