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Combination of all-trans retinoic acid and paclitaxel-induced differentiation and apoptosis in human glioblastoma U87MG xenografts in nude mice.

Karmakar S, Banik NL, Ray SK

Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.

BACKGROUND: Glioblastoma, which is the most malignant brain tumor, remains incurable and almost always causes death. As a new treatment strategy, the combination of all-trans retinoic acid (ATRA) and paclitaxel was explored for controlling the growth of glioblastoma U87MG xenografts. METHODS: Human glioblastoma U87MG xenografts were developed in athymic nude mice for treatments with ATRA, paclitaxel, and ATRA plus paclitaxel. The efficacy of treatments in controlling tumor growth was assessed by histologic examination, Western blot analysis, and immunofluorescent labelings. RESULTS: Astrocytic differentiation in U87MG xenografts was associated with increased GFAP expression and decreased telomerase expression. The combination of ATRA and paclitaxel was found to cause more apoptosis than paclitaxel alone. Apoptosis occurred with down-regulation of MEK-2 and overexpression of p-ERK, p-JNK, and p-p38 MAPK. Down-regulation of both Akt and p-Akt also favored the apoptotic process. Combination therapy activated the receptor-mediated pathway of apoptosis with induction of TNF-alpha, activation of caspase-8, and cleavage of Bid to tBid. Combination therapy also induced the mitochondria-mediated pathway of apoptosis with an increase in the Bax:Bcl-2 ratio and mitochondrial release of cytochrome c and Smac/Diablo into the cytosol. In addition, combination therapy promoted phosphorylation of Bcl-2 for its inactivation and down-regulated NF-kappaB and BIRC proteins, indicating suppression of several cell survival factors. Western blot analysis demonstrated that activation of cysteine proteases such as calpain, caspase-12, caspase-9, and caspase-3 contributed to apoptosis. Immunofluorescent labelings confirmed overexpression of cysteine proteases in apoptosis. CONCLUSIONS: Treatment of U87MG xenografts with a combination of ATRA and paclitaxel induced differentiation and also multiple molecular mechanisms for apoptosis.

Published 25 February 2008 in Cancer, 112(3): 596-607.
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