Signal transduction therapy of cancer

Levitzki, Alexander; Klein, Shoshana

doi:10.1016/j.mam.2010.04.001

Cited by 79 publications

(104 citation statements)

References 161 publications

(163 reference statements)

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“…By now it is well known that development, survival, and metastasis of cancer cells depend on a crosstalk of numerous signal transduction pathways (1,5). Therefore, a change of paradigms has occurred in drug design during recent years: Instead of monospecific agents, those hitting rather a range of metastatic signaling targets are urgently needed (6).…”

Section: Introductionmentioning

confidence: 99%

Indirubin Derivative 6BIO Suppresses Metastasis

et al. 2013

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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.

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Section: Introductionmentioning

confidence: 99%

Indirubin Derivative 6BIO Suppresses Metastasis

et al. 2013

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“…Specific inhibitors of PI3K, AKT and mTOR have shown significant promise in preclinical studies and are now under evaluation in clinical trials (Tab. 1) (Fathi et al, 2010;Levitzki & Klein, 2010;Zhao, 2010). Levy et al (2009) reported that GSK690693, a pan-AKT kinase inhibitor, induces growth inhibition and www.intechopen.com Table 1.…”

Section: Multidrug Resistancementioning

confidence: 99%

Aberrant Proliferative and Apoptotic Pathways in Acute Lymphoblastic Leukemia (ALL): Molecular Therapies to Overcome Chemo-Resistance

et¹,

Milella

Iacovelli³

et al. 2011

Novel Aspects in Acute Lymphoblastic Leukemia

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“…N-terminal pleckstrin homology (PH) domain, a central kinase catalytic (CAT) domain and a C-terminal extension (EXT) containing a regulatory hydrophobic motif (HM) (Kumar, 2005; Levitzki and Klein, 2010;Altman, 2011).…”

Section: Introduction *mentioning

confidence: 99%