Novel application of rhein and its prodrug diacerein for reversing cancer-related multidrug resistance through the dual inhibition of P-glycoprotein efflux and STAT3-mediated P-glycoprotein expression

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Title:	Novel application of rhein and its prodrug diacerein for reversing cancer-related multidrug resistance through the dual inhibition of P-glycoprotein efflux and STAT3-mediated P-glycoprotein expression
Authors:	Teng, Yu-Ning;Teng, Yu-Ning;Ming-Chang, K;Kao, Ming-Chang;Huan, Shih-Ya;Huang, Shih-Ya;Tian-Shung, W;Wu, Tian-Shung;李翠娥;Lee, Tsui-Er;Kuo, Chan-Yen;Kuo, Chan-Yen;洪靚娟;Hung, Chin-Chuan
Contributors:	醫學暨健康學院健康產業管理學系
Keywords:	Diacerein;Multi-drug resistance;P-glycoprotein;Rhein;Signal transducer and activator of transcription 3.
Date:	2022-06-01
Issue Date:	2023-03-29 01:28:18 (UTC+0)
Publisher:	亞洲大學
Abstract:	Multidrug resistance (MDR) is a multifactorial issue in cancer treatment. Drug efflux transporters, particularly P-glycoprotein (P-gp), are major contributors to such resistance. In the present study, we evaluated the P-gp-inhibiting and MDR-reversing effects of two compounds, namely rhein, an anthraquinone, and diacerein, the acetylated prodrug of rhein. ABCB1/Flp-In-293 was used as a model for investigating the related molecular mechanisms, and the multi-drug-resistant cancer cell line KB/VIN was used as a platform for evaluating the reversal of MDR0. The results indicated that at a concentration of 2.5 μM, both diacerein and rhein significantly inhibited P-gp efflux function. They also downregulated P-gp expression by interacting with the signal transducer and activator of transcription 3. Further investigation of the inhibitory mechanism of these compounds revealed that both stimulated P-gp ATPase activity dose dependently and engaged in the noncompetitive inhibition of rhodamine 123 efflux. Furthermore, rhein was revealed to be a potent reverser of MDR in cancer, and the combination of 30 μM rhein and 1000 nM vincristine exerted a strong synergistic effect, achieving a high combination index (CI) of 0.092. Diacerein demonstrated potential applications as a selective cytotoxic agent against multi-drug-resistant cancer cells at a concentration of > 18.92 μM and as a mild MDR reverser at doses of < 10 μM. In conclusion, diacerein and rhein are potential candidates for P-gp inhibition and MDR reversal in cancer cells.
Appears in Collections:	[Department of Healthcare Administration] Journal Article

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