Anticancer flavonoids are mouse-selective STING agonists

ACS Chem Biol. 2013 Jul 19;8(7):1396-401. doi: 10.1021/cb400264n. Epub 2013 May 23.

Abstract

The flavonoids FAA and DMXAA showed impressive activity against solid tumors in mice but failed clinical trials. They act on a previously unknown molecular target(s) to trigger cytokine release from leukocytes, which causes tumor-specific vascular damage and other antitumor effects. We show that DMXAA is a competitive agonist ligand for mouse STING (stimulator of interferon genes), a receptor for the bacterial PAMP cyclic-di-GMP (c-di-GMP) and an endogenous second messenger cyclic-GMP-AMP. In our structure-activity relationship studies, STING binding affinity and pathway activation activity of four flavonoids correlated with activity in a mouse tumor model measured previously. We propose that STING agonist activity accounts for the antitumor effects of FAA and DMXAA in mice. Importantly, DMXAA does not bind to human STING, which may account for its lack of efficacy or mechanism-related toxicity in man. We propose that STING is a druggable target for a novel innate immune activation mechanism of chemotherapy.

Publication types

  • Letter
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Flavonoids / pharmacology*
  • Humans
  • Immunity, Innate / drug effects
  • Membrane Proteins / agonists*
  • Membrane Proteins / metabolism
  • Mice
  • Molecular Targeted Therapy
  • Protein Binding
  • Structure-Activity Relationship
  • Xanthones / pharmacology

Substances

  • Antineoplastic Agents
  • Flavonoids
  • Membrane Proteins
  • STING1 protein, human
  • Sting1 protein, mouse
  • Xanthones
  • vadimezan