전립선암 세포주에서 vascular disrupting agent인 CKD-516의 항암 효과와 기전 연구

Abstract

Purpose: CKD-516 is a novel vascular disrupting agent. In this study, we investigated the anticancer effects and mechanisms of CKD-516 on prostate cancer cell line and animal model. Furthermore, we investigated the synergistic effect of combination therapy with CKD-516 and immune checkpoint inhibitor.

Material and methods: S516, the active metabolite of CKD-516, was used for in vitro studies. The mouse prostate epithelial adenocarcinoma cell line TRAMP-C1 and human prostate cancer cell lines including PC3, DU145, LNCaP, and 22Rv1 were obtained. Cell viability assay was performed and mechanisms of CKD-516 was confirmed by western blot analysis. For in vivo analysis, TRAMP-C1 cells were implanted into the mice and CKD-516 was administered via oral gavage at 3mg/kg or 6mg/kg twice per week for 3 weeks. For combination therapy studies, anti-PD-1 was injected 5mg/kg twice per week for 3 weeks. Dendritic cell (DC) was obtained to verify maturation effect of CKD-516 on DC.

Results: S516 inhibited the cell viability of all prostate cancer cells in a concentration-dependent manner, with IC50 values of 0.045 μmol/L, DU145 and LNCaP-0.04 μmol/L, 22Rv-0.004 μmol/L and TRAMP-C1 0.68 μmol/L. S516 induced apoptosis of prostate cancer cell lines by phosphorylation of c-JUN and JNK. In vivo studies demonstrated significant synergistic effect by using both CKD-516 and anti-PD-1. The percentage of tumor growth inhibition was significantly higher in the combination therapy group (36.03% in CKD-516 3mg/kg, 94.11% in CKD-516 and anti-PD-1 combination therapy). DC maturation was induced by CKD-516 and expression of cell surface markers such as CD80 and CD86 were significantly increased.

Conclusions: CKD-516 is a promising agent inducing apoptosis of tumor cells and enhances anticancer effect in combination with an immune checkpoint inhibitor.