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

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Hua Sui, Shu-Fang Pan, Yu Feng, Bao-Hui Jin, Xuan Liu, Li-Hong Zhou, Feng-Gang Hou, Wen-Hai Wang, Xiao-Ling Fu, Zhi-Fen Han, Jian-Lin Ren, Xiao-Lan Shi, Hui-Rong Zhu, Qi Li
• Journal: BMC complementary and alternative medicine (BMC Complement Altern Med) Vol. 14 Pg. 279 (Aug 01 2014) ISSN: 1472-6882 [Electronic] England
• PMID: 25085593 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCC2 protein, human
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Drugs, Chinese Herbal
• Multidrug Resistance-Associated Protein 2
• NF-kappa B
• Organoplatinum Compounds
• Zuo-Jin-Wan
• Oxaliplatin
• Proto-Oncogene Proteins c-akt

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, metabolism)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Colonic Neoplasms (drug therapy, metabolism, physiopathology)
• Drug Resistance, Neoplasm
• Drug Synergism
• Drugs, Chinese Herbal (pharmacology)
• Humans
• Multidrug Resistance-Associated Protein 2
• NF-kappa B (metabolism)
• Neoplasms (drug therapy, metabolism)
• Organoplatinum Compounds (pharmacology)
• Oxaliplatin
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)