Teratogenic jervine increases the activity of doxorubicin in MCF-7/ADR cells by inhibiting ABCB1

Biomed Pharmacother. 2019 Sep:117:109059. doi: 10.1016/j.biopha.2019.109059. Epub 2019 Jun 14.

Abstract

Jervine is a natural teratogenic compound isolated from Veratrum californicum. In this study, for the first time, we revealed a novel activity of jervine in sensitizing the anti-proliferation effect of doxorubicin (DOX). We demonstrated that the synergistic mechanism was related to the intracellular accumulation of DOX via modulating ABCB1 transportation. Jervine did not affect the expression of ABCB1 in mRNA nor protein levels. However, jervine increased the ATPase activity of ABCB1 and possibly served as a substrate of ABCB1. The molecular docking results indicated that jervine was bound to a closed ABCB1 conformation and blocked drug entrance to the central binding site at the transmembrane domain. The present study identifies jervine acts as a substrate of ABCB1, and has potential to be developed as a novel and potent chemotherapy sensitizer used for patients developing multidrug resistance.

Keywords: ABCB1; Chemotherapy; Drug resistance; Jervine; MCF-7/ADR.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B / chemistry
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Doxorubicin / chemistry
  • Doxorubicin / pharmacology*
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Humans
  • MCF-7 Cells
  • Protein Structure, Secondary
  • Substrate Specificity / drug effects
  • Teratogens / chemistry
  • Teratogens / toxicity*
  • Veratrum Alkaloids / chemistry
  • Veratrum Alkaloids / pharmacology
  • Veratrum Alkaloids / toxicity*

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • Teratogens
  • Veratrum Alkaloids
  • jervine
  • Doxorubicin
  • cyclopamine