Targeting the NRF-2/RHOA/ROCK signaling pathway with a novel aziridonin, YD0514, to suppress breast cancer progression and lung metastasis

Cancer Lett. 2018 Jun 28;424:97-108. doi: 10.1016/j.canlet.2018.03.029. Epub 2018 Mar 23.

Abstract

Metastasis is a major cause of breast cancer-associated mortality. Natural products extracted from herbs provide rich bioactive compounds with anticancer efficacy but may have limited or moderate potency and considerable toxicity. We developed a novel aziridonin, YD0514, by aziridinating oridonin, a natural product of the medicinal herb Rabdosia rubescens. In this study, we found that YD0514 significantly inhibited proliferation, motility, and adhesion of metastatic breast cancer cell lines MDA-MB-231, GI101, GILM2, and GILM3. YD0514 also decreased the protein expression of matrix metalloproteinases 2 and 9 (MMP2 and MMP9), focal adhesion kinase (FAK), and integrin family members. Importantly, YD0514 suppressed the growth of metastatic breast cancer xenograft tumors and significantly inhibited lung metastasis in vivo. Lastly, we showed that YD0514's anti-metastatic effect on highly aggressive breast cancer is mediated via regulating the NRF-2/RHOA/ROCK signaling pathway. These results demonstrate that YD0514, the first active analog based on an oridonin D-ring modification, has the potential to be developed as an anti-metastasis therapy for patients with metastatic cancers.

Keywords: Aziridonin; Breast cancer; Metastasis; NRF-2/RHOA/ROCK pathway; Oridonin; YD0514.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Aziridines / administration & dosage*
  • Aziridines / pharmacology
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Cell Adhesion / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Disease Progression
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary*
  • Mice
  • NF-E2-Related Factor 2 / metabolism
  • Signal Transduction / drug effects*
  • Xenograft Model Antitumor Assays
  • rho-Associated Kinases / metabolism
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Aziridines
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • aziridonin 44
  • RHOA protein, human
  • rho-Associated Kinases
  • rhoA GTP-Binding Protein