Targeting the Hedgehog Signaling Pathway by Glasdegib Limits the Self- Renewal of MDS-Derived Induced Potent Stem Cells (iPSC)Tetsuzo Tauchi1*, Seiichi Okabe1, Seiichiro Katagiri1, Yuko Tanaka1, Kaoru Tohyama2 and Kazuma Ohyashiki1
- *Corresponding Author:
- Tetsuzo Tauchi
Department of Hematology, Tokyo Medical University
6-7-1 Nishishinjuku, Shinjukuku, Tokyo, 160-0023, Japan
E-mail: [email protected]
Received date: May 16, 2017; Accepted date: June 13, 2017; Published date: June 15, 2017
Citation: Tauchi T, Okabe S, Katagiri S, Tanaka Y, Tohyama K, et al. (2017) Targeting the Hedgehog Signaling Pathway by Glasdegib Limits the Self-Renewal of MDS-Derived Induced Potent Stem Cells (iPSC). J Cancer Sci Ther 9:479-484. doi: 10.4172/1948-5956.1000462
Copyright: © 2017 Tauchi T, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Objective: Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by no efficient hematopoiesis and frequent progression to acute myeloid leukemia (AML). Even in low risk MDS, clonal hematopoiesis already dominates at diagnosis, and clones found in secondary AML originate from the MDS stage of disease, highlighting the need to specifically target the MDS-initiating clone. Glasdegib is a potent and selective hedgehog pathway inhibitor that acts by binding Smoothened (SMO) and blocking signal transduction. Glasdegib demonstrated preliminary antitumor activity in a phase I trial, when given as monotherapy in patients with several hematopoietic malignancies. In the present study, we investigated the molecular mechanisms by which glasdegib regulate the self-renewal of MDS-derived iPS cells (iPSCs) in vivo.
Methods: We generated iPSCs from bone marrow mononuclear cells of an MDS patient with chromosome 5 deletion and complex karyotypic abnormalities. We examined the activity of glasdegib against MDS-derived iPSCs transferred NOD/SCID mice in vivo and in vitro. We performed the serial in vivo transplantation to assess the effects of hedgehog inhibition on long term self-renewal. NOD/SCID mice were injected with MDS-iPSCs then treated with glasdegib.
Results: We observed that glasdegib significantly reduced the self-renewal of NOD/SCID re-populating cells from MDS-derived iPSC during serial transplantation in vivo. Further, NOD/SCID mice were injected with MDS-iPSCs, and then treated with glasdegib on day 21 for 7 days. These treatments reduced the population of CD34+CD38-cells. To investigate the entire the apoptosis-induction pathways by hedgehog inhibition, MSD-L cells were incubated with 5-azacytidine and glasdegib for 72 hrs. Glasdegib enhanced the expression of cleaved PARP, cleaved caspase-3, p21 and reduced expression of c-Myc.
Conclusion: Our pre-clinical results indicate that glasdegib have potential as an important option for controlling the drug-resistant MDS-initiating cells. It is expected that the glasdegib may become extremely useful therapeutic interventions in a number of hematological neoplasms, including MDS, where the persistence of cancer stem cells.