Abstract | BACKGROUND AND PURPOSE: EXPERIMENTAL APPROACH: Cultures of several cancer cell lines, including Huh7, U251, HCT116 and A549 cells, were exposed to tetrandrine, chloroquine or a combination of these compounds. Cell viability and content of reactive oxygen species (ROS) were measured and synergy assessed by calculation of the combination index. Western blot and RT-PCR assays were also used along with fluorescence microscopy and histochemical techniques. KEY RESULTS: Combinations of tetrandrine and chloroquine were more cytotoxic than the same concentrations used separately and these effects showed synergy. Such effects involved increased ROS generation and were dependent on caspase-3 but independent of Akt activity. Blockade of tetrandrine-induced autophagy with 3-methyladenine or bafilomycin-A1 induced apoptosis in cancer cells. Lack of p21 protein (p21(-/-) HCT116 cells) increased sensitivity to the apoptotic effects of the combination of tetrandrine and chloroquine. In a tumour xenograft model in mice, combined treatment with tetrandrine and chloroquine induced ROS accumulation and cell apoptosis, and decreased tumour growth. CONCLUSIONS AND IMPLICATIONS: The combinations of tetrandrine and chloroquine exhibited synergistic anti-tumour activity, in vitro and in vivo. Our results suggest a novel therapeutic strategy for tumour treatment.
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Authors | Liufeng Mei, Yicheng Chen, Zhimeng Wang, Jian Wang, Jiali Wan, Chunrong Yu, Xin Liu, Wenhua Li |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 172
Issue 9
Pg. 2232-45
(May 2015)
ISSN: 1476-5381 [Electronic] England |
PMID | 25521075
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2014 The British Pharmacological Society. |
Chemical References |
- Benzylisoquinolines
- CDKN1A protein, human
- Cyclin-Dependent Kinase Inhibitor p21
- Reactive Oxygen Species
- tetrandrine
- Chloroquine
- CASP3 protein, human
- Caspase 3
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Topics |
- Animals
- Antineoplastic Combined Chemotherapy Protocols
(pharmacology)
- Apoptosis
(drug effects)
- Autophagy
(drug effects)
- Benzylisoquinolines
(pharmacology)
- Caspase 3
(metabolism)
- Cell Survival
(drug effects)
- Chloroquine
(pharmacology)
- Colonic Neoplasms
(drug therapy, genetics, metabolism, pathology)
- Cyclin-Dependent Kinase Inhibitor p21
(genetics, metabolism)
- Dose-Response Relationship, Drug
- Drug Synergism
- HCT116 Cells
- HeLa Cells
- Humans
- Lung Neoplasms
(drug therapy, genetics, metabolism, pathology)
- Male
- Mice, Inbred BALB C
- Mice, Nude
- Oxidative Stress
(drug effects)
- Reactive Oxygen Species
(metabolism)
- Signal Transduction
(drug effects)
- Time Factors
- Transfection
- Tumor Burden
(drug effects)
- Xenograft Model Antitumor Assays
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