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.

• Authors: Wenzhe Ma, Senling Feng, Xiaojun Yao, Zhongwen Yuan, Liang Liu, Ying Xie
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 18789 (Dec 22 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26689156 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• Antineoplastic Agents
• Flavones
• Flutax 2
• Taxoids
• Docetaxel
• Rhodamine 123
• Doxorubicin
• nobiletin
• Paclitaxel
• Fluorouracil

Topics

• ATP Binding Cassette Transporter, Subfamily B (metabolism)
• Adsorption
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Docetaxel
• Doxorubicin (pharmacology)
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Flavones (chemistry, pharmacology)
• Fluorouracil (pharmacology)
• Humans
• Intracellular Space (metabolism)
• Models, Biological
• Molecular Docking Simulation
• Paclitaxel (pharmacology)
• Rhodamine 123 (metabolism)
• Signal Transduction (drug effects)
• Taxoids (pharmacology)
• Treatment Outcome