title: Benzo[b]tryptanthrin inhibits MDR1, topoisomerase activity, and reverses adriamycin resistance in breast cancer cells.
abstract: Tryptanthrin is an indoloquinazoline alkaloid isolated from indigo. Tryptanthrin and its benzo-annulated derivative, benzo[b]tryptanthrin, inhibit both topoisomerases I (topo I) and II (topo II) and cause cytotoxicity in several human cancer cell lines. From diverse assessment methods, including cleavage complex stabilization, comet, DNA unwinding/intercalation, topo II ATPase inhibition, ATP competition for topo II, and wound-healing assays, we determined that the mode of action of benzo[b]tryptanthrin is as a DNA non-intercalative and ATP-competitive topo I and II dual catalytic inhibitor. Benzo[b]tryptanthrin induced apoptosis through the cleavage of caspase-3 and PARP in HCT15 colon cancer cells. Additionally, benzo[b]tryptanthrin reversed adriamycin resistance by down-regulation of multidrug resistance protein 1 (MDR1) in adriamycin-resistant MCF7 breast cancer cells (MCF7adr) with more potent inhibitory activity than tryptanthrin. Taken together, derivatization by benzo-annulation of tryptanthrin ameliorated the MDR-reversing effect of tryptanthrin and may pave the way to the discovery of a novel potent adjuvant agent for chemotherapy.
authors: College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top 5, Ewha Womans University, Seoul 120-750 (Republic of Korea).
authors: Kyu-Yeon
authors: KY
authors: Jun
authors: So-Eun
authors: SE
authors: Park
authors: Jing Lu
authors: JL
authors: Liang
authors: Yurngdong
authors: Y
authors: Jahng
authors: Youngjoo
authors: Y
authors: Kwon
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D059003:Topoisomerase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; D011799:Quinazolines; D059003:Topoisomerase Inhibitors; C000604646:benzo(b)tryptanthrin; D004317:Doxorubicin; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II
keywords: ATP competitive; MDR1; adriamycin; benzo[b]tryptanthrin; topoisomerases