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

Sui H, Pan SF, Feng Y, Jin BH, Liu X, Zhou LH, Hou FG, Wang WH, Fu XL, Han ZF, Ren JL, Shi XL, Zhu HR, Li Q - BMC Complement Altern Med (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Lzwf@hotmail.com.

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.

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Schematic summary of the inhibition mechanisms of ZJW on the PI3K/Akt/NF-κB signaling pathway. Activation of PI3K/Akt/NF-κB pathway could reduce MDR phenotype. ZJW suppress phosphorylation of Akt (Ser473) and NF-κB.
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Fig6: Schematic summary of the inhibition mechanisms of ZJW on the PI3K/Akt/NF-κB signaling pathway. Activation of PI3K/Akt/NF-κB pathway could reduce MDR phenotype. ZJW suppress phosphorylation of Akt (Ser473) and NF-κB.

Mentions: In conclusion, based on our previous clinical and experimental studies, ZJW can be used as an inhibitor of chemoresistance in CRC. The present investigation has shown that the anti-MDR activity of ZJW can be partially attributed to the inhibition of the PI3K/Akt/NF-κB pathway and can modulate the binding of the ABCB1 promoter (Figure 6). Therefore, this study has provided a natural potent inhibitor of drug-resistance in human cancer. Compared with modern medicine, the combination of multiple herbs may yield better results in cancer treatment. The development of treatment with ZJW will be explored as a potential therapeutic strategy in human drug-resistance cancer.Figure 6


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

Sui H, Pan SF, Feng Y, Jin BH, Liu X, Zhou LH, Hou FG, Wang WH, Fu XL, Han ZF, Ren JL, Shi XL, Zhu HR, Li Q - BMC Complement Altern Med (2014)

Schematic summary of the inhibition mechanisms of ZJW on the PI3K/Akt/NF-κB signaling pathway. Activation of PI3K/Akt/NF-κB pathway could reduce MDR phenotype. ZJW suppress phosphorylation of Akt (Ser473) and NF-κB.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4288643&req=5

Fig6: Schematic summary of the inhibition mechanisms of ZJW on the PI3K/Akt/NF-κB signaling pathway. Activation of PI3K/Akt/NF-κB pathway could reduce MDR phenotype. ZJW suppress phosphorylation of Akt (Ser473) and NF-κB.
Mentions: In conclusion, based on our previous clinical and experimental studies, ZJW can be used as an inhibitor of chemoresistance in CRC. The present investigation has shown that the anti-MDR activity of ZJW can be partially attributed to the inhibition of the PI3K/Akt/NF-κB pathway and can modulate the binding of the ABCB1 promoter (Figure 6). Therefore, this study has provided a natural potent inhibitor of drug-resistance in human cancer. Compared with modern medicine, the combination of multiple herbs may yield better results in cancer treatment. The development of treatment with ZJW will be explored as a potential therapeutic strategy in human drug-resistance cancer.Figure 6

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Lzwf@hotmail.com.

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.

Show MeSH
Related in: MedlinePlus