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Benzo[ b ]tryptanthrin Inhibits MDR1, Topoisomerase Activity, and Reverses Adriamycin Resistance in Breast Cancer Cells
Author(s) -
Jun KyuYeon,
Park SoEun,
Liang Jing Lu,
Jahng Yurngdong,
Kwon Youngjoo
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500068
Subject(s) - topoisomerase , cytotoxicity , multiple drug resistance , apoptosis , chemistry , cancer cell , caspase , biochemistry , pharmacology , biology , enzyme , in vitro , programmed cell death , cancer , genetics , antibiotics
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.