Human Adipose Stem Cells Engineered to Express Carboxylesterase Confer Anti-Tumoral Efficacy of Irinotecan in Castration-Resistant Prostate Cancer Bone Metastasis Growth and Osteolysis.

Purpose: Castration-resistant prostate cancer (CRPC) presents a significant clinical challenge, particularly when it metastasizes to bone, leading to skeletal-related events such as osteolysis. Conventional therapies offer limited efficacy and high toxicity, highlighting the need for innovative treatments. This study investigates the use of human telomerase reverse transcriptase-immortalized adipose-derived stem cells engineered to express carboxylesterase (hTERT-ADSC.CE) to enhance the local activation and efficacy of irinotecan (CPT-11) in targeting CRPC.

Materials and methods: hTERT-ADSC.CE1 and hTERT-ADSC.CE2 cells were generated by lentiviral transduction with two genes encoding carboxylesterase enzymes CES1 or CES2 (referred to as CE1 or CE2 in this manuscript), respectively. The migration of hTERT-ADSC.CE1 and hTERT-ADSC.CE2 cells toward prostate cancer cells was evaluated in a transwell migration assay. The cytotoxicity of irinotecan in combination with hTERT-ADSC.CE1 and hTERT-ADSC.CE2 cells on PC3 prostate cancer cells was assessed via MTT viability and apoptosis assays. An in vivo CRPC bone metastasis model in mice was used to examine the therapeutic effects of co-administered hTERT-ADSC.CE2 cells and CPT-11 on tumor growth and tumor-induced osteolysis.

Results: hTERT-ADSC.CE1 and hTERT-ADSC.CE2 cells demonstrated selective migration toward PC3 cells and significantly enhanced the cytotoxic effects of CPT-11 on prostate cancer cells in vitro. In vivo, the combined treatment with hTERT-ADSC.CE2 and CPT-11 significantly reduced tumor growth and osteolytic activity in the bone metastasis model. Histological analysis confirmed increased apoptosis in tumor cells and reduced osteolysis, indicating effective local drug activation by hTERT-ADSC.CE1 and/or hTERT-ADSC.CE2.

Conclusions: Our findings suggest that hTERT-ADSC.CE1 and hTERT-ADSC.CE2 cells combined with irinotecan offer a promising targeted therapy for CRPC, enhancing drug efficacy while minimizing systemic toxicity. This cell-based enzyme-prodrug therapy could address the limitations of current therapies, especially in bone metastatic CRPC, and warrants further investigation for clinical translation.