Abstract 2125: AN-162, a targeted cytotoxic analog of somatostatin, suppresses growth of human hormone refractory prostate cancers in vitro and in vivo.
Authors: Rick Ferenc G. , Abi-Chaker Andrew , Szalontay Luca , Block Norman L. , Halmos Gabor , Schally Andrew V. 
Published: August 2014

BACKGROUND: Prostate cancer is the most common non-cutaneous human cancer found in the US. Although generally prostate cancer does not have overwhelming effects on patient mortality, the management of hormone refractory prostate cancers (HRPC) has been found to be challenging because of the limitations of current therapeutic modalities. Due to these cancers being hormone refractory alternative therapies have been sought after. One such therapy focuses on the unusual expression of somatostatin receptors in a large percentage of human HRPC samples. Here we tested targeted somatostatin analog, AN-162, consisting of doxorubicin (DOX) conjugated to a somatostatin analog which acts as a carrier in cell lines of human hormone refractory prostate cancer in vitro and in vivo.

METHODS: Expression of mRNA for the five subtypes of the somatostatin receptor in PC-3 and DU-145 human prostate cancer cell lines was evaluated by RT-PCR. Somatostatin receptor binding was measured with radioligand assays. The influence of AN-162 and DOX on the viability of PC-3 and DU-145 cells was assessed by MTS assay. Nude mice bearing PC-3 and DU-145 tumors were randomized to 5 groups (control, AN-162, DOX, somatostatin analog RC-160 as a control, and DOX + RC-160). Treatment consisted i.v. injections of AN-162, DOX, RC-160, DOX + RC-160, or vehicle once a week for 4 weeks. Tumor volume was measured every week; the study lasted 28 days. The doses of AN-162 were equivalent to 1.45 mg/kg DOX (2.5 μmol/kg). In addition, cell cycle analysis was performed via laser flow cytometry at concentrations of 1μM for each group.

RESULTS: The expression of mRNA for the five subtypes of the somatostatin receptor were demonstrated in PC-3 and DU-145 cell lines and xenografts. Specific, high-affinity binding sites for somatostatin were demonstrated. AN-162 and DOX (0.10-10 μM) suppressed the proliferation of PC-3 and DU-145 prostate cancer cells in a dose-dependent manner. In vivo, AN-162 exerted a stronger inhibition of growth than DOX alone; but in vitro the difference was not significant. In vivo, AN-162 significantly inhibited growth of both tumor models’ compared with the controls and with the groups given equimolar doses of doxorubicin, RC-160, or doxorubicin plus RC-160. Treatment of these cell lines with 1μM of AN-162, Doxorubicin, and the combination of Doxorubicin with RC-160 all expressed significant blocks in the G2/M phase with AN-162 exhibiting the most effective blockage of cell growth and leading to an increased number of apoptotic cells.

CONCLUSIONS: Our work establishes potent inhibitory effects of AN-162 on somatostatin receptor positive hormone refractory prostate cancers. The effects were superior to any of the components of AN-162. The mechanisms of action of targeted cytotoxic somatostatin analog, AN-162, in HRPC should be explored. Our findings suggest a possible use of AN-162 in HRPC patients.

Citation Format: Ferenc G. Rick, Andrew Abi-Chaker, Luca Szalontay, Norman L. Block, Gabor Halmos, Andrew V. Schally. AN-162, a targeted cytotoxic analog of somatostatin, suppresses growth of human hormone refractory prostate cancers in vitro and in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2125. doi:10.1158/1538-7445.AM2013-2125