3,3',4,4',5,5'-hexahydroxystilbene impairs melanoma progression in a metastatic mouse model.
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.
Paulitschke
Verena
V
Department of Dermatology, Medical University of Vienna, Währingergürtel 18-20, Vienna, Austria.
Schicher
Nikolaus
N
Szekeres
Thomas
T
Jäger
Walter
W
Elbling
Leonilla
L
Riemer
Angelika B
AB
Scheiner
Otto
O
Trimurtulu
Golakoti
G
Venkateswarlu
Somepalli
S
Mikula
Mario
M
Swoboda
Alexander
A
Fiebiger
Edda
E
Gerner
Christopher
C
Pehamberger
Hubert
H
Kunstfeld
Rainer
R
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
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