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

BACKGROUND Since neuroendocrine (NE) cells play an important role in the development of castration-resistant prostate cancer (CRPC), target therapy to NE cells should be considered for treating CRPC. We investigated the effects zoledronic acid (ZOL) and two somatostatin analogs (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. METHODS We examined the in vivo effects of ZOL, SMS and SOM as single agents and their combinations on subcutaneously inoculated NE-10 allografts and the in vitro effects on NE-CS cells. Apoptosis and cell cycle activity were assessed by immunohistochemistry using TdT-mediated dUTP-biotin nick-end labeling (TUNEL) and a Ki-67 antibody, respectively. RESULTS In vivo growth of NE-10 tumors treated with ZOL, ZOL plus SMS, or ZOL plus SOM was significantly inhibited 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 analogs (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. CONCLUSIONS ZOL, but not SMS or SOM, induced apoptosis and inhibition of proliferation and migration through impaired prenylation of Ras in NE carcinoma models. Our findings support the possibility that ZOL could be used in the early phase for controlling NE cells, which may trigger progression to CRPC.