Inhibition of hedgehog signaling by GANT58 induces apoptosis and shows synergistic antitumor activity with AKT inhibitor in acute T cell leukemia cells.

Abstract

The hedgehog (Hh) signaling pathways have a crucial role in cell proliferation and survival, and the de-regulation of these pathways can lead to tumorigenesis. Here we investigated the expression and function of these pathways in acute T lymphocytic leukemia cells (T-ALL). Profiling of Hh pathway members revealed common expression of key Hh signaling effectors in all T-ALL cells. We found that T-ALL cells were insensitive to specific Smoothened (SMO) inhibition following the use of low concentrations of the SMO antagonist cyclopamine. In contrast, treatment with the novel GLI antagonist GANT58 reduced expression of the target gene Patched 1 as well as GLI family zinc finger 1 (GLI1) and preferentially decreased the viability of T-ALL cells. We also found perifosine, a novel AKT inhibitor, down-regulated GLI1 protein by dephosphorylation of AKT and GSK3β dose-dependently and that pre-treatment with PD98059, a MEK/ERK pathway inhibitor, enhanced this down-regulation by 20%-30%. Then we questioned whether use of both GANT58 and AKT inhibitor together could confer a synergistic effect to decrease T-ALL cell viability. By applying the Chou-Talalay method, low concentration of GANT58 induced T-ALL cell death in a synergism fashion with perifosine or GSK690693 when used simultaneously. These findings indicate that the combined use of GANT58 and AKT inhibitor could help treat a broad range of malignant tumors in conjunction with existing cancer treatments.

• Authors: Xiaoming Hou, Xing Chen, Ping Zhang, Youfei Fan, Aihua Ma, Tingting Pang, Zhao Song, Youpeng Jin, Wei Hao, Fengqin Liu, Wei Wang, Yulin Wang
• Journal: Biochimie (Biochimie) Vol. 101 Pg. 50-9 (Jun 2014) ISSN: 1638-6183 [Electronic] France
• PMID: 24394624 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• GANT58
• GLI1 protein, human
• GSK690693
• Hedgehog Proteins
• Oxadiazoles
• Pyridines
• Thiophenes
• Transcription Factors
• Veratrum Alkaloids
• Zinc Finger Protein GLI1
• Phosphorylcholine
• perifosine
• Proto-Oncogene Proteins c-akt
• cyclopamine

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Drug Screening Assays, Antitumor
• Drug Synergism
• Hedgehog Proteins (metabolism)
• Humans
• Jurkat Cells
• MAP Kinase Signaling System
• Oxadiazoles (pharmacology)
• Phosphorylcholine (analogs & derivatives, pharmacology)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Pyridines (pharmacology)
• Thiophenes (pharmacology)
• Transcription Factors (antagonists & inhibitors, metabolism)
• Veratrum Alkaloids (pharmacology)
• Zinc Finger Protein GLI1