Systemic approaches identify a garlic-derived chemical, Z-ajoene, as a glioblastoma multiforme cancer stem cell-specific targeting agent.

Abstract

Glioblastoma multiforme (GBM) is one of the most common brain malignancies and has a very poor prognosis. Recent evidence suggests that the presence of cancer stem cells (CSC) in GBM and the rare CSC subpopulation that is resistant to chemotherapy may be responsible for the treatment failure and unfavorable prognosis of GBM. A garlic-derived compound, Z-ajoene, has shown a range of biological activities, including anti-proliferative effects on several cancers. Here, we demonstrated for the first time that Z-ajoene specifically inhibits the growth of the GBM CSC population. CSC sphere-forming inhibition was achieved at a concentration that did not exhibit a cytotoxic effect in regular cell culture conditions. The specificity of this inhibitory effect on the CSC population was confirmed by detecting CSC cell surface marker CD133 expression and biochemical marker ALDH activity. In addition, stem cell-related mRNA profiling and real-time PCR revealed the differential expression of CSC-specific genes, including Notch, Wnt, and Hedgehog, upon treatment with Z-ajoene. A proteomic approach, i.e., reverse-phase protein array (RPPA) and Western blot analysis, showed decreased SMAD4, p-AKT, 14.3.3 and FOXO3A expression. The protein interaction map (http://string-db.org/) of the identified molecules suggested that the AKT, ERK/p38 and TGFβ signaling pathways are key mediators of Z-ajoene's action, which affects the transcriptional network that includes FOXO3A. These biological and bioinformatic analyses collectively demonstrate that Z-ajoene is a potential candidate for the treatment of GBM by specifically targeting GBM CSCs. We also show how this systemic approach strengthens the identification of new therapeutic agents that target CSCs.

• Authors: Yuchae Jung, Heejoo Park, Hui-Yuan Zhao, Raok Jeon, Jae-Ha Ryu, Woo-Young Kim
• Journal: Molecules and cells (Mol Cells) Vol. 37 Issue 7 Pg. 547-53 (Jul 2014) ISSN: 0219-1032 [Electronic] Korea (South)
• PMID: 25078449 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Disulfides
• FOXO3 protein, human
• Forkhead Box Protein O3
• Forkhead Transcription Factors
• Growth Inhibitors
• Hedgehog Proteins
• Receptors, Notch
• Smad4 Protein
• Sulfoxides
• Transforming Growth Factor beta1
• Wnt Proteins
• ajoene
• Oncogene Protein v-akt

Topics

• Disulfides (pharmacology)
• Drug Resistance, Neoplasm
• Forkhead Box Protein O3
• Forkhead Transcription Factors (genetics, metabolism)
• Garlic
• Gene Expression Regulation, Developmental (drug effects)
• Glioblastoma (drug therapy, pathology)
• Growth Inhibitors (pharmacology)
• Hedgehog Proteins (genetics, metabolism)
• Humans
• MAP Kinase Signaling System (drug effects)
• Molecular Targeted Therapy
• Neoplastic Stem Cells (drug effects, pathology)
• Oncogene Protein v-akt (metabolism)
• Receptors, Notch (genetics, metabolism)
• Smad4 Protein (genetics, metabolism)
• Sulfoxides
• Transforming Growth Factor beta1 (metabolism)
• Tumor Cells, Cultured
• Wnt Proteins (genetics, metabolism)