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Ailanthone reverses multidrug resistance by inhibiting the P-glycoprotein-mediated efflux in resistant K562/A02 cells
Fang Han1, Guoqiang Liu1, Caifeng Sun1
1Hematology Department, Shengli Oilfield Central Hospital, No. 31 Ji'nan Road, Dongying District, Dongying, Shandong, 257034, China.
Abstract:
Multidrug resistance (MDR) poses a great impediment to cancer treatment. Excessive expression of ATP-binding cassette transport protein AC-1 (P-glycoprotein, P-GLP) is usually involved in MDR. In this study, ailanthone (AIL), a natural compound extracted from the whole seedlings of Ailanthus altissima (Simaroubaceae) was shown to mediate the reversal of P-GLP-induced MDR and restore the susceptibility of K562/A02 cells to doxorubicin (DOX). Further mechanistic studies revealed that AIL increased intracellular DOX accumulation and interrupted Rh123 efflux through suppression of P-GLP, and also suppressed P-GLP ATPase activity. At the same time, it markedly inhibited MDR1 gene expression and P-GLP protein to sensitize the cytotoxic effect of DOX. Furthermore, AIL down-regulated P-GLP expression by inhibiting the PI3K/Akt pathway. Thus, AIL could be a potential therapeutic compound for reversing P-GLP-mediated drug resistant cancer.
Insights
Ailanthone (AIL) reverses multidrug resistance (MDR) in cancer by inhibiting P-glycoprotein (P-GLP). This natural compound restores cancer cell sensitivity to chemotherapy drugs like doxorubicin (DOX).
Area of Science:
- Pharmacology
- Biochemistry
- Oncology
Background:
- Multidrug resistance (MDR) significantly hinders effective cancer chemotherapy.
- Overexpression of P-glycoprotein (P-GLP), an ATP-binding cassette transporter, is a primary mechanism of MDR.
- There is a critical need for novel agents to overcome P-GLP-mediated drug resistance.
Purpose of the Study:
- To investigate the potential of ailanthone (AIL), a natural compound, in reversing P-GLP-induced MDR.
- To elucidate the mechanisms by which AIL overcomes P-GLP-mediated drug resistance in cancer cells.
- To evaluate AIL's efficacy in restoring sensitivity to doxorubicin (DOX).
Main Methods:
- Treatment of K562/A02 cells with ailanthone (AIL) and doxorubicin (DOX).
- Measurement of intracellular doxorubicin (DOX) accumulation and rhodamine 123 (Rh123) efflux.
- Assessment of P-glycoprotein (P-GLP) expression, P-GLP ATPase activity, and MDR1 gene expression.
- Investigation of the involvement of the PI3K/Akt signaling pathway in AIL's mechanism of action.
Main Results:
- Ailanthone (AIL) effectively reversed P-glycoprotein (P-GLP)-mediated multidrug resistance (MDR).
- AIL increased intracellular doxorubicin (DOX) accumulation and inhibited Rh123 efflux by suppressing P-GLP.
- AIL suppressed P-GLP ATPase activity, reduced P-GLP protein and MDR1 gene expression, and inhibited the PI3K/Akt pathway.
Conclusions:
- Ailanthone (AIL) demonstrates significant potential as a therapeutic agent for reversing P-glycoprotein (P-GLP)-mediated multidrug resistance (MDR) in cancer.
- AIL restores cancer cell sensitivity to doxorubicin (DOX) by down-regulating P-GLP expression and activity via the PI3K/Akt pathway.
- AIL represents a promising natural compound for developing novel strategies against drug-resistant cancers.
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