Apigenin is a common dietary flavonoid with considerable cytotoxic activity in vitro and in vivo. Despite many mechanistic studies, less is known about resistance factors hampering apigenin's activity. We investigated the ATP-binding cassette (ABC) transporters BCRP/. ABCG2, P-glycoprotein/. ABCB1 and its close relative ABCB5. Multidrug-resistant cells overexpressing these ABC transporters were not cross-resistant toward apigenin. Moreover, apigenin inhibited not only P-glycoprotein but also BCRP by increasing cellular uptake of doxorubicin and synergistic inhibition of cell viability in combination with doxorubicin or docetaxel in multidrug-resistant cells. To perform in silico molecular docking studies, we first generated homology models for human P-glycoprotein and ABCB5 based on the crystal structure of murine P-glycoprotein. Their nucleotide binding domains (NDBs) revealed the highest degrees of sequence homologies (89%-100%), indicating that ATP binding and cleavage is of crucial importance for ABC transporters. Molecular docking of apigenin bound to the NDBs of P-glycoprotein and ABCB5 in molecular docking studies. Hence, apigenin may compete with ATP for NDB-binding leading to energy depletion to fuel the transport of ABC transporter substrates. Furthermore, we performed COMPARE and hierarchical cluster analyses of transcriptome-wide mRNA expression profiles of the National Cancer Institute tumor cell line panel. Microarray-based mRNA expressions of genes of diverse biological functions (signal transduction, transcriptional regulation, ubiquitination, autophagy, metabolic activity, xenobiotic detoxification and microtubule formation) significantly predicted responsiveness of tumor cells to apigenin. In conclusion, apigenin's activity is not hampered by classical mechanisms of multidrug resistance and the inhibition of ABC transporters by apigenin indicates that apigenin may overcome multidrug resistance in otherwise refractory tumors.
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