3-4--5-trimethoxystilbene and Adenocarcinoma

Resveratrol (3,5,4'-trihydroxystilbene) is a natural polyphenol that presents various physiological activities. It has been reported that the methylated derivatives of resveratrol show better potential antifungal and antiproliferative activities than resveratrol. In the present study, we investigated the inhibitory effect of 3,5,4'-trimethoxy-trans-stilbene (MR-3), a methylated derivative of resveratrol, on the invasion of A549 cells (a human lung adenocarcinoma cell line). We found that treatment with MR-3 at the concentration of 5 muM resulted in antiadhesive, antimigratory, and antiinvasive activities on A549 cells through the suppression of matrix metalloproteinase (MMP)-2 protein expression and transcriptional levels in a time-dependent manner. The suppression of MMP-2 expression by MR-3 led to an inhibition of A549 cell invasion by inactivating phosphorylation of SAPK/c-Jun N-terminal kinase (JNK) and p38 MAPK signaling pathways. A time-dependent inhibition of protein levels for p65, c-Jun, and c-Fos in the nucleus by MR-3 treatment was also observed. In conclusion, our data demonstrate that the antiinvasive effects of MR-3 on A549 cells are likely mediated through the inhibition of phosphorylation of JNK and p38, as well as a reduction in the protein levels of nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) in the nucleus, ultimately leading to downregulation of MMP-2 expression.

Topics: Adenocarcinoma; Cell Line, Tumor; Cell Nucleus; Enzyme Inhibitors; Gene Expression; Humans; JNK Mitogen-Activated Protein Kinases; Lung Neoplasms; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; Mitogen-Activated Protein Kinases; Neoplasm Invasiveness; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Phosphorylation; RNA, Messenger; Signal Transduction; Stilbenes; Transcription Factor AP-1

Resveratrol (R-3), a trihydroxy trans-stilbene from grape, inhibits multistage carcinogenesis in animal models. Here we report that 3,5,4'-trimethoxystilbene (MR-3), the permethylated derivative of R-3 was more potent against the growth of human cancer cells (HT-29, PC-3, COLO 205) with estimated IC(50) values of 81.31,42.71, and 6.25 microM, respectively. We further observed that MR-3 induced apoptosis in COLO 205 cells through modulation of mitochondrial functions regulated by reactive oxygen species (ROS). ROS generation occurs in the early stages of MR-3-induced apoptosis, preceding cytochrome-c release, caspase activation, and DNA fragmentation. Significant therapeutic effects were demonstrated in vivo by treating severe combined immune deficiency (SCID) mice bearing COLO 205 tumor xenografts with MR-3 (50 mg/kg ip). Assays on DNA fragmentation and caspase activation were performed and demonstrated that apoptosis occurred in tumor tissues treated with MR-3. The appearance of apoptotic cells, as shown by Hematoxylin and Eosin (H&E) staining, and an increase in p21 and decrease in proliferating cell nuclear antigen (PCNA) protein by immuno-histochemistry were observed in tumor tissues under MR-3 treatment. Our study identifies the novel mechanisms of the antitumor effects of MR-3 and indicates that these results may have significant applications for cancer chemotherapy.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Apoptosis; Caspases; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; DNA Fragmentation; Drug Evaluation, Preclinical; Enzyme Activation; Humans; Immunohistochemistry; Inhibitory Concentration 50; Membrane Potentials; Mice; Mice, SCID; Mitochondria; Molecular Structure; Proliferating Cell Nuclear Antigen; Reactive Oxygen Species; Stilbenes; Xenograft Model Antitumor Assays