Nobiletin enhances the efficacy of chemotherapeutic agents in ABCB1 overexpression cancer cells

Abstract

Multidrug resistance (MDR) is the major obstacle to the successful chemotherapy treatment of many cancers. Here we found that nobiletin, a citrus methoxyflavone, significantly sensitized ABCB1 overexpressing cells A2780/T and A549/T to chemotherapeutic agents such as paclitaxel (a 433-fold reversal of MDR to PTX at 9 μM), doxorubicin (DOX), docetaxel and dounorubicin. Nobiletin profoundly inhibited ABCB1 transporter activity since it significantly increased the intracellular accumulation of DOX and Flutax-2 in A2780/T cells and decreased the efflux of ABCB1 substrates in Caco2 cells without altering the mRNA and protein expression of ABCB1. Moreover, nobiletin stimulated ATPase activity and inhibited verapamil-stimulated ATPase activity in a concentration-dependent manner, indicating a direct interaction with the transporter. Consistent with these findings, molecular docking analysis also identified favorable binding of nobiletin with the transmemberane region site 1 of homology modeled human ABCB1 transporter. Moreover, the Nrf2 protein expression and phosphorylation levels of AKT/ERK were suppressed by co-treated with nobiletin and PTX at the reversal concentrations, suggesting that inhibition of the AKT/ERK/Nrf2 pathway was associated with the sensitizing effect of nobiletin. These findings encourage further animal and clinical MDR studies with the combination therapy of nobiletin and chemotherapeutic drugs.

The Effects of 5,6,7,8,3′,4′-Hexamethoxyflavone on Apoptosis of Cultured Human Choriocarcinoma Trophoblast Cells

“…The pro-apoptotic effect of NOB was also affected by culture time. The apoptosis of MCF-7 human breast cancer cells was enhanced in response to NOB treatment for 24 h [32], but not for 48 or 72 h [31]. The results of the present study found that low doses of NOB (10 and 33 μM) had no significant effects on the apoptosis of BeWo cells, while high doses of NOB (100 μM) alleviated the apoptosis of cells after 48 h of culturing.…”

Nobiletin, a citrus polymethoxyflavone, enhances the effects of bicalutamide on prostate cancer cellsviadown regulation of NF-κB, STAT3, and ERK activation

“…Furthermore, NBT has been studied due to it low cytotoxicity and enhances the efficacy of chemotherapeutic agents. 5,14 In the present study, we showed that combination treatment of NBT and BCT (at 30 mM group) on normal epithelial cells had a lower cytotoxicity (viable cell inhibition rate was 13% in HaCaT cells, Fig. 3E) than that in prostate cancer cells (viable cell inhibition rate was 31% and 33% in PC-3 and VCaP cell, respectively, Fig.…”

Nobiletin Inhibits CD36-Dependent Tumor Angiogenesis, Migration, Invasion, and Sphere Formation Through the Cd36/Stat3/Nf-Κb Signaling Axis

“…Targeted treatment with natural products would be more efficacious. Here we investigated a natural flavonoid, nobiletin, that acts as an anti-cancer agent against various cancers [ 20 , 21 , 22 ]. However, the molecular mechanisms underlying the effects of nobiletin remain unclear.…”