6-bromo-indirubin-3’-oxime (6BIO), a Glycogen synthase kinase-3β inhibitor,
activates cytoprotective cellular modules and suppresses cellular senescence-
mediated biomolecular damage in human fibroblasts
Aimilia D. Sklirou 1, Maria Halabalaki 2, Issidora Papassideri 1, Alexios-Leandros Skaltsounis 2 and Ioannis P. Trougakos 1
1 Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens 15784, Greece
2 Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, University of Athens, Panepistimiopolis Zografou, 15771, Athens, Greece
As genetic interventions or extended caloric restriction cannot be applied in humans, many studies have been devoted to the identification of natural products that can prolong healthspan. 6-bromoindirubin-3'-oxime (6BIO), a hemi-synthetic derivative of indirubins found in edible mollusks, is a potent inhibitor of Glycogen synthase kinase 3β (Gsk-3β). Gsk-3β has been implicated in various age-related diseases including tumorigenesis, neurodegeneration and diabetes; consequently, 6BIO has shown anti-tumor and anti-neurodegenerative activities. We found that treatment of normal human diploid skin fibroblasts with 6BIO reduced the oxidative load, conferred protection against oxidative stress-mediated DNA damage, and it also promoted the activation of antioxidant and proteostatic modules; these effects were largely phenocopied by genetic inhibition of Gsk-3. Furthermore, prolonged treatment of cells with 6BIO decreased the rate of cell cycling and significantly suppressed cellular senescence-related accumulation of biomolecular damage. Our findings suggest that 6BIO is a novel activator of antioxidant responses and of the proteostasis network in normal human cells; moreover, and given the low levels of biomolecules damage in 6BIO treated senescing cells, this compound should exert potent anti-tumor properties.
Conflict of interest: The authors declare no conflict of interest.
Acknowledgement: We acknowledge the Special Account for Research Grants of NKUA, Greece for funding.
1 Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens 15784, Greece
2 Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, University of Athens, Panepistimiopolis Zografou, 15771, Athens, Greece
As genetic interventions or extended caloric restriction cannot be applied in humans, many studies have been devoted to the identification of natural products that can prolong healthspan. 6-bromoindirubin-3'-oxime (6BIO), a hemi-synthetic derivative of indirubins found in edible mollusks, is a potent inhibitor of Glycogen synthase kinase 3β (Gsk-3β). Gsk-3β has been implicated in various age-related diseases including tumorigenesis, neurodegeneration and diabetes; consequently, 6BIO has shown anti-tumor and anti-neurodegenerative activities. We found that treatment of normal human diploid skin fibroblasts with 6BIO reduced the oxidative load, conferred protection against oxidative stress-mediated DNA damage, and it also promoted the activation of antioxidant and proteostatic modules; these effects were largely phenocopied by genetic inhibition of Gsk-3. Furthermore, prolonged treatment of cells with 6BIO decreased the rate of cell cycling and significantly suppressed cellular senescence-related accumulation of biomolecular damage. Our findings suggest that 6BIO is a novel activator of antioxidant responses and of the proteostasis network in normal human cells; moreover, and given the low levels of biomolecules damage in 6BIO treated senescing cells, this compound should exert potent anti-tumor properties.
Conflict of interest: The authors declare no conflict of interest.
Acknowledgement: We acknowledge the Special Account for Research Grants of NKUA, Greece for funding.
