title: Pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinolines: Novel compounds that reverse ABCG2-mediated resistance in cancer cells.
abstract: Overexpression of ATP-binding cassette transporter (ABC) subfamily G2 in cancer cells is known to elicit a MDR phenotype, ultimately resulting in cancer chemotherapy failure. Here, we report, for the first time, the effect of eight novel pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinoline (IND) derivatives that inhibit ABCG2 transporter restoring cancer cell chemosensitivity. IND -4, -5, -6, -7, and -8, at 10 µM, and nilotinib at 5 µM, significantly potentiated (8-10 fold) the cytotoxicity of the ABCG2 substrates mitoxantrone (MX) and doxorubicin in HEK293 cells overexpressing ABCG2 transporter, MX (~14 fold) in MX-resistant NCI-H460/MX-20 small cell lung cancer, and of topotecan (~7 fold) in S1-M1-80 colon cancer cells which all stably expressing ABCG2. In contrast, cytotoxicity of cisplatin, which is not an ABCG2 substrate, was not altered. IND-5,-6,-7, and -8 significantly increased the accumulation of rhodamine-123 in multidrug resistant NCI-H460/MX-20 cells overexpressing ABCG2. Both IND-7 and -8, the most potent ABCG2 inhibitors, had the highest affinities for the binding sites of ABCG2 in modeling studies. In conclusion, the beneficial actions of new class of agents warrant further development as potential MDR reversal agents for clinical anticancer agents that suffer from ABCG2-mediated MDR insensitivity.
authors.affiliation: School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal, MP 462036, India.
authors.forename: Chandrabose
authors.initials: C
authors.lastname: Karthikeyan
authors.affiliation: Department of Physiology and Pharmacology, Thomas J. Long School of Pharmacy and Health Sciences University of the Pacific, Stockton, CA,USA.
authors.forename: Ritu
authors.initials: R
authors.lastname: Malla
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Ashby
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA.
authors.forename: Haneen
authors.initials: H
authors.lastname: Amawi
authors.affiliation: Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36832, USA; Auburn University Research Initiative in Cancer, Auburn University, Auburn, AL 36849, USA.
authors.forename: Kodye L
authors.initials: KL
authors.lastname: Abbott
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Nursing and Allied Health, Tuskegee University, Tuskegee, AL 36088, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Moore
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA.
authors.forename: Curt
authors.initials: C
authors.lastname: Balch
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Nursing and Allied Health, Tuskegee University, Tuskegee, AL 36088, USA.
authors.forename: Crystal
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36832, USA; Auburn University Research Initiative in Cancer, Auburn University, Auburn, AL 36849, USA.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Flannery
authors.affiliation: School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal, MP 462036, India.
authors.forename: Piyush
authors.initials: P
authors.lastname: Trivedi
authors.affiliation: Department of Physiology and Pharmacology, Thomas J. Long School of Pharmacy and Health Sciences University of the Pacific, Stockton, CA,USA.
authors.forename: Jesika S
authors.initials: JS
authors.lastname: Faridi
authors.affiliation: Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36832, USA; Auburn University Research Initiative in Cancer, Auburn University, Auburn, AL 36849, USA.
authors.forename: Satyanarayana R
authors.initials: SR
authors.lastname: Pondugula
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA. Electronic address: amit.tiwari@utoledo.edu.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Tiwari
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004790:Enzyme Induction; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008942:Mitoxantrone / Q000494:pharmacology; D062105:Molecular Docking Simulation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011487:Protein Conformation; D011720:Pyrazoles / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011987:Receptors, Steroid / Q000819:agonists / Q000235:genetics; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; C501412:Abcg2 protein, mouse; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D000077297:Pregnane X Receptor; D011720:Pyrazoles; D011743:Pyrimidines; D011804:Quinolines; D011987:Receptors, Steroid; D004317:Doxorubicin; D008942:Mitoxantrone; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C498826:nilotinib; D002945:Cisplatin
keywords: ABCG2 transporter; Chemosensitivity; Cytotoxicity; Multidrug resistance; Novel MDR modulators