Inhibited effects of CAPE-pNO2 on cervical carcinoma in vivo and in vitro and its detected metabolites

Abstract

The development of advanced cervical cancer therapies is a particularly urgent need due to the strong side effects and toxicities of current treatments. Caffeic acid phenethyl ester (CAPE) exhibits broad-spectrum antitumor activities and little toxicity or side effects. In our previous study, caffeic acid para-nitro phenethyl ester (CAPE-pNO₂) significantly improved the effect of anti-platelet aggregation and attenuated myocardial ischemia. Based on this finding, we aimed to further explore the antitumor activity of CAPE-pNO₂ in cervical cancer cells and tumor xenografts. In addition, we assessed the biotransformation of CAPE-pNO₂ in cervical cancer cells. Our study demonstrated that both CAPE and CAPE-pNO₂ can inhibit cell proliferation via the induction of G2/M cell cycle arrest. More importantly, CAPE-pNO₂ dramatically induced cell apoptosis via significant down-regulation of pro-caspase-3, pro-caspase-9, Bcl-2, Cyclin B1 and Cdc2 and up-regulation of cleaved-caspase-3, Bax, CytoC and P21^Cip1. Moreover, CAPE and CAPE-pNO₂ significantly suppressed the growth and angiogenesis of nude mice xenografts. CAPE and CAPE-pNO₂ were found to degrade into four and six metabolites, respectively. The metabolites of CAPE and CAPE-pNO₂ were different, and the major metabolic pathway may be phase II reactions. These results suggest that CAPE-pNO₂ induced cell apoptosis and cell cycle arrest via a strong regulatory effect on relevant apoptotic proteins. Therefore, CAPE-pNO₂ should be further studied as a potent anti-cancer agent.