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.
Keywords: Naphthyridine derivative, Cell cycle, Apoptosis, Propidium iodide, Annexin V, Cytotoxicity, Topoisomerase II, Hep-2 cells, Mitochondria, Mitochondrial Membrane Potential, Microtubules, Tubulin, JC-1, Bromodeoxyuridine, Cancer
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Published on: 09 May, 2012
Page: [653 - 662]