title: Saquinavir-NO-targeted S6 protein mediates sensitivity of androgen-dependent prostate cancer cells to TRAIL.
abstract: We previously reported that the NO-modified form of HIV protease inhibitor Saquinavir (Saq) is a potent antitumoral agent efficient against numerous tumor cell lines in vitro and in vivo. In acute toxicity studies, doses of Saq-NO equivalent to DL100 of the parental drug were completely nontoxic. Beside direct effect on malignant cell growth, Saq-NO sensitizes certain type of cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated cell death. In this study, we evaluated the effects of Saq-NO on androgen-dependent prostate cancer LNCaP. Saq-NO inhibited both the growth of LNCaP cells in vitro and in xenograft models. Suppression of tumor growth was accompanied with cell cycle arrest in G 0/G 1 phase and established a persistent inhibition of proliferation. Furthermore, Saq-NO reverted sensitivity of LNCaP cells to TRAIL but not to TNF. Treatment of cells with Saq-NO induced transient upregulation of Akt and ERK1/2. This, however, did not represent the primary mode of action of Saq-NO, as elimination with specific inhibitors did not compromise the chemotherapic efficacy of the drug. However, permanent abrogation of phosphorylation of the S6 protein, which is the downstream target of both signaling pathways, was observed. Diminished S6 phosphorylation was associated with re-established sensitivity to TRAIL and reduction of X-linked inhibitor of apoptosis protein (XIAP). In summary, NO modification of Saq led to a new chemical entity with stronger and more pleiotropic antitumor activity than the parental drug.
authors.affiliation: Department of Immunology; Institute for Biological Research Sinisa Stankovic, Belgrade University, Belgrade, Serbia.
authors.forename: Marija
authors.initials: M
authors.lastname: Mojic
authors.forename: Sanja
authors.initials: S
authors.lastname: Mijatovic
authors.forename: Danijela
authors.initials: D
authors.lastname: Maksimovic-Ivanic
authors.forename: Svetlana
authors.initials: S
authors.lastname: Dinic
authors.forename: Nevena
authors.initials: N
authors.lastname: Grdovic
authors.forename: Djordje
authors.initials: D
authors.lastname: Miljkovic
authors.forename: Stanislava
authors.initials: S
authors.lastname: Stosic-Grujicic
authors.forename: Salvatore
authors.initials: S
authors.lastname: Tumino
authors.forename: Paolo
authors.initials: P
authors.lastname: Fagone
authors.forename: Katia
authors.initials: K
authors.lastname: Mangano
authors.forename: Mai-Britt
authors.initials: MB
authors.lastname: Zocca
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
authors.forename: James A
authors.initials: JA
authors.lastname: McCubrey
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
mesh_terms: D000818:Animals; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism*; D019258:Saquinavir / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C557004:saquinavir-NO; C546842:MTOR protein, human; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D019258:Saquinavir