Oncotarget

Research Papers:

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

Petra Popovics, Andrew V. Schally, Luca Szalontay, Norman L. Block, Ferenc G. Rick _

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Oncotarget. 2014; 5:4567-4578. https://doi.org/10.18632/oncotarget.2146

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Abstract

Petra Popovics1,5,7, Andrew V. Schally1,2,3,4, Luca Szalontay1, Norman L. Block1,2,3 and Ferenc G. Rick1,6

1 Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL

2 Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL

3 Division of Hematology/Oncology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL

4 Division of Endocrinology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL

5 Division of Cardiovascular Diseases, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL

6 Department of Urology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL

7 Department of Medicine III, Medical Faculty Carl Gustav Carus, Dresden, Germany

Correspondence:

Ferenc G. Rick, email:

Keywords: cytotoxic peptide analog, targeted therapy, GnRH, reactive oxygen species, hormone-naive prostate cancer, CRPC, LHRH agonist

Received: June 19, 2014 Accepted: June 26, 2014 Published: June 29, 2014

Abstract

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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