Dihydrotanshinone-Induced NOX5 Activation Inhibits Breast Cancer Stem Cell through the ROS/Stat3 Signaling Pathway

Oxid Med Cell Longev. 2019 Mar 24;2019:9296439. doi: 10.1155/2019/9296439. eCollection 2019.


Cancer stem cells (CSCs) are known to mediate metastasis and recurrence and are therefore a promising therapeutic target. In this study, we found that dihydrotanshinone (DHTS) inhibits CSC formation. DHTS inhibited mammosphere formation in a dose-dependent manner and showed significant tumor growth inhibition in a xenograft model. This compound reduced the CD44high/CD24low- and aldehyde dehydrogenase- (ALDH-) expressing cell population and the self-renewal-related genes Nanog, SOX2, OCT4, C-Myc, and CD44. DHTS induced NOX5 activation by increasing calcium, and NOX5 activation induced reactive oxygen species (ROS) production. ROS production reduced the nuclear phosphorylation levels of Stat3 and secreted IL-6 levels in the mammospheres. DHTS deregulated the dynamic equilibrium from non-stem cancer cells to CSCs by dephosphorylating Stat3 and decreasing IL-6 secretion and inhibiting CSC formation. These novel findings showed that DHTS-induced ROS deregulated the Stat3/IL-6 pathway and induced CSC death. NOX5 activation by DHTS inhibits CSC formation through ROS/Stat3/IL-6 signaling, and DHTS may be a promising potential therapeutic agent against breast CSCs.

MeSH terms

  • Acetylcysteine / pharmacology
  • Animals
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Calcium / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Self Renewal / drug effects
  • Drugs, Chinese Herbal / pharmacology*
  • Enzyme Activation / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Interleukin-6 / metabolism
  • Mice, Nude
  • NADPH Oxidase 2 / metabolism
  • NADPH Oxidase 5 / genetics
  • NADPH Oxidase 5 / metabolism*
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / enzymology*
  • Neoplastic Stem Cells / pathology
  • Reactive Oxygen Species / metabolism*
  • STAT3 Transcription Factor / metabolism*
  • Salvia miltiorrhiza
  • Signal Transduction / drug effects*
  • Spheroids, Cellular / drug effects
  • Spheroids, Cellular / metabolism
  • Spheroids, Cellular / pathology
  • Transcription, Genetic / drug effects
  • Xenograft Model Antitumor Assays


  • Drugs, Chinese Herbal
  • Interleukin-6
  • Reactive Oxygen Species
  • STAT3 Transcription Factor
  • dan-shen root extract
  • NADPH Oxidase 2
  • NADPH Oxidase 5
  • Calcium
  • Acetylcysteine