title: Targeted cytotoxic analog of luteinizing hormone-releasing hormone (LHRH), AEZS-108 (AN-152), inhibits the growth of DU-145 human castration-resistant prostate cancer in vivo and in vitro through elevating p21 and ROS levels.
abstract: Management of castration-resistant prostate cancer (CRPC) is challenging due to lack of efficacious therapy. Luteinizing hormone-releasing hormone analogs appear to act directly on cells based on the LHRH receptors on human prostate adenocarcinoma cells. We explored anticancer activity of a cytotoxic analog of LHRH, AEZS-108 consisting of LHRH agonist linked to doxorubicin. Nude mice bearing DU-145 tumors were used to compare antitumor effects of AEZS-108 with its individual constituents or their unconjugated combination. The tumor growth inhibition of conjugate was greatest among treatment groups (90.5% inhibition vs. 41% by [D-Lys(6)]LHRH+DOX). The presence of LHRH receptors on DU-145 cells was confirmed by immunocytochemistry. In vitro, AEZS-108 significantly inhibited cell proliferation (61.2% inhibition) and elevated apoptosis rates (by 46%). By the detection of the inherent doxorubicin fluorescence, unconjugated doxorubicin was seen in the nucleus; the conjugate was perinuclear and at cell membrane. Autophagy, visualized by GFP-tagged p62 reporter, was increased by AEZS-108 (7.9-fold vs. 5.3-fold by DOX+[D-Lys(6)]LHRH. AEZS-108 more effectively increased reactive oxygen species (ROS, 2-fold vs. 1.4-fold by DOX+[D-Lys(6)]LHRH) and levels of the apoptotic regulator p21 in vivo and in vitro. We demonstrate robust inhibitory effects of the targeted cytotoxic LHRH analog AEZS-108 on LHRHR positive castration-resistant prostate cancer cells.
authors.affiliation: Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL; Cardiovascular Diseases, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL; Department of Medicine III, Medical Faculty Carl Gustav Carus, Dresden, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Popovics
authors.affiliation: Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL; Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL; Divisions of Hematology/Oncology, University of Miami, Miller School of Medicine, Miami, FL; Endocrinology University of Miami, Miller School of Medicine, Miami, FL.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.affiliation: Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL.
authors.forename: Luca
authors.initials: L
authors.lastname: Szalontay
authors.affiliation: Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL; Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL; Divisions of Hematology/Oncology, University of Miami, Miller School of Medicine, Miami, FL.
authors.forename: Norman L
authors.initials: NL
authors.lastname: Block
authors.affiliation: Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL; Department of Urology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL.
authors.forename: Ferenc G
authors.initials: FG
authors.lastname: Rick
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species; D011966:Receptors, LHRH / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics*
chemical_list: D017382:Reactive Oxygen Species; D011966:Receptors, LHRH; C080883:LHRH, lysine(6)-doxorubicin; D007987:Gonadotropin-Releasing Hormone; D004317:Doxorubicin; D020741:rho GTP-Binding Proteins