Zuo Jin Wan reverses P-gp-mediated drug-resistance by inhibiting activation of the PI3K/Akt/NF-κB pathway

Zuo-Jin-Wan (ZJW), a traditional Chinese medicine formula, has been identified to be effective against drug resistance in cancer. In the present study, we investigated the effect of ZJW on acquired oxaliplatin-resistant and the PI3K/Akt/NF-κB pathway in vitro. We tested the dose-response relationshi...

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Bibliographic Details
Published in:	BMC complementary and alternative medicine 2014-08, Vol.14 (1), p.279, Article 279
Main Authors:	Sui, Hua, Pan, Shu-Fang, Feng, Yu, Jin, Bao-Hui, Liu, Xuan, Zhou, Li-Hong, Hou, Feng-Gang, Wang, Wen-Hai, Fu, Xiao-Ling, Han, Zhi-Fen, Ren, Jian-Lin, Shi, Xiao-Lan, Zhu, Hui-Rong, Li, Qi
Format:	Article
Language:	eng
Subjects:	Antineoplastic Agents - pharmacology Apoptosis - drug effects ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism Colonic Neoplasms - drug therapy Colonic Neoplasms - metabolism Colonic Neoplasms - physiopathology Drug Resistance, Neoplasm Drug Synergism Drugs, Chinese Herbal - pharmacology Humans Neoplasms - drug therapy Neoplasms - metabolism NF-kappa B - metabolism Organoplatinum Compounds - pharmacology Phosphatidylinositol 3-Kinases - metabolism Phosphorylation - drug effects Proto-Oncogene Proteins c-akt - metabolism Signal Transduction - drug effects
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Summary:	Zuo-Jin-Wan (ZJW), a traditional Chinese medicine formula, has been identified to be effective against drug resistance in cancer. In the present study, we investigated the effect of ZJW on acquired oxaliplatin-resistant and the PI3K/Akt/NF-κB pathway in vitro. We tested the dose-response relationship of ZJW on reversing drug-resistance by CCK-8 assay and flow cytometry analysis in vitro. The protein expression of P-gp, MRP-2, LRP, and ABCB1 mRNA expression level were evaluated by Western blot and quantitative RT-PCR. The activities of PI3K/Akt/NF-κB pathway were also examined with or without ZJW, including Akt, IκB, p65 and their phosphorylation expression. We found that ZJW significantly enhanced the sensitivity of chemotherapeutic drugs and increased oxaliplatin (L-OHP)-induced cell apoptosis in a time- and dose-dependent manner. Moreover, both ZJW and a PI3K specific inhibitor (LY294002) suppressed phosphorylation of Akt (Ser473) and NF-κB, which is necessary in the activation of the PI3K/Akt/NF-κB pathway. The effect of ZJW in reversing drug-resistance and suppressing phosphorylation of Akt (Ser473) and NF-κB were weakened after treatment with a PI3K/Akt activator in HCT116/L-OHP cells. Our study has provided the first direct evidence that ZJW reverses drug-resistance in human colorectal cancer by blocking the PI3K/Akt/NF-κB signaling pathway, and could be considered as a useful drug for cancer therapy.
ISSN:	1472-6882 1472-6882