Targeted cytotoxic analog of luteinizing hormone-releasing hormone (LHRH), AEZS-108 (AN-152), inhibits the growth of DU-145 human castration-resistant prostate cancerin vivoandin vitrothrough 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 (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.

Potentiating effects of GHRH analogs on the response to chemotherapy

“…Among the affected pathways are the PI3K/AKT and inflammatory cytokine pathways that regulate EMT. 18,25,37 This reduction as described above in the expression of the multidrug resistance (MDRI) gene, the drug resistance regulator, NANOG, and the suppression of efflux pump function produced by GHRH antagonists in doxorubicintreated HCC1806 and MX-1 breast cancers was similar to those obtained in many cancers employing other therapies targeted to peptide receptors of tumors, using, for example, cytotoxic analogs of luteinizing hormone-releasing hormone (LHRH), AN-152 or AN-207, [38][39][40][41][42] or other targeted cytotoxic analogs including AN-162 and AN-238 [43][44][45][46] which are based on somatostatin. 47,48 In both circumstances of therapy with GHRH antagonists or other targeted analogs these findings clearly demonstrate a more efficacious chemotherapeutic result by the mechanism of disabling of the efflux pumps and the reduction in resulting resistance to chemotherapy.…”

The targeted LHRH analog AEZS-108 alters expression of genes related to angiogenesis and development of metastasis in uveal melanoma

“…The compounds were dissolved in NaCl (Salsol-A, Teva Pharmaceutical Works Ltd., Hungary) containing 0.01 M aqueous acetic acid at a stock concentration of 100 µM. Based on previous studies, compounds were used in 5 µM concentration [33,51].…”

Bench-to-bedside development of agonists and antagonists of luteinizing hormone–releasing hormone for treatment of advanced prostate cancer

“…Hormonal therapy for PCa, based on agonistic analogues of LHRH, was also developed in our laboratory [2]. In addition to agonistic analogues of LHRH, our group has also developed antagonistic analogues and cytotoxic analogues of LHRH [2,[5][6][7].…”

“…To eliminate the undesirable edematogenic effect, new analogues with neutral D-ureidoalkyl amino acids were synthesized in our laboratory [5]. Among these antagonists devoid of any significant edematogenic effects, cetrorelix had the highest overall inhibitory activity and receptor binding affinity [13].…”