Yun Da Hyun, Kim Jae Heon, Lee Sang Hun, Lee Eun Jung, Park Serk In, Song Yun Seob
Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Korea.
Department of Urology, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea.
World J Mens Health. 2025 Jun 11. doi: 10.5534/wjmh.240284.
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.
hTERT-ADSC.CE1 and hTERT-ADSC.CE2 cells were generated by lentiviral transduction with two genes encoding carboxylesterase enzymes or (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 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.
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 . , 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.
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.
去势抵抗性前列腺癌（CRPC）是一项重大的临床挑战，尤其是当它转移至骨骼时，会引发诸如骨溶解等骨相关事件。传统疗法疗效有限且毒性高，凸显了创新治疗方法的必要性。本研究调查了经工程改造以表达羧酸酯酶的人端粒酶逆转录酶永生化脂肪来源干细胞（hTERT - ADSC.CE）在增强伊立替康（CPT - 11）靶向CRPC的局部激活和疗效方面的应用。
hTERT - ADSC.CE1和hTERT - ADSC.CE2细胞分别通过慢病毒转导编码羧酸酯酶的两个基因产生（在本手稿中分别称为CE1或CE2）。在Transwell迁移试验中评估hTERT - ADSC.CE1和hTERT - ADSC.CE2细胞向前列腺癌细胞的迁移。通过MTT活力和凋亡试验评估伊立替康与hTERT - ADSC.CE1和hTERT - ADSC.CE2细胞联合对PC3前列腺癌细胞的细胞毒性。使用小鼠CRPC骨转移模型来检查联合给予hTERT - ADSC.CE2细胞和CPT - 11对肿瘤生长和肿瘤诱导的骨溶解的治疗效果。
hTERT - ADSC.CE1和hTERT - ADSC.CE2细胞表现出对PC3细胞的选择性迁移，并显著增强了CPT - 11对前列腺癌细胞的细胞毒性作用。此外，在骨转移模型中，hTERT - ADSC.CE2和CPT - 11的联合治疗显著降低了肿瘤生长和骨溶解活性。组织学分析证实肿瘤细胞凋亡增加且骨溶解减少，表明hTERT - ADSC.CE1和/或hTERT - ADSC.CE2有效激活了局部药物。
我们的研究结果表明，hTERT - ADSC.CE1和hTERT - ADSC.CE2细胞与伊立替康联合为CRPC提供了一种有前景的靶向治疗方法，在将全身毒性降至最低的同时提高了药物疗效。这种基于细胞的酶 - 前药疗法可以解决当前疗法的局限性，特别是在骨转移性CRPC中，值得进一步研究以实现临床转化。
