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Combination of all‐ trans retinoic acid and paclitaxel‐induced differentiation and apoptosis in human glioblastoma U87MG xenografts in nude mice
Author(s) -
Karmakar Surajit,
Banik Naren L.,
Ray Swapan K.
Publication year - 2007
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.23223
Subject(s) - apoptosis , paclitaxel , cancer research , retinoic acid , protein kinase b , medicine , caspase , cytochrome c , mapk/erk pathway , programmed cell death , microbiology and biotechnology , biology , kinase , cell culture , chemotherapy , biochemistry , genetics
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‐α, 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‐κB 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. Cancer 2008. © 2007 American Cancer Society.