Abstract
Adenoid cystic carcinoma (ACC) is a highly malignant tumor that is generally unresponsive or only weakly responsive to the currently available antineoplastic agents. Thus, novel therapeutic strategies and agents are urgently needed to treat this aggressive neoplasm. Curcumin, a component of turmeric (Curcuma longa), has been shown to have a diversity of antitumor activities. We show here that curcumin is a potent inhibitor of ACC progression in vitro and in vivo. Curcumin concentration-dependently inhibited the growth of ACC cells via induction of apoptosis. The ability of ACC cells to migrate/invade and induce angiogenesis was also significantly attenuated by curcumin, accompanied by the down-regulation of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 and -9. Moreover, our data also demonstrated that the inhibitory effects of curcumin on ACC cells were due to its dual inhibition of both mammalian target of rapamycin (mTOR) and nuclear factor-κB (NF-κB) pathways through a crossed phosphatidylinositol 3-kinase/Akt/IκBα kinase signaling axis. Most importantly, curcumin effectively prevented the in vivo growth and angiogenesis of ACC xenografts in nude mice, as revealed by the induction of cell apoptosis and reduction of microvessel density in tumor tissues. In addition, we further assessed the nature activation status of both mTOR and NF-κB pathways in ACC tissues and confirmed the concurrent high activation of these two pathways in ACC for the first time. Taken together, our findings suggest that further clinical investigation is warranted to apply curcumin as a novel chemotherapeutic regimen for ACC because of its dual suppression of both mTOR and NF-κB pathways.
Footnotes
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The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This study was supported in part by the National Natural Science Foundation of China [Grants 30872894, 30973330, 81072203], and the National Undergraduate Innovative Experiment Project [Grant 091048654].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.066910.
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ABBREVIATIONS:
- ACC
- adenoid cystic carcinoma
- mTOR
- mammalian target of rapamycin
- MAPK
- mitogen-activated protein kinase
- JNK
- c-Jun NH2-terminal kinase
- ERK
- extracellular signal-regulated kinase
- NF-κB
- nuclear factor-κB
- IKK
- IκBα kinase
- PI3K
- phosphatidylinositol 3-kinase
- VEGF
- vascular endothelial growth factor
- bFGF
- basic fibroblast growth factor
- IL
- interleukin
- MMP
- matrix metalloproteinase
- CM
- conditioned medium
- NSG
- normal salivary gland
- DMSO
- dimethyl sulfoxide
- PDTC
- pyrrolidine dithiocarbamate
- DMEM
- Dulbecco's modified Eagle's medium
- FBS
- fetal bovine serum
- PBS
- phosphate-buffered saline
- CAM
- chick chorioallantoic membrane
- TUNEL
- terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling
- PARP
- poly(ADP-ribose) polymerase
- PI
- propidium iodide
- CTG
- Cell Titer-Glo
- RT
- reverse transcription
- PCR
- polymerase chain reaction
- ELISA
- enzyme-linked immunosorbent assay
- CA
- constitutively active
- LY294002
- 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride
- PS1145
- N-(6-chloro-9H-pyrido[3,4-b]indol-8-yl)-3-pyridinecarboxamide dihydrochloride.
- Received June 15, 2010.
- Accepted October 19, 2010.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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