Abstract
Malignant gliomas are a debilitating class of brain tumors that are resistant to radiation and chemotherapeutic drugs, contributing to the poor prognosis associated with these tumors. Over-expression of transcription factors such as NFkappaB and AP-1 contribute to the enhanced glioma survival, radioresistance, and chemoresistance. Curcumin, which may inhibit these pathways, was therefore investigated for a potential therapeutic role in glioma. The effect of curcumin on glioma survival was investigated in human (T98G, U87MG, and T67) and rat (C6) glioma cell lines. The ability of curcumin to overcome glioma cell radioresistance and chemoresistance was also explored. Curcumin reduced cell survival in a p53- and caspase-independent manner, an effect correlated with the inhibition of AP-1 and NFkappaB signaling pathways via prevention of constitutive JNK and Akt activation. Curcumin-sensitized glioma cells to several clinically utilized chemotherapeutic agents (cisplatin, etoposide, camptothecin, and doxorubicin) and radiation, effects correlated with reduced expression of bcl-2 and IAP family members as well as DNA repair enzymes (MGMT, DNA-PK, Ku70, Ku80, and ERCC-1). These findings support a role for curcumin as an adjunct to traditional chemotherapy and radiation in the treatment of brain cancer.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Brain Neoplasms / drug therapy*
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Brain Neoplasms / metabolism
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Brain Neoplasms / physiopathology
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Caspases / drug effects
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Caspases / metabolism
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Cell Proliferation / drug effects*
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Cell Survival / drug effects
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Cell Survival / physiology
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Curcumin / pharmacology*
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Curcumin / therapeutic use
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DNA Repair / drug effects
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DNA Repair / physiology
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Drug Resistance, Neoplasm / drug effects*
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Drug Resistance, Neoplasm / physiology
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / physiology
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Glioblastoma / drug therapy*
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Glioblastoma / metabolism
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Glioblastoma / physiopathology
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Humans
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JNK Mitogen-Activated Protein Kinases / drug effects
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JNK Mitogen-Activated Protein Kinases / metabolism
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NF-kappa B / drug effects
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NF-kappa B / metabolism
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Proto-Oncogene Proteins c-akt / drug effects
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Proto-Oncogene Proteins c-akt / metabolism
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Rats
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Transcription Factor AP-1 / drug effects
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Transcription Factor AP-1 / metabolism
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Transcriptional Activation / drug effects
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Transcriptional Activation / physiology
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / drug effects
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Tumor Suppressor Protein p53 / metabolism
Substances
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Antineoplastic Agents
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NF-kappa B
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Transcription Factor AP-1
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Tumor Suppressor Protein p53
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Proto-Oncogene Proteins c-akt
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JNK Mitogen-Activated Protein Kinases
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Caspases
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Curcumin