In the present study, we synthesized several non-aldehyde analogues of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal which showed anti-cancer effect. Interestingly, among the 16 compounds, we found that (E)-2-methoxy-4-(3-(4-methoxyphenyl)prop-1-en-1-yl)phenol (MMPP) showed the most significant anti-proliferative effect on PA-1 and SK-OV-3 ovarian epithelial cancer cells. MMPP treatment (0-15 µg/mL) induced apoptotic cell death, enhanced the expression of cleaved caspase-3, and cleaved caspase-9 in a concentration dependent manner. Notably, DNA binding activity of STAT3, phosphorylation of extracellular signal-regulated kinase (ERK) and p38 was significantly decreased by MMPP treatment. However, ERK siRNA augmented MMPP-induced inhibitory effect on cell growth rather than p38 siRNA or JNK siRNA. Moreover, combination treatment of MMPP with ERK inhibitor U0126 (10 µM) augmented MMPP-induced inhibitory effect on cell growth and DNA binding activity of STAT3, and enhanced expression of cleaved caspase-3 and cleaved caspase-9. In addition, STAT3 siRNA transfection augmented MMPP-induced cell growth inhibition. In PA-1 bearing xenograft mice model, MMPP (5 mg/kg) suppressed tumor growth significantly. Immunohistochemistry staining showed that the expression levels of p-ERK, PCNA, p-STAT3 were decreased while the expression level of caspase-3 was increased by MMPP treatment. Thus, MMPP may be a promising anti-cancer agent in ovarian epithelial cancer treatment.
Keywords: ERK; MMPP; STAT3; apoptosis; ovarian epithelial cancer.
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