Small-Molecule Inhibitor of Glycogen Synthase Kinase 3β 6-Bromoindirubin-3-oxime Inhibits Hematopoietic Regeneration in Stem Cell Recipient Mice

Abstract

Small-molecule inhibitors of glycogen synthase kinase 3β (GSK3β) have demonstrated strong anti-leukemia effects in preclinical studies. Here, we investigated the effect of GSK3β inhibitor 6-Bromoindirubin-3-oxime (BIO) previously shown to inhibit leukemia cell growth in vitro and of animal models on hematopoietic regeneration in recipients of stem cell transplant. BIO administered to immunocompromised mice transplanted with human hematopoietic stem cells inhibited human stem cell engraftment in the bone marrow (BM) and peripheral blood. BIO reduced CD34(+) progenitor cells in the BM, and primitive lymphoid progenitors re-populated host thymus at later stages post-transplant. The development of all T-cell subsets in the thymus was suppressed in BIO-treated mice. Human cell engraftment was gradually restored after discontinuation of BIO treatment; however, T-cell depletion remained until the end of experiment, which correlated with the attenuated thymic function in the host. BIO delayed CD34(+) cell expansion in stroma-supported or cytokine-only cultures. BIO treatment delayed progenitor cell divisions and induced apoptosis in cultures with sub-optimal cytokine support. In addition, BIO inhibited B- and T-cell development in co-cultures with MS5 and OP9-DL1 BM stroma cells, respectively. These data suggest that administration of GKS3β inhibitors may act to delay hematopoietic regeneration in patients who received stem cell transplant.

GSK-3 Inhibitors: A Double-Edged Sword? – An Update on Tideglusib

“…The proliferation of human mesenchymal stem cells have been reported to increase 4 fold when treated with 6-BIO [83]. Contrastingly, 6-BIO has also been reported to delay CD34 + cell expansion [84]. The apoptotic role of 6-BIO, BIOacetoxime in cancer has been vastly exploited in human melanoma cells, human leukemia cells, human ovarian cancer cells, human neuroblastoma cells [58,[85][86][87].…”

6-Bromoindirubin-3′-Oxime (6BIO) Suppresses the mTOR Pathway, Promotes Autophagy, and Exerts Anti-aging Effects in Rodent Liver

“…Currently, 6BIO has been tested in certain preclinical disease models, such as in Parkinson disease models, intracerebral hemorrhage models, and leukemia models, and such research has provided promising evidence of efficacy (Shen et al., 2015; Suresh et al., 2017; Zhao et al., 2017). Our study also points to the clinical potential of therapeutic 6BIO in liver.…”

“…In fact, some matters still require attention before being applied to a clinical setting. A recent study indicated that GSK-3β inhibitor suppresses B- and T-cell development in stem cells, which signifies it should be tested carefully, particularly in conjunction with stem cell transplantation and adoptive T-cell immunotherapy (Shen et al., 2015).…”

“…6-Bromoindirubin-3′-oxime (6BIO) is a selective inhibitor of glycogen synthase kinase-3α/β (GSK-3α/β) derived from Tyrian purple indirubin (Zhao et al., 2017). It is reported as a promising novel agent for therapeutic intervention in several age-related diseases, including diabetes, neurodegenerative disorders, leukemia, and cancer (Avrahami et al., 2013; Shen et al., 2015; Zhang et al., 2017; Li et al., 2018; Liu et al., 2018). It also suppresses the cellular senescence-related accumulation of damaged biomolecules and modulates cellular processes associated with aging, such as inflammation, oxidative stress, cellular viability, proliferation, and apoptosis (Nicolaou et al., 2012; Tsakiri et al., 2017; Zhang et al., 2017).…”

Oximes: Novel Therapeutics with Anticancer and Anti-Inflammatory Potential

“…Indeed, the anti-inflammatory activity of some oximes has been reported to be comparable to standard anti-inflammatory drugs, such as indomethacin, diclofenac, and dexamethasone [ 18 , 19 , 20 ]. On the other hand, the introduction of an oxime group into an appropriate chemical backbone is a reasonable approach for the preparation of cytotoxic agents, and many oxime derivatives have been reported to have therapeutic activity for cancer [ 2 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ] and neurodegenerative disorders [ 28 , 29 , 30 ].…”