Anti-colon cancer effect of caffeic acid p-nitro-phenethyl ester in vitro and in vivo and detection of its metabolites.

Caffeic acid phenethyl ester (CAPE), extracted from propolis, was proven to inhibit colon cancer. Caffeic acid p-nitro-phenethyl ester (CAPE-pNO2), a derivative of CAPE, was determined to be an anti-platelet agent and a protector of myocardial ischaemia with more potent effects. In the present study, CAPE-pNO2 showed stronger cytotoxic activity than CAPE. We revealed interactions between CAPE-pNO2 and experimental cells. CAPE-pNO2 induced apoptosis in HT-29 cells by up-regulating P53, cleaved-caspase-3, Bax, P38 and CytoC; CAPE-pNO2 also up-regulated P21Cip1 and P27Kip1 and down-regulated CDK2 and c-Myc to promote cell cycle arrest in G0/G1. In xenograft studies, CAPE-pNO2 remarkably suppressed tumour growth dose dependently and decreased the expression of VEGF (vascular endothelial growth factor) in tumour tissue. Moreover, HE staining showed that no observable toxicity was found in the heart, liver, kidney and spleen. In addition, metabolites of CAPE-pNO2 in HT-29 cells and organs were detected. In conclusion, para-nitro may enhance the anticancer effect of CAPE by inhibiting colon cancer cell viability, inducing apoptosis and cell cycle arrest via the P53 pathway and inhibiting tumour growth and reducing tumour invasion by decreasing the expression of VEGF; additionally, metabolites of CAPE-pNO2 showed differences in cells and organs.