|Cancer||Cell death||Cell cycle||Cytoskeleton||Exo/endocytosis||Differentiation||Division||Organelles||Signalling||Stem cells||Trafficking|
Cell Biology International (2010) 34, S40 (Printed in Great Britain)
Valproic acid eliminates quiescent cancer stem-like cells in pediatric GBMS by driving them into cell cycle and promoting radiation induced-DNA damages: an in vivo study in orthotopic xenograft models
Zhigang Liu123, Yunfei Xia1* and Xiao‑Nan Li23*
1Department of Radiation Oncology, Cancer Center, Sun Yat-sen University, Guanzhou, China, 2Laboratory of Molecular Neuro-oncology, and 3Texas Children’s Cancer Center; Baylor College of Medicine, Houston, TX, USA
Clinical outcomes in patients with glioblastoma multiforme (GBM) remain dismal. Failure to eliminate cancer stem cells, particularly those in the quiescent G0 phase, is believed to be a primary cause of tumor recurrence. This is because quiescent cancer stem cells are inherently resistant to chemo- and radiation therapies that are designed to kill rapidly proliferating cells. Here, we examined our hypothesis that valproic acid, a histone deacetylase inhibitor, can activate cell cycle progression of quiescent GBM cells and sensitize them to radiation induced cell killing in a panel of primary tumor-based orthotopic xenograft mouse models of pediatric GBMs. Our results showed that systemic treatment of GBM xenografts with VPA (600 mg/ml) through a subcutaneous osmotic pump at 1 ul/hr for 7 days activated the cell cycle progression of the quiescent GBM stem cells in vivo, leading to depletion of G0 phase CD133+ GBM stem cells with concomitant increase of CD133+ populations as detected with flow cytometric analysis of Hoechst 33342/Pyronin Y stained cells. In the activated cycling cells, VPA significantly elevated the intracellular levels of reactive oxygen species, the key mediators of radiation induced cell killing. As expected, VPA radiosensitized a panel of glioma stem-like cells and inhibited DNA repair, as evidenced by enhanced expression of DNA strand break marker histone r-H2AX, leading to significantly suppressed neurosphere formation in vitro. More importantly, VPA combined with radiation could prolong survive time of IC-1406GBM orthotopic xenograft model in vivo. In conclusion, our study identified a novel activity of valproic acid on quiescent GBM stem-like cells. Since VPA is an established drug that can pass through blood-brain-barrier, our findings have a great potential of expedited application in clinical applications.
Published online 1 August 2010, doi:10.1042/CBI034S040b
© The Author(s) Journal compilation © 2010 Portland Press Limited