Combination of all-<Emphasis Type="Italic">trans</Emphasis> retinoic acid and taxol regressed glioblastoma T98G xenografts in nude mice |
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Authors: | Surajit Karmakar Naren L Banik Sunil J Patel Swapan K Ray |
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Institution: | (1) Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 325E, P.O. Box 250606, Charleston, SC 29425, USA |
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Abstract: | Glioblastoma is the most prevalent and highly malignant brain tumor that continues to defy current treatment strategies. This
investigation used all-trans retinoic acid (ATRA) and taxol (TXL) as a combination therapy for controlling the growth of human glioblastoma T98G xenografted
in athymic nude mice. Histopathological examination revealed that ATRA induced differentiation and combination of ATRA and
TXL caused more apoptosis than either treatment alone. Combination therapy decreased expression of telomerase, nuclear factor
kappa B (NFκВ), and inhibitor-of-apoptosis proteins (IAPs) indicating suppression of survival factors while upregulated Smac/Diablo.
Combination therapy also changed expression of Bax and Bcl-2 proteins leading to increased Bax:Bcl-2 ratio, mitochondrial
release of cytochrome c and apoptosis-inducing factor (AIF), and activation of caspase-9. Increased activities of calpain and caspase-3 degraded
270 kD α-spectrin at the specific sites to generate 145 kD spectrin breakdown product (SBDP) and 120 kD SBDP, respectively.
Further, increased activity of caspase-3 cleaved inhibitor-of-caspase-activated DNase (ICAD). In situ double immunofluorescent
labelings showed overexpression of calpain, caspase-12, caspase-3, and AIF during apoptosis, suggesting involvement of both
caspase-dependent and caspase-independent pathways for apoptosis. Our investigation revealed that treatment of glioblastoma
T98G xenografts with the combination of ATRA and TXL induced differentiation and multiple molecular mechanisms for apoptosis. |
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Keywords: | Apoptosis Calpain and caspases Glioblastoma Retinoid Taxol |
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