2-4-bis(p-hydroxyphenyl)-2-butenal and Ovarian-Neoplasms

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.

Topics: Aldehydes; Animals; Antineoplastic Agents; Apoptosis Regulatory Proteins; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cell Proliferation; DNA, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Female; Guaiacol; Humans; Male; Mice; Mice, Inbred BALB C; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Phenols; Protein Binding; STAT3 Transcription Factor

Ovarian cancer is a cancerous growth arising from the ovary and with poor prognosis that usually have resistant to all currently available treatments. Whether (E)-2,4-bis(p-hydroxyphenyl)-2-butenal (butenal) synthesized by Maillard reaction from fructose-tyrosine, has potential therapeutic activity against human ovarian cancer was investigated using two ovarian cancer cell lines (PA-1, SK-OV-3). We found that butenal could inhibit NF-κB/STAT3 activity, thereby inducing apoptotic cell death of ovarian cancer cells. We treated with several concentration of butenal each cell line differently (PA-1; 5, 10 and 15 μg/ml, SK-OV-3; 10, 20 and 30 μg/ml). First, ovarian cancer cell lines exhibited constitutively active NF-κB, and treatment with butenal abolished this activation as indicated by DNA binding activity. Second, butenal suppressed activation of signal transducer and activator of transcription-3 as indicated by decreased phosphorylation and inhibition of Janus kinase-2 phosphorylation. Third, butenal induced expression of pro-apoptotic proteins such as proteolytic cleavage of PARP, Bax and activation of caspase-3, -8 and -9. Lastly, combination of butenal and TRAIL causes enhanced induction of apoptosis. Overall, our results indicate that butenal mediates its anti-proliferative and apoptotic effects through activation of multiple cell signaling pathways and enhances the TRAIL-induced apoptosis. These data suggested that butenal may be a potential anti-cancer agent in ovarian cancer.

Topics: Aldehydes; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Female; Humans; Janus Kinase 2; NF-kappa B; Ovarian Neoplasms; Phenols; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; STAT3 Transcription Factor; TNF-Related Apoptosis-Inducing Ligand