title: In vitro and in vivo anticancer action of Saquinavir-NO, a novel nitric oxide-derivative of the protease inhibitor saquinavir, on hormone resistant prostate cancer cells.
abstract: The NO-derivative of the HIV protease inhibitor saquinavir (Saq-NO) is a nontoxic variant of the parental drug with enhanced anticancer activity on several cell lines. However, it is still unclear whether the p53 status of the target cell might influence the sensitivity to Saq-NO. In this study we evaluated the in vitro and in vivo activity of Saq-NO on the p53-deficient hormone resistant prostate cancer PC-3 cells. We demonstrate that the absence of functional p53 is not essential for the capacity of Saq-NO to reduce prostate cancer cell growth. In contrast to its previously described cytostatic action in B16 and C6 cell lines, Saq-NO exerted cytotoxic effects in PC-3 cells leading to dominant induction of apoptosis and enhanced production of proapoptotic Bim. In addition, differently from saquinavir, Saq-NO restored TRAIL sensitivity that was correlated with increased expression of DR5 independent from ROS/RNS production and YY1 repression. NF-κB activation may be responsible of the Saq-NO induced DR5 expression. Moreover, Saq-NO but not saquinavir, exerted synergistic activity with conventional cytostatic therapy. In agreement with these in vitro studies, Saq-NO inhibited the in vivo growth of PC-3 cells xenotransplants to a greater extent than the parental compound. Taken together, these data indicate that Saq-NO possesses powerful and suitable in vitro and in vivo chemotherapeutic potential to be further studied as a novel drug for the treatment of prostate cancer in the clinical setting.
authors.affiliation: Department of Biomedical Sciences, University of Catania, Catania, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Donia
authors.forename: Danijela
authors.initials: D
authors.lastname: Maksimovic-Ivanic
authors.forename: Sanja
authors.initials: S
authors.lastname: Mijatovic
authors.forename: Marija
authors.initials: M
authors.lastname: Mojic
authors.forename: Djordje
authors.initials: D
authors.lastname: Miljkovic
authors.forename: Gordana
authors.initials: G
authors.lastname: Timotijevic
authors.forename: Paolo
authors.initials: P
authors.lastname: Fagone
authors.forename: Salvatore
authors.initials: S
authors.lastname: Caponnetto
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
authors.forename: James
authors.initials: J
authors.lastname: McCubrey
authors.forename: Stanislava
authors.initials: S
authors.lastname: Stosic-Grujicic
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019258:Saquinavir / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D011480:Protease Inhibitors; D016159:Tumor Suppressor Protein p53; C557004:saquinavir-NO; D004317:Doxorubicin; D019258:Saquinavir; D017239:Paclitaxel; D002945:Cisplatin