Carboxylesterase-overexpressing hTERT-immortalized human adipose stem cells in prostate tumor growth inhibition by irinotecan.

Abstract

Effective chemotherapy has not yet to be developed for castration-resistant prostate cancer (CRPC). Cell-mediated enzyme prodrug therapy (EPT), including a combination of carboxylesterase (CE) and irinotecan (CPT-11), could be a possible treatment option. This study explored a cell-mediated EPT, including a combination of CE and irinotecan (CPT-11), to inhibit CRPC tumor growth using rabbit CE-overexpressing human TERT-immortalized adipose-derived stem cells (hTERT-ADSC.CE). An hTERT ADSC.CE cell line was established by transfection with a lentiviral vector (CLV-Ubic) encoding the rabbit CE gene. To determine the in vitro suicide effects of hTERT-ADSC.CE, cell cultures were performed using various concentrations of CPT-11 (0.01-5 μM), and to determine the in vitro cytotoxic effects of hTERT-ADSC.CE cells, PC3 and hTERT-ADSC.CE cells were co-cultured. For the in vivo model, PC3 cells (1 × 106 cells) were injected subcutaneously into the flanks of nude mice and hTERT-ADSC.CE cells were injected via an intracardiac route, followed by the continuous treatment using CPT-11 for 2 weeks. The final change in tumor volume was measured and immunohistochemical analysis was performed. The directional and selective migration of hTERT-ADSC.CE cells toward PC3 cells was significantly stimulated by PC3 cells in vitro. The number of apoptotic PC3 cells significantly increased in the presence of hTERT-ADSC.CE and CPT-11 compared to CPT-11 alone. In the in vivo study, the inhibitory effects of hTERT-ADSC.CE combined with CPT-11 were higher than those of CPT-11 monotherapy. After treatment with CPT-11 alone or ADSC.CE in combination with CPT-11, the removed tumor tissues showed hyperchromatic nuclei and apoptotic bodies. CE-overexpressing ADSCs potentiated the inhibition of tumor growth in CRPC-bearing mice in the presence of CPT-11 prodrugs. This report suggests that cell-mediated EPT including CE and CPT-11 may be efficacious in treating CRPC.