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Zoledronic acid but not somatostatin analogs exerts anti-tumor effects in a model of murine prostatic neuroendocrine carcinoma of the development of castration-resistant prostate cancer

Hashimoto, Kohei and Masumori, Naoya and Tanaka, Toshiaki and Maeda, Toshihiro and Kobayashi, Ko and Kitamura, Hiroshi and Hirata, Koichi and Tsukamoto, Taiji (2012) Zoledronic acid but not somatostatin analogs exerts anti-tumor effects in a model of murine prostatic neuroendocrine carcinoma of the development of castration-resistant prostate cancer. The Prostate. ISSN 0270-4137

Abstract

Since neuroendocrine (NE) cells play an important role in the development of castration-resistant prostate cancer (CRPC), targeting therapy for NE cells should be considered for treating CRPC. We investigated the effects zoledronic acid (ZOL) and two somatostatin analogues (octreotide: SMS, and pasireotide: SOM) on an NE allograft (NE-10) and its cell line (NE-CS), which were established from the prostate of the LPB-Tag 12T-10 transgenic mouse. We examined the in vivo effects of ZOL, SMS and SOM as single agents and their combinatorial effects on subcutaneously inoculated NE-10 allografts and the in vitro effects on NE-CS cells. Apoptosis and cell cycle activity were assessed in vivo and in vitro by immunohistochemistry using TdT-mediated dUTP-biotin nick-end labeling (TUNEL) and a Ki-67 antibody, respectively. In vivo growth of NE-10 tumors treated with ZOL, ZOL plus SMS, or ZOL plus SOM was significantly slowed compared to the control as a consequence of induction of apoptosis and cell cycle arrest. ZOL induced time- and dose-dependent inhibition of in vitro proliferation of NE-CS cells, but the somatostatin analogues (SMS and SOM) did not. ZOL also inhibited migration of NE-CS cells. These effects were caused by inhibition of Erk1/2 phosphorylation via impairment of prenylation of Ras. Thus ZOL, but not SMS or SOM, induced antiproliferation, apoptosis and antimigration via impaired prenylation of Ras in NE carcinoma models. Our findings support the possibility that ZOL can be used in the early phase for controlling NE cells that may be potential triggers of prostate cancer leading to CRPC.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/6764

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