title: Activity of different anthracycline formulations in hormone-refractory prostate cancer cell lines: role of Golgi apparatus.
abstract: The efficacy of therapy for hormone-refractory prostate cancer (HRPC) is still unsatisfactory and new agents and therapeutic modalities are needed. The aims of the present work were to examine the in vitro activity and mechanisms of action of doxorubicin (DX), pegylated liposomal DX (PLDX), and non-pegylated liposomal DX (NPLDX) in DU145 and taxane-resistant DU145-R HRPC cell lines. Drug activity and incorporation, apoptosis, and expression of cell death-related markers were evaluated by SRB test, cytofluorimetric assays, and Western blot, respectively. Among the different DX formulations, NPLDX showed the highest cytotoxic activity in both cell lines, with more than 50% of apoptotic cells at only 1/10 of the plasma peak concentration after 72 h exposure. Anthracyclines, in particular NPLDX, were highly concentrated in the Golgi apparatus. Moreover, a significant increase was observed in the expression of CD95 receptor, GD3 ganglioside and, caspase-2 and -8 active forms in both cell lines followed by caspase-3 activation and mitochondrial membrane depolarization. The Golgi apparatus, probably acting as a stress sensor, intensified the conventional apoptotic mechanism induced by anthracyclines. Our data support the hypothesis that organelle-dependent initiation of cell death other than that induced by mitochondria and nucleus is a research area worthy of pursuing and suggest that the Golgi apparatus could be an ideal target for anti-cancer therapy. Of note, the activity of NLPDX in taxane-resistant DU145-R cells warrants further evaluation as second-line treatment of advanced HRPC after taxane failure.
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Fabbri
authors.forename: Wainer
authors.initials: W
authors.lastname: Zoli
authors.forename: Silvia
authors.initials: S
authors.lastname: Carloni
authors.forename: Paola
authors.initials: P
authors.lastname: Ulivi
authors.forename: Chiara
authors.initials: C
authors.lastname: Arienti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Brigliadori
authors.forename: Marco
authors.initials: M
authors.lastname: Montanari
authors.forename: Anna
authors.initials: A
authors.lastname: Tesei
authors.forename: Rosella
authors.initials: R
authors.lastname: Silvestrini
authors.forename: Dino
authors.initials: D
authors.lastname: Amadori
mesh_terms: D018943:Anthracyclines / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D020169:Caspases / Q000096:biosynthesis; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005732:Gangliosides / Q000096:biosynthesis; D006056:Golgi Apparatus / Q000187:drug effects*; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000378:metabolism*; D043823:Taxoids / Q000494:pharmacology; D019014:fas Receptor / Q000096:biosynthesis
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; C491901:FAS protein, human; D005732:Gangliosides; D043823:Taxoids; D019014:fas Receptor; C080625:taxane; C026226:ganglioside, GD3; D020169:Caspases