Modulation of multidrug resistance 1 expression and function in retinoblastoma cells by curcumin

Abstract

Objective:To determine the possible interaction of curcumin with P-glycoprotein (P-gp) expression and function by in vitro and in silico studies.Materials and Methods:In this study, curcumin was compared for its potential to modulate the expression and function of P-gp in Y79 RB cells by western blot, RT-PCR (reverse transcription polymerase chain reaction) and functional assay. Further, in silico molecular modeling and docking simulations were performed to deduce the inhibitory binding mode of curcumin.Results:Western blot and RT-PCR analysis decreased the expression of P-gp in a dose-dependent manner. The effect of curcumin on P-gp function was demonstrated by Rhodamine 123 (Rh123) accumulation and efflux study. Curcumin increased the accumulation of Rh123 and decreased its efflux in retinoblastoma (RB) cells. In addition, curcumin inhibited verapamil stimulated ATPase activity and photoaffinity labeling study showed no effect on the binding of 8-azido-ATP-biotin, indicating its interaction at the substrate binding site. Moreover, molecular docking studies concurrently infer the binding of curcumin into the substrate binding site of P-gp with a binding energy of -7.66 kcal/mol.Conclusion:These findings indicate that curcumin suppresses the MDR1 expression and function, and therefore may be useful as modulators of multidrug resistance in RB tumor.

RETRACTED ARTICLE: Curcumin inhibits proliferation, migration, invasion and promotes apoptosis of retinoblastoma cell lines through modulation of miR-99a and JAK/STAT pathway

“…Recently, several researchers also focused on the potential role of curcumin in Rb. Sreenivasan and his colleagues have reported that curcumin suppressed the expression of multidrug resistance associated protein 1 (MDR1) [ 29 ], thereby rendering Rb cells more sensitive to chemotherapy [ 30 ]. Another investigation demonstrated that curcumin induced the apoptosis of Y79 cells possibly through activating JNK and p38 MAPK pathways [ 31 ].…”

A Role for P-Glycoprotein in Clearance of Alzheimer Amyloid ? -Peptide from the Brain

“…(30). Pgp activity can be modulated by a variety of non-substrate compounds which include physiological agents such as progesterone and curcumin (30, 31) and environmental toxins such as sterigmatocystin (32). In addition to altering Pgp activity, chemicals such as steroids and xenobiotics and several physiological/pathological conditions including chronic inflammation and oxidative stress could change its mRNA and protein levels (33).…”

Natural Inhibitors of P-glycoprotein in Acute Myeloid Leukemia

“…The effects of curcumin on P-gp expression, both at the mRNA and protein levels, are documented in many MDR tumor models [ 34 ], although its action on the pump function is more interesting. The action of curcumin on P-gp function, in fact, was demonstrated by studies on rhodamine 123 (Rh123) accumulation and efflux in different tumor models, as well as retinoblastoma, breast cancer, human cervical carcinoma, and chronic myeloid leukemia cell lines [ 35 , 92 , 93 , 94 ]. In particular, Sreenivasan et al [ 92 ] showed that curcumin-inhibited verapamil-stimulated ATPase activity of P-gp at higher concentrations and interacted at the substrate binding site of P-gp and not at the nucleotide-binding region.…”

“…The action of curcumin on P-gp function, in fact, was demonstrated by studies on rhodamine 123 (Rh123) accumulation and efflux in different tumor models, as well as retinoblastoma, breast cancer, human cervical carcinoma, and chronic myeloid leukemia cell lines [ 35 , 92 , 93 , 94 ]. In particular, Sreenivasan et al [ 92 ] showed that curcumin-inhibited verapamil-stimulated ATPase activity of P-gp at higher concentrations and interacted at the substrate binding site of P-gp and not at the nucleotide-binding region. Analysis of the modulation of MDR by curcumin derivatives provided some evidence that confirms an inhibitory action on P-gp, both on its expression, mediated by three natural curcuminoids present in turmeric [ 95 ], and on its function, modulating P-gp mediated efflux through synthetic analogs of curcumin [ 35 , 96 , 97 , 98 ].…”