title: Screening dietary flavonoids for the reversal of P-glycoprotein-mediated multidrug resistance in cancer.
abstract: P-Glycoprotein (P-gp) serves as a therapeutic target for the development of inhibitors to overcome multidrug resistance in cancer cells. Although various screening procedures have been practiced so far to develop first three generations of P-gp inhibitors, their toxicity and drug interaction profiles are still a matter of concern. To address the above important problem of developing safe and effective P-gp inhibitors, we have made systematic computational and experimental studies on the interaction of natural phytochemicals with human P-gp. Molecular docking and QSAR studies were carried out for 40 dietary phytochemicals in the drug-binding site of the transmembrane domains (TMDs) of P-gp. Dietary flavonoids exhibit better interactions with homology modeled human P-gp. Based on the computational analysis, selected flavonoids were tested for their inhibitory potential against P-gp transport function in drug resistant cell lines using calcein-AM and rhodamine 123 efflux assays. It has been found that quercetin and rutin were the highly desirable flavonoids for the inhibition of P-gp transport function and they significantly reduced resistance in cytotoxicity assays to paclitaxel in P-gp overexpressing MDR cell lines. Hence, quercetin and rutin may be considered as potential chemosensitizing agents to overcome multidrug resistance in cancer.
authors.affiliation: Department of Biochemistry and Biotechnology, Annamalai University, Annamalai Nagar-608 002, Tamilnadu, India. drprasadnr@gmail.com.
authors.forename: S
authors.initials: S
authors.lastname: Mohana
authors.affiliation: Department of Biochemistry and Biotechnology, Annamalai University, Annamalai Nagar-608 002, Tamilnadu, India. drprasadnr@gmail.com.
authors.forename: M
authors.initials: M
authors.lastname: Ganesan
authors.affiliation: Department of Biochemistry and Biotechnology, Annamalai University, Annamalai Nagar-608 002, Tamilnadu, India. drprasadnr@gmail.com.
authors.forename: B
authors.initials: B
authors.lastname: Agilan
authors.affiliation: Department of Biochemistry and Biotechnology, Annamalai University, Annamalai Nagar-608 002, Tamilnadu, India. drprasadnr@gmail.com.
authors.forename: R
authors.initials: R
authors.lastname: Karthikeyan
authors.affiliation: Department of Biochemistry and Biotechnology, Annamalai University, Annamalai Nagar-608 002, Tamilnadu, India. drprasadnr@gmail.com.
authors.forename: G
authors.initials: G
authors.lastname: Srithar
authors.affiliation: Department of Biochemistry and Biotechnology, Annamalai University, Annamalai Nagar-608 002, Tamilnadu, India. drprasadnr@gmail.com.
authors.forename: R
authors.initials: R
authors.lastname: Beaulah Mary
authors.affiliation: Bioinformatics Infrastructure Facility (BIF), University of Madras, Guindy Campus, Chennai, Tamil Nadu, India.
authors.forename: D
authors.initials: D
authors.lastname: Ananthakrishnan
authors.affiliation: Bioinformatics Infrastructure Facility (BIF), University of Madras, Guindy Campus, Chennai, Tamil Nadu, India and CAS in Crystallography and Biophysics, University of Madras, Guindy Campus, Chennai, Tamil Nadu, India.
authors.forename: D
authors.initials: D
authors.lastname: Velmurugan
authors.affiliation: Department of Biochemistry and Biotechnology, Annamalai University, Annamalai Nagar-608 002, Tamilnadu, India. drprasadnr@gmail.com.
authors.forename: N
authors.initials: N
authors.lastname: Rajendra Prasad
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, Maryland 20892-4256, USA. ambudkar@mail.nih.gov.
authors.forename: Suresh V
authors.initials: SV
authors.lastname: Ambudkar
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D003198:Computer Simulation; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004354:Drug Screening Assays, Antitumor; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D005419:Flavonoids; D008024:Ligands