期刊
ONCOTARGET
卷 5, 期 12, 页码 4567-4578出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2146
关键词
cytotoxic peptide analog; targeted therapy; GnRH; reactive oxygen species; hormone-naive prostate cancer; CRPC; LHRH agonist
资金
- Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development of the Miami VA Healthcare System
- Department of Pathology, Sylvester Comprehensive Cancer Center
- Department of Medicine, Sylvester Comprehensive Cancer Center
- Division of Hematology/Oncology of the Miller Medical School, Department of the Miller School of Medicine, University of Miami
- South Florida Veterans Affairs Foundation for Research and Education
- L. Austin Weeks Endowment for Urologic Research
- Department of Medicine, Dresden, Germany
- Helmholtz Alliance Imaging and Curing Environmental Metabolic Diseases through the Initiative and Networking Fund of the Helmholtz Association
- Urology Care Foundation Research Scholars Program
- AUA Southeastern Section
Management of castration-resistant prostate cancer (CRPC) is challenging due to lack of efficacious therapy. Luteinizing hormone-releasing hormone (LHRH) 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.
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