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Molecular Pharmacology

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Research ArticleArticle

Evidence That Curcumin Suppresses the Growth of Malignant Gliomas in Vitro and in Vivo through Induction of Autophagy: Role of Akt and Extracellular Signal-Regulated Kinase Signaling Pathways

Hiroshi Aoki, Yasunari Takada, Seiji Kondo, Raymond Sawaya, Bharat B. Aggarwal and Yasuko Kondo
Molecular Pharmacology July 2007, 72 (1) 29-39; DOI: https://doi.org/10.1124/mol.106.033167
Hiroshi Aoki
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Yasunari Takada
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Seiji Kondo
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Raymond Sawaya
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Bharat B. Aggarwal
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Yasuko Kondo
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Abstract

Autophagy is a response of cancer cells to various anticancer therapies. It is designated as programmed cell death type II and characterized by the formation of autophagic vacuoles in the cytoplasm. The Akt/mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6K) and the extracellular signal-regulated kinases 1/2 (ERK1/2) pathways are two major pathways that regulate autophagy induced by nutrient starvation. These pathways are also frequently associated with oncogenesis in a variety of cancer cell types, including malignant gliomas. However, few studies have examined both of these signal pathways in the context of anticancer therapy-induced autophagy in cancer cells, and the effect of autophagy on cell death remains unclear. Here, we examined the anticancer efficacy and mechanisms of curcumin, a natural compound with low toxicity in normal cells, in U87-MG and U373-MG malignant glioma cells. Curcumin induced G2/M arrest and nonapoptotic autophagic cell death in both cell types. It inhibited the Akt/mTOR/p70S6K pathway and activated the ERK1/2 pathway, resulting in induction of autophagy. It is interesting that activation of the Akt pathway inhibited curcumin-induced autophagy and cytotoxicity, whereas inhibition of the ERK1/2 pathway inhibited curcumin-induced autophagy and induced apoptosis, thus resulting in enhanced cytotoxicity. These results imply that the effect of autophagy on cell death may be pathway-specific. In the subcutaneous xenograft model of U87-MG cells, curcumin inhibited tumor growth significantly (P < 0.05) and induced autophagy. These results suggest that curcumin has high anticancer efficacy in vitro and in vivo by inducing autophagy and warrant further investigation toward possible clinical application in patients with malignant glioma.

Footnotes

  • Institutional Research Grant from The University of Texas M. D. Anderson Cancer Center (to Y.K.), United States Public Health Service grants CA088936 and CA108558 (to S.K.), Institutional Cancer Core grant CA16672, and a generous donation from the Anthony D. Bullock III Foundation (to S.K. and Y.K.).

  • ABBREVIATIONS: NF-κB, nuclear factor κB; mTOR, mammalian target of rapamycin; ERK1/2, extracellular signal-regulated kinases 1 and 2; p70S6K, p70 ribosomal protein S6 kinase; PTEN, phosphatase and tensin homolog; MEK1, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1; DMSO, dimethyl sulfoxide; 3-MA, 3-methyladenine; PI3K, phosphatidylinositol 3-phosphate kinase; PD98059, 2′-amino-3′-methoxyflavone; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; AVO, acidic vesicular organelle; GFP, green fluorescent protein; LC3, light chain 3; PARP, poly(ADP-ribose) polymerase; TNF, tumor necrosis factor; PBS, phosphate-buffered saline; siRNA, small interfering RNA; PP1, protein phosphatase type 1; PP2A, protein phosphatase type 2A; Atg, autophagy-related gene.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Received December 1, 2006.
    • Accepted March 28, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 72 (1)
Molecular Pharmacology
Vol. 72, Issue 1
1 Jul 2007
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Research ArticleArticle

Evidence That Curcumin Suppresses the Growth of Malignant Gliomas in Vitro and in Vivo through Induction of Autophagy: Role of Akt and Extracellular Signal-Regulated Kinase Signaling Pathways

Hiroshi Aoki, Yasunari Takada, Seiji Kondo, Raymond Sawaya, Bharat B. Aggarwal and Yasuko Kondo
Molecular Pharmacology July 1, 2007, 72 (1) 29-39; DOI: https://doi.org/10.1124/mol.106.033167

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Research ArticleArticle

Evidence That Curcumin Suppresses the Growth of Malignant Gliomas in Vitro and in Vivo through Induction of Autophagy: Role of Akt and Extracellular Signal-Regulated Kinase Signaling Pathways

Hiroshi Aoki, Yasunari Takada, Seiji Kondo, Raymond Sawaya, Bharat B. Aggarwal and Yasuko Kondo
Molecular Pharmacology July 1, 2007, 72 (1) 29-39; DOI: https://doi.org/10.1124/mol.106.033167
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