Role of NAD(P)H oxidase in the tamoxifen-induced generation of reactive oxygen species and apoptosis in HepG2 human hepatoblastoma cells

Cell Death Differ. 2000 Oct;7(10):925-32. doi: 10.1038/sj.cdd.4400717.


Previously, tamoxifen (TAM) has been shown to induce apoptosis through elevation of intracellular Ca2+ in HepG2 human hepatoblastoma cells. In this study we investigated the role of reactive oxygen species (ROS) in the TAM-induced apoptosis, and interrelationship between intracellular Ca2+ and ROS. TAM induced a slow and sustained increase in intracellular ROS level. An antioxidant, N-acetylcysteine significantly inhibited both ROS production and apoptosis induced by TAM, suggesting that ROS may play an essential role in the TAM-induced apoptosis. In a time frame ROS generation followed intracellular Ca2+ increase, and the extracellular and intracellular Ca2+ chelation with EGTA and BAPTA/AM, respectively, completely inhibited the TAM-induced ROS production, indicating that intracellular Ca2+ may mediate the ROS generation. Inhibitors of NAD(P)H oxidase, diphenylene iodonium, phenylarsine oxide and neopterine, significantly blocked the TAM-induced ROS generation and apoptosis, implying that this oxidase may act as a source enzyme for the production of ROS. These results suggest that non-phagocytic NAD(P)H oxidase may play a novel role as a mediator of the apoptosis associated with intracellular Ca2+ in HepG2 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Hormonal / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Calcium / metabolism
  • Hepatoblastoma*
  • Humans
  • Liver Neoplasms*
  • NADPH Oxidases / metabolism*
  • Reactive Oxygen Species / metabolism*
  • Tamoxifen / pharmacology*
  • Tumor Cells, Cultured / cytology
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / enzymology


  • Antineoplastic Agents, Hormonal
  • Reactive Oxygen Species
  • Tamoxifen
  • NADPH Oxidases
  • Calcium