Indirubin derivative 6BIO suppresses metastasis.
While metastasis is the chief cause of cancer mortality, there nonetheless remains a lack of antimetastatic therapies that are clinically available. In this study, we present the indirubin derivative 6-bromo-indirubin-3'-oxime (6BIO) as a promising antimetastatic agent. 6BIO strongly reduced formation of lung metastasis in the well-established 4T1 mouse model of aggressive breast cancer. Several major hallmarks of the metastatic process were affected by subtoxic concentrations of 6BIO, which inhibited adhesion, migration, and invasion of a variety of metastatic cell types in vitro. Mechanistic analyses focused on known targets of 6BIO, which were silenced by this compound. Unexpectedly, RNAi-mediated silencing of glycogen synthase kinase 3β (GSK3β) and phosphoinositide-dependent protein kinase 1 (PDK1), both modulators of cellular metastasis targeted by 6BIO, were not found to affect invasive migration in this study. Instead, the Jak/STAT3 signaling pathway appeared to play a major role through modulation of its downstream migration regulators C-terminal tensin-like protein and matrix metalloproteinase 2. However, PDK1 and GSK3β contributed to the overall response to 6BIO, as silencing of all three pathways resulted in almost complete inhibition of migration, phenocopying the 6BIO response. Taken together, our findings illustrate the antimetastatic activity of 6BIO on the basis of its ability to simultaneously inhibit several kinase cascades involved in metastasis of cancer cells, supporting the concept of "polypharmacology" in developing drugs to attack metastasis, the most deadly aspect of cancer.
Authors' Affiliations: Pharmaceutical Biology, Department of Pharmacy, University of Munich, Munich, Germany; and Centre Nationale de la Recherche Scientifique, Station Biologique, Roscoff, France.
Simone
S
Braig
Christine A
CA
Kressirer
Johanna
J
Liebl
Fabian
F
Bischoff
Stefan
S
Zahler
Laurent
L
Meijer
Angelika M
AM
Vollmar
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002633:Chemotaxis; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010091:Oximes / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000187:drug effects*
C483321:6-bromoindirubin-3'-oxime; D007211:Indoles; D010091:Oximes; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D050791:STAT Transcription Factors; D017346:Protein Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D020778:Matrix Metalloproteinase 2