Valproic Acid Induced Differentiation and Potentiated Efficacy of Taxol and Nanotaxol for Controlling Growth of Human Glioblastoma LN18 and T98G Cells
- 451 Downloads
Glioblastoma shows poor response to current therapies and warrants new therapeutic strategies. We examined the efficacy of combination of valproic acid (VPA) and taxol (TX) or nanotaxol (NTX) in human glioblastoma LN18 and T98G cell lines. Cell differentiation was manifested in changes in morphological features and biochemical markers. Cell growth was controlled with down regulation of vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), nuclear factor-kappa B (NF-κB), phospho-Akt (p-Akt), and multi-drug resistance (MDR) marker, indicating suppression of angiogenic, survival, and multi-drug resistance pathways. Cell cycle analysis showed that combination therapy (VPA and TX or NTX) increased the apoptotic sub G1 population and apoptosis was further confirmed by Annexin V-FITC/PI binding assay and scanning electron microscopy. Combination therapy caused activation of caspase-8 and cleavage of Bid to tBid and increased Bax:Bcl-2 ratio and mitochondrial release of cytochrome c and apoptosis-inducing factor (AIF). Upregulation of calpain and caspases (caspase-9 and caspase-3) and substrate degradation were also detected in course of apoptosis. The combination of VPA and NTX most effectively controlled the growth of LN18 and T98G cells. Therefore, this combination of drugs can be used as an effective treatment for controlling growth of human glioblastoma cells.
KeywordsApoptosis Glioblastoma Nanotaxol Taxol Valproic acid
This investigation was supported in part by the NS-57811 and NS-62327 grants from the National Institutes of Health and the SCIRF-11-002 grant from the State of South Carolina.
- 1.Narayana A, Leibel SA (2004) Primary and metastatic brain tumors in adults. In: Leibel SA, Phillips TL (eds) Textbook of radiation oncology. Elsevier, Philadelphia, pp 463–495Google Scholar
- 16.Abe T, Hasegawa S, Taniguchi K, Yokomizo A, Kuwano T, Ono M et al (1994) Possible involvement of multidrug-resistance-associated protein (MRP) gene expression in spontaneous drug resistance to vincristine, etoposide and adriamycin in human glioma cells. Int J Cancer 58:860–864PubMedCrossRefGoogle Scholar
- 17.Rieger L, Rieger J, Winter S, Streffer J, Esser P, Dichgans J, Meyermann R, Weller M (2000) Evidence for a constitutive, verapamil-sensitive, non-P-glycoprotein multidrug resistance phenotype in malignant glioma that is unaltered by radiochemotherapy in vivo. Acta Neuropathol 99:555–562PubMedCrossRefGoogle Scholar
- 20.Karmakar S, Davis KA, Choudhury SR, Deeconda A, Banik NL, Ray SK (2009) Bcl-2 inhibitor and apigenin worked synergistically in human malignant neuroblastoma cell lines and increased apoptosis with activation of extrinsic and intrinsic pathways. Biochem Biophys Res Commun 388:705–710PubMedCrossRefGoogle Scholar
- 21.Roy Choudhury S, Karmakar S, Banik NL, Ray SK (2010) Synergistic efficacy of sorafenib and genistein in growth inhibition by down regulating angiogenic and survival factors and increasing apoptosis through upregulation of p53 and p21 in malignant neuroblastoma cells having N-Myc amplification or non-amplification. Invest New Drugs 28:812–824PubMedCrossRefGoogle Scholar
- 36.Roth W, Wagenknecht B, Grimmel C, Dichgans J, Weller M (1998) Taxol-mediated augmentation of CD95 ligand-induced apoptosis of human malignant glioma cells: association with bcl-2 phosphorylation but neither activation of p53 nor G2/M cell cycle arrest. Br J Cancer 77:404–411PubMedCrossRefGoogle Scholar