title: A new 4-phenyl-1,8-naphthyridine derivative affects carcinoma cell proliferation by impairing cell cycle progression and inducing apoptosis.
abstract: In targeted cancer therapy the search for novel molecules led to the discovery of a plethora of small organic molecules inhibiting cancer cell proliferation. Among these, quinazoline and derivatives, such as quinolines and naphthyridines, have been considered as of particular interest. One of these, the naphthyridine derivative 4-phenyl-2,7-di(piperazin-1-yl)-1,8-naphthyridine, has been analyzed in detail in the present work. We found that this compound elicited a powerful anti-proliferative activity on carcinoma cells, with IC50 values comparable with paradigmatic microtubule-deranging drugs. The mechanisms underlying this effect were seemingly due to a framework of cellular alterations that include peculiar alterations of mitochondria, i.e. an increase of mitochondrial membrane potential (MMP), followed by the typical MMP loss leading to the release of apoptogenic factors, and cell death by apoptosis. Furthermore, the analysis of cell cycle revealed that a significant percentage of treated cells was in G2/M phase. This block was seemingly due to a target effect of the naphthyridine derivative on microtubular network dynamic instability, which impaired mitotic spindle formation, possibly leading to mitotic catastrophy. Since the dual effects of naphthyridine derivative on cell cycle and mitotic spindle were obtained at very low concentrations, i.e. micromolar concentrations, we hypothesize that this compound could represent a new promising tool in the control of cancer cell proliferation.
authors.affiliation: Dipartimento di Medicina Sperimentale, Sapienza University, Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Capozzi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mantuano
authors.forename: Paola
authors.initials: P
authors.lastname: Matarrese
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saccomanni
authors.forename: Clementina
authors.initials: C
authors.lastname: Manera
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mattei
authors.forename: Lucrezia
authors.initials: L
authors.lastname: Gambardella
authors.forename: Walter
authors.initials: W
authors.lastname: Malorni
authors.forename: Maurizio
authors.initials: M
authors.lastname: Sorice
authors.forename: Roberta
authors.initials: R
authors.lastname: Misasi
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007822:Laryngeal Neoplasms; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008870:Microtubules / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D008941:Spindle Apparatus / Q000187:drug effects*
chemical_list: C577092:4-phenyl-2,7-di(piperazin-1-yl)-1,8-naphthyridine; D000970:Antineoplastic Agents; D009287:Naphthyridines; D010879:Piperazines