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

Autor: Yu-Ning Teng, Ming-Chang Kao, Shih-Ya Huang, Tian-Shung Wu, Tsui-Er Lee, Chan-Yen Kuo, Chin-Chuan Hung
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Biomedicine & Pharmacotherapy, Vol 150, Iss , Pp 112995- (2022)
Druh dokumentu: article
ISSN: 0753-3322
DOI: 10.1016/j.biopha.2022.112995
Popis: 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
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