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

Multidrug resistance (MDR) is a multifactorial issue in cancer treatment. Drug efflux transporters, particularly Pglycoprotein (P-gp), are major contributors to such resistance. In the present study, we evaluated the P-gpinhibiting 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 mu M, 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 mu M 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 mu M and as a mild MDR reverser at doses of < 10 mu M. In conclusion, diacerein and rhein are potential candidates for P-gp inhibition and MDR reversal in cancer cells.

Automated summary

This study evaluated the P-gp inhibiting and MDR-reversing effects of two compounds, rhein and diacerein, in cancer cells. The results showed that both compounds can inhibit P-gp efflux function and downregulate P-gp expression by interacting with STAT3. In addition, rhein demonstrated a strong MDR-reversing effect, while diacerein showed selective cytotoxicity and mild MDR-reversing ability.