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Activity of the dietary flavonoid, apigenin, against multidrug-resistant tumor cells as determined by pharmacogenomics and molecular docking
  1. Mohamed Saeed1,
  2. Thomas Efferth1,
  3. Onat Kadioglu1,
  4. Hassan Khalid2 and
  5. Yoshikazu Sugimoto3
  1. Aff1 grid.5802.f0000000119417111Department of Pharmaceutical BiologyInstitute of Pharmacy and Biochemistry - Johannes Gutenberg-University Mainz Germany
  2. Aff2 grid.9763.b0000000106746207Department of PharmacognosyUniversity of Khartoum Khartoum Sudan
  3. Aff3 grid.26091.3c0000000419369959Division of ChemotherapyFaculty of Pharmacy - Keio University Tokyo Japan

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Meeting abstracts

Natural products have been extensively studied and involved in cancer therapy field [1], apigenin has 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. Apigenin inhibited not only P-glycoprotein, but also BCRP by increasing cellular uptake of doxorubicin and showed synergistic inhibitory effect in combination with doxorubicin or docetaxel against multidrug-resistant cells. To perform in silico 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 (NBDs) revealed the highest degrees of sequence homologies (89%-100%), indicating that ATP binding and cleavage is of crucial importance for ABC transporters. In silico studies showed a pigenin bound to the NBDs of P-glycoprotein and ABCB5. Hence, apigenin may compete with ATP for NBD-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 significantly predicted responsiveness of tumor cells to apigenin [2].


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