title: 3,3',4,4',5,5'-hexahydroxystilbene impairs melanoma progression in a metastatic mouse model.
abstract: Stilbenes comprise a group of polyphenolic compounds, which exert inhibitory effects on various malignancies. The aim of this study was to evaluate the antitumor effects of a previously unreported stilbene derivative-3,3',4,4',5,5'-hexahydroxystilbene, termed M8-on human melanoma cells. Cell-cycle analysis of the metastatic melanoma cell line M24met showed that M8 treatment induces G(2)/M arrest accompanied with a dose- and time-dependent upregulation of p21 and downregulation of CDK-2 and leads to apoptosis. M8 induces the expression of phosphorylated p53, proteins involved in the mismatch repair machinery (MSH6, MSH2, and MLH1) and a robust tail moment in a comet assay. In addition, M8 inhibited cell migration in Matrigel assays. Shotgun proteomics and western analysis showed the regulation among others of paxillin, integrin-linked protein kinase, p21-activated kinase, and ROCK-1 indicating that M8 inhibits mesenchymal and amoeboid cell migration. These in vitro data were confirmed in vivo in a metastatic human melanoma severe combined immunodeficient (SCID) mouse model. We showed that M8 significantly impairs tumor growth. M8 also interfered with the metastatic process, as M8 treatment prevented the metastatic spread of melanoma cells to distant lymph nodes in vivo. In summary, M8 exerts strong antitumor effects with the potential to become a new drug for the treatment of metastatic melanoma.
authors: Department of Dermatology, Medical University of Vienna, Währingergürtel 18-20, Vienna, Austria.
authors: Verena
authors: V
authors: Paulitschke
authors: Nikolaus
authors: N
authors: Schicher
authors: Thomas
authors: T
authors: Szekeres
authors: Walter
authors: W
authors: Jäger
authors: Leonilla
authors: L
authors: Elbling
authors: Angelika B
authors: AB
authors: Riemer
authors: Otto
authors: O
authors: Scheiner
authors: Golakoti
authors: G
authors: Trimurtulu
authors: Somepalli
authors: S
authors: Venkateswarlu
authors: Mario
authors: M
authors: Mikula
authors: Alexander
authors: A
authors: Swoboda
authors: Edda
authors: E
authors: Fiebiger
authors: Christopher
authors: C
authors: Gerner
authors: Hubert
authors: H
authors: Pehamberger
authors: Rainer
authors: R
authors: Kunstfeld
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D051419:Paxillin / Q000378:metabolism; D011748:Pyrogallol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013267:Stilbenes / Q000494:pharmacology / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C514772:3,3',4,4',5,5'-hexahydroxystilbene; D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051419:Paxillin; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; D011748:Pyrogallol; D051357:Cyclin-Dependent Kinase 2