p-hydroxycinnamaldehyde and cinnamaldehyde

p-Hydroxylcinnamaldehyde (CMSP) has been identified as an inhibitor of the growth of various cancer cells. However, its function in oesophageal squamous cell carcinoma (ESCC) and the underlying mechanism remain unclear. The aim of the present study was to characterize the differentiation effects of CMSP, as well as its mechanism in the differentiation of ESCC Kyse30 and TE-13 cells. The function of CMSP in the viability, colony formation, migration and invasion of Kyse30 and TE-13 cells was determined by MTS, colony-formation, wound healing and transwell assays. Western blotting and pull-down assays were used to investigate the effect of CMSP on the expression level of malignant markers of ESCC, as well as the activity of MAPKs, RhoA and GTP-RhoA in Kyse30 and TE-13 cells. We found that CMSP could inhibit proliferation and migration and induce Kyse30 and TE-13 cell differentiation, characterized by dendrite-like outgrowth, decreased expression of tumour-associated antigens, as well as the decreased expression of malignant markers. Furthermore, increased cAMP, p-P38 and decreased activities of ERK, JNK and GTP-RhoA, were detected after treatment with CMSP. These results indicated that CMSP induced the differentiation of Kyse30 and TE-13 cells through mediating the cAMP-RhoA-MAPK axis, which might provide new potential strategies for ESCC treatment.

Topics: Acrolein; Animals; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cell Differentiation; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cinnamates; Cyclic AMP; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagus; Humans; MAP Kinase Signaling System; Medicine, Chinese Traditional; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; rhoA GTP-Binding Protein

The natural product 2'-hydroxycinnamaldehyde (HCA) and its analogue, 2'-benzoyloxycinnamaldehyde (BCA), have been previously shown to have antiproliferative and proapoptotic effects in vitro and inhibit tumor growth in vivo. In this study, we use structure-activity analysis to define structural features that are important for the activity of cinnamaldehyde analogues. Our results emphasize an important role for both the propenal group as well as the modification at the 2'-position. Further studies were aimed to characterize the mechanism of action of BCA. Exposure to BCA induced cell death via caspase-dependent and -independent pathways. Cell death was not due to autophagy or necrosis as a result of energy depletion or induction of reactive oxygen species. Our findings have important implications for future drug design and highlight the importance of defining molecular drug targets for this promising class of potential anticancer agents.

Topics: Acrolein; Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Benzoates; Cell Line, Tumor; Cinnamates; Drug Design; Humans; Proteasome Endopeptidase Complex; Structure-Activity Relationship

Cinnamaldehyde derivatives isolated from Cinnamomum cassia have been widely used for treating dyspepsia, gastritis, and inflammatory disease as well as cancer. To investigate the anti-tumor activities of several cinnamaldehyde derivatives, we compared the inhibitory effect of cinnamaldehyde derivatives on cell growth and AP-1 transcriptional activity in SW620 human colon cancer cells since AP-1 is a transcriptional factor implicated to control cancer cell growth. Among the derivatives, 2'-hydroxycinnamaldehyde (HCA) most significantly inhibited cancer cell growth and AP-1 transcriptional activity in a dose-dependent manner with an IC50 value of 12.5 and 9 microg/ml, respectively. In further studies on the mechanism, we found that consistent with the inhibitory effect on cell growth, HCA dose-dependently (0-20 microg/ml) inhibited DNA binding activity of AP-1 accompanied with down regulation of c-Jun and c-Fos expressions. HCA also induced apoptotic cell death as well as expression of the apoptosis-regulating gene caspase-3, but inhibited the anti-apoptosis regulating gene bcl-2 in a dose-dependent manner. These results suggested that HCA has the most potent inhibitory effect against human colon cancer cell growth, and AP-1 may be an important target of HCA.

Topics: Acrolein; Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cinnamates; DNA-Binding Proteins; Dose-Response Relationship, Drug; Electrophoretic Mobility Shift Assay; Growth Inhibitors; Humans; In Situ Nick-End Labeling; Inhibitory Concentration 50; Luciferases; Molecular Structure; Oligonucleotides; Protein Binding; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Structure-Activity Relationship; Transcription Factor AP-1; Transfection