Indirubin Derivative 6BIO Suppresses Metastasis

Abstract

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 0 -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 3b (GSK3b) 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 Cterminal tensin-like protein and matrix metalloproteinase 2. However, PDK1 and GSK3b 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. Cancer Res; 73(19); 6004-12. Ó2013 AACR.

6BIO Enhances Oligonucleotide Activity in Cells: A Potential Combinatorial Anti-androgen Receptor Therapy in Prostate Cancer Cells

“…26 Strikingly, we found that it also represses both the AR and the AR-V7 gene expression as a single agent, and it enhances AR-ASO function when the ASO is delivered by gymnosis to prostate cancer cells. To our knowledge, there is no therapeutic agent currently available that can effectively repress the AR-V7 splice variant.…”

“…These include the CDK family members CDK1, CDK2, and CDK5, in addition to PDK1, JAK/STAT3, and GSK-3a/b. 22,26,40,[43][44][45] GSK-3a/b is a ubiquitously expressed serine-threonine kinase encoded by distinct genes. 47 The two isoforms share 97% sequence homology within their catalytic domains but differ in their C and N termini.…”

“…Among the reported targets of 6BIO is the GSK-3 kinase, 22,26,40,[43][44][45] which consists of two distinct isoforms, GSK-3a and GSK-3b, and which has been implicated in multiple cellular processes and in prostate cancer pathogenesis. 46,47 To understand the mechanism of action of 6BIO, we used another GSK-3a/b inhibitor, CHIR99021, to determine whether it had similar effects as 6BIO on ASO activity and AR regulation.…”

Some leopards can change their spots: potential repositioning of stem cell reprogramming compounds as anti-cancer agents

“…Thus, drugs that can block the metastatic spread of cancer cells would have a major impact on cancer patient survival. Employing the 4T1 mouse model of aggressive breast cancer, it was observed that 1 mg/kg BIO pre-treatment dramatically reduced lung metastasis 8 days after intravenous delivery of cancer cells (Braig et al 2013). BIO treatment reduced the cell invasiveness by down-regulating expression of the pro-migratory factors, C-terminal tensinlike protein, and matrix metalloproteinase 2, which was also linked to inhibition of the JAK/STAT3 pathway.…”

Modeling conformational transitions in kinases by molecular dynamics simulations: achievements, difficulties, and open challenges

“…These deep roots made possible the successful application of in silico rational drug design in a growing number of cases: (1) the so-called hybrid-design was carried out, in which the same kinase inhibitor targets different protein regions, thus merging the characteristic of potency (typical of first generation inhibitors) and selectivity (obtained by second generation ones) (Albaugh et al, 2012); (2) imatinib was also reengineered to reduce its cardiotoxicity, by making use of a different water propensity of two residues in the principal and secondary target kinases (Fernandez et al, 2007). Several MD simulations were carried out at this scope, that were able to discriminate the dynamic and structural characteristics of Bcr-Abl and C-Abl kinases, this last responsible for the cardiotoxic effects; (3) systematic rigid body docking of potential inhibitors against 84 unique protein kinases identified three derivatives of indirubin (Zahler et al, 2007), one of which has been recently indicated as particularly active against cancer metastasis (Braig et al, 2013). …”