title: Synthetic polyamines activating autophagy: effects on cancer cell death.
abstract: The ability of symmetrically substituted long chain polymethylene tetramines, methoctramine (1) and its analogs 2-4 to kill cancer cells was studied. We found that an elevated cytotoxicity was correlated with a 12 methylene chain length separating the inner amine functions (6-12-6 carbon backbone), together with the introduction of diphenylethyl moieties on the terminal nitrogen atoms (compound 4) of a tetramine backbone. Compound 4 triggered dissipation of mitochondrial transmembrane potential and increased intracellular peroxide levels, leading to a caspase-independent HeLa cell death associated with a rapid activation of autophagy. The antioxidant N-acetylcysteine inhibited cell death and activation of autophagy, indicating a link between oxidative stress and autophagy. Autophagy was rapidly triggered even by tetramines 2 and 3, indicating that is related to their polyamine structure. Autophagy did not protect HeLa cells against cytotoxicity elicited by compound 4. The present study shows that, by modifications of the methoctramine structure, it is possible to design polyamine derivatives highly cytotoxic against tumor cells and that the appropriate design of molecules bearing polyamine-like structures leads to powerful inducers of autophagy.
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Minarini
authors.forename: Maddalena
authors.initials: M
authors.lastname: Zini
authors.forename: Andrea
authors.initials: A
authors.lastname: Milelli
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Tumiatti
authors.forename: Chiara
authors.initials: C
authors.lastname: Marchetti
authors.forename: Benedetta
authors.initials: B
authors.lastname: Nicolini
authors.forename: Mirella
authors.initials: M
authors.lastname: Falconi
authors.forename: Giovanna
authors.initials: G
authors.lastname: Farruggia
authors.forename: Concettina
authors.initials: C
authors.lastname: Cappadone
authors.forename: Claudio
authors.initials: C
authors.lastname: Stefanelli
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000473:pathology*; D011073:Polyamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D011073:Polyamines
keywords: 3,3′-dihexyloxacarbocyanine iodide; AO; AVOs; Atg5; Autophagy; Cancer therapy; DCFDA; DENSPM; DFMO; DMSO; DiOC6; N(1),N(11)-diethylnorspermine; N-acetylcysteine; NAC; Oxidative stress; Polyamine analogs; TEM; acidic vesicular organelles; acridine orange; autophagy gene 5; dichlorofluoresceine diacetate; dimethylsulphoxide; transmission electron microscopy; α-difluoromethylornithine