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,Norman L Block,Ferenc G Rick,Luca Szalontay,Andrew V Schally

doi:10.18632/oncotarget.2146

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.

Highlights

In 2014, prostate cancer is expected to account for 27% of newly detected cancers and 10% of cancerrelated deaths in men in the US [1]
Tumor growth was already significantly decreased compared to control at week 1 (71% inhibition vs control, p
More than 80% of resected human prostate cancers express LHRH receptors suggesting that patients with prostatic malignancies would benefit from therapy with the cytotoxic LHRH analog, AEZS-108 [23]

Summary

Introduction

In 2014, prostate cancer is expected to account for 27% of newly detected cancers and 10% of cancerrelated deaths in men in the US [1]. Standard therapy of metastatic prostate cancer is androgen deprivation therapy (ADT) currently achieved by surgical orchiectomy or by treatment with LHRH agonist or antagonist [2,3,4]. Antagonistic analogs of LHRH, that completely lack LH-releasing activity, have been developed and approved for the management of advanced androgen-dependent prostate cancer [8,9,10]. Despite the initial success of ADT on suppressing tumor growth, prostate cancer cells may progress to androgen independence ( referred to as castration resistance) which situation narrows the number of effective treatments. Patients with castrate resistant prostate cancer (CRPC) have a poor prognosis with an expected survival of less than 19 months [11]. There are a few treatment options of chemotherapy for advanced CRPC but none of them are markedly effective [12]

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Results

Conclusion