Individual and Combined Treatments with Methylated Resveratrol Analogue DMU-214 and Gefitinib Inhibit Tongue Cancer Cells Growth via Apoptosis Induction and EGFR Inhibition.

The methylated resveratrol analogue 3'-hydroxy-3,4,5,4'-tetramethoxystilbene (DMU-214) has been revealed to exert the anti-cancer activity by a block of the cell cycle at the G2/M phase, apoptosis induction, and metastasis inhibition. These biological events may be involved in crosstalk with the epidermal growth factor receptor (EGFR), which belongs to the ErbB family of receptor tyrosine kinases. Several cancer therapeutic approaches employ small molecules capable of inhibiting tyrosine kinases (e.g., gefitinib). According to more recent reports, combining gefitinib with chemotherapeutics, such as cisplatin, seems to be more effective than monotherapy. The present study aimed to assess the molecular mechanism of the potential anti-proliferative activity of individual and combined treatments with DMU-214 and gefitinib in SCC-25 and CAL-27 human tongue cancer cell lines. We showed for the first time the anti-cancer effects of DMU-214, gefitinib, and their combination in tongue cancer cells triggered via cell cycle arrest, apoptosis induction, and inhibition of the EGFR signaling pathway. The anti-proliferative effects of DMU-214 and gefitinib are also suggested to be related to the EGFR and EGFRP (phosphorylated epidermal growth factor receptor) expression status since we found significantly weaker cytotoxic activity of the compounds tested in SCC-25 cells, which overexpressed EGFR and EGFRP proteins.

The Effect of 4'-hydroxy-3,4,5-trimetoxystilbene, the Metabolite of Resveratrol Analogue DMU-212, on Growth, Cell Cycle and Apoptosis in DLD-1 and LOVO Colon Cancer Cell Lines.

Resveratrol is a phytoalexin that naturally occurs in grapes, blueberries, cranberries, peanuts and many other plants. Although resveratrol inhibits carcinogenesis in all three stages, its clinical application is restricted due to poor pharmacokinetics. The methylated analogues of resveratrol have been found to have higher bioavailability and cytotoxic activity than that of the prototupe compound. Among the various methoxy derivatives of resveratrol, 3,4,5,4'-tetrametoxystilbene (DMU-212) is suggested to be one of the strongest activators of cytotoxicity and apoptosis. DMU-212 has been shown to exert anti-tumor activity in DLD-1 and LOVO colon cancer cells. Since colorectal cancer is the third most common cause of cancer-related deaths worldwide, the development of new anticancer agents is nowadays of high significance. The aim of the present study was to assess the anticancer activity of 4'-hydroxy-3,4,5-trimetoxystilbene (DMU-281), the metabolite of DMU-212, in DLD-1 and LOVO cell lines. We showed for the first time the cytotoxic activity of DMU-281 triggered via cell cycle arrest at G2/M phase and apoptosis induction accompanied by the activation of caspases-9, -8, -3/7. Furthermore, DMU-281 has been found to change the expression pattern of genes and proteins related to intrinsic as well as extrinsic apoptosis. Since the activation of these pathways of apoptosis is still the most desired strategy in anticancer research, DMU-281 seems to provide a promising approach to the treatment of colon cancer.

The Effect of 3'-Hydroxy-3,4,5,4'-Tetramethoxy -stilbene, the Metabolite of the Resveratrol Analogue DMU-212, on the Motility and Proliferation of Ovarian Cancer Cells.

Targeting tumor cell motility and proliferation is an extremely important challenge in the prevention of metastasis and improving the effectiveness of cancer treatment. We recently published data revealing that DMU-214, the metabolite of firmly cytotoxic resveratrol analogue DMU-212, exerted significantly higher biological activity than the parent compound in ovarian cancer cells. The aim of the present study was to assess the molecular mechanism of the potential anti-migration and anti-proliferative effect of DMU-214 in ovarian cancer cell line SKOV-3. We showed that DMU-214 reduced the migratory capacity of SKOV-3 cells. The microarray analysis indicated ontology groups of genes involved in processes of negative regulation of cell motility and proliferation. Furthermore, we found DMU-214 triggered changes in expression of several migration- and proliferation-related genes (SMAD7, THBS1, IGFBP3, KLF4, Il6, ILA, SOX4, IL15, SRF, RGCC, GPR56) and proteins (GPR56, RGCC, SRF, SMAD7, THBS1), which have been shown to interact to each other to reduce cell proliferation and motility. Our study showed for the first time that DMU-214 displayed anti-migratory and anti-proliferative activity in SKOV-3 ovarian cancer cells. On the basis of whole transcriptome analysis of these cells, we provide new insight into the role of DMU-214 in inhibition of processes related to metastasis.