Abstract
Abstract Isodon rubescens (a Chinese herb named “Donglingcao”) has been used as a folk, botanical medicine for treatment of inflammatory diseases and cancer for many years. Oridonin, a complex ent-kaurane diterpenoid that was isolated from this herb, has been demonstrated as a promising anti-cancer agent. However, the anti-cancer potency of oridonin and its in vivo stability remains unsatisfactory for its clinical development. Therefore, we have designed and synthesized a series of acetal and halogen oridonin analogues at the 20 position of the chemical skeleton. All these analogues have demonstrated improved potency over oridonin against the growth of bladder, breast, colon, lung and prostate cancer cell lines with low micromolar to submicromolar IC50 values. In particular, compound 10 potently induces apoptosis in both androgen-sensitive and castration-resistant prostate cancer cell lines, including LAPC4, LNCaP, 22Rv1, PC3 and DU145. Compound 10 increased the expression of YAP1 and its phosphorylation, as well as expression of p73 and p53, which further led to upregulation of p73/p53 target gene PUMA. The apoptotic effect of compound 10 is at least in part dependent on the existence of p53 and PUMA. These results demonstrated the potential of compound 10 as a novel apoptosis inducer for treatment of prostate cancer. The evaluation of the in vivo anti-tumor efficacy of compound 10 is in progress. Note: This abstract was not presented at the meeting. Citation Format: Yu Ke, Zhongbo Liu, Hong-Min Liu, Xiaolin Zi. Novel acetal and halogen oridonin analogues potently induce apoptosis in prostate cancer cell lines via induction of p53/p73 and PUMA expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1254. doi:10.1158/1538-7445.AM2014-1254
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