Benzo[b]tryptanthrin Inhibits MDR1, Topoisomerase Activity, and Reverses Adriamycin Resistance in Breast Cancer Cells

• Published in: ChemMedChem Vol. 10; no. 5; pp. 827 - 835
• Main Authors: Jun, Kyu-Yeon, Park, So-Eun, Liang, Jing Lu, Jahng, Yurngdong, Kwon, Youngjoo
• Format: Journal Article
• Language: English; German
• Published: Weinheim WILEY-VCH Verlag 01.05.2015; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: adriamycin; Antibiotics, Antineoplastic - pharmacology; ATP Binding Cassette Transporter, Sub-Family B - antagonists & inhibitors; ATP competitive; benzo[b]tryptanthrin; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cell Survival - drug effects; Cells, Cultured; DNA Topoisomerases, Type I - metabolism; DNA Topoisomerases, Type II - metabolism; Doxorubicin - pharmacology; Drug Resistance, Neoplasm - drug effects; Drug Screening Assays, Antitumor; Enzyme Activation - drug effects; Female; HEK293 Cells; Humans; MCF-7 Cells; MDR1; Medical research; Molecular Docking Simulation; Molecular Structure; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacology; Topoisomerase Inhibitors - chemical synthesis; Topoisomerase Inhibitors - chemistry; Topoisomerase Inhibitors - pharmacology; topoisomerases; MDR1; topoisomerases; ATP competitive; benzo[b]tryptanthrin; adriamycin
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201500068

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. Double threat! Benzo[b]tryptanthrin is a topo I and II dual catalytic inhibitor. Benzo[b]tryptanthrin was found to induce apoptosis through cleavage of caspase‐3 and PARP in HCT15 colon cancer cells and to reverse adriamycin resistance by down‐regulating multidrug resistance protein 1 (MDR1) in adriamycin‐resistant MCF7 breast cancer cells (MCF7adr).