Benzo[b]tryptanthrin inhibits MDR1, topoisomerase activity, and reverses adriamycin resistance in breast cancer cells

ChemMedChem. 2015 May;10(5):827-35. doi: 10.1002/cmdc.201500068. Epub 2015 Mar 24.

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.

Keywords: ATP competitive; MDR1; adriamycin; benzo[b]tryptanthrin; topoisomerases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
  • Antibiotics, Antineoplastic / pharmacology
  • 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
  • Molecular Docking Simulation
  • Molecular Structure
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry
  • Quinazolines / pharmacology*
  • Topoisomerase Inhibitors / chemical synthesis
  • Topoisomerase Inhibitors / chemistry
  • Topoisomerase Inhibitors / pharmacology*

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • Antibiotics, Antineoplastic
  • Quinazolines
  • Topoisomerase Inhibitors
  • benzo(b)tryptanthrin
  • Doxorubicin
  • DNA Topoisomerases, Type I
  • DNA Topoisomerases, Type II