Inhibition of NADPH oxidase by glucosylceramide confers chemoresistance.

Academic Article

Abstract

  • The bioactive sphingolipid ceramide induces oxidative stress by disrupting mitochondrial function and stimulating NADPH oxidase (NOX) activity, both implicated in cell death mechanisms. Many anticancer chemotherapeutics (anthracyclines, Vinca alkaloids, paclitaxel, and fenretinide), as well as physiological stimuli such as tumor necrosis factor α (TNFα), stimulate ceramide accumulation and increase oxidative stress in malignant cells. Consequently, ceramide metabolism in malignant cells and, in particular the up-regulation of glucosylceramide synthase (GCS), has gained considerable interest in contributing to chemoresistance. We hypothesized that increases in GCS activity and thus glucosylceramide, the product of GCS activity, represents an important resistance mechanism in glioblastoma. In our study, we determined that increased GCS activity effectively blocked reactive oxygen species formation by NOX. We further showed, in both glioblastoma and neuroblastoma cells that glucosylceramide directly interfered with NOX assembly, hence delineating a direct resistance mechanism. Collectively, our findings indicated that pharmacological or molecular targeting of GCS, using non-toxic nanoliposome delivery systems, successfully augmented NOX activity, and improved the efficacy of known chemotherapeutic agents.
  • Authors

  • Barth, Brian
  • Gustafson, Sally J
  • Young, Megan M
  • Fox, Todd E
  • Shanmugavelandy, Sriram S
  • Kaiser, James M
  • Cabot, Myles C
  • Kester, Mark
  • Kuhn, Thomas B
  • Status

    Publication Date

  • December 1, 2010
  • Published In

    Keywords

  • Catalase
  • Cell Line, Tumor
  • Cell Survival
  • Doxorubicin
  • Drug Resistance, Neoplasm
  • Glioblastoma
  • Glucosylceramides
  • Glucosyltransferases
  • Humans
  • NADPH Oxidases
  • Neuroblastoma
  • Oxidative Stress
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Superoxide Dismutase
  • Tumor Necrosis Factor-alpha
  • Digital Object Identifier (doi)

    Start Page

  • 1126
  • End Page

  • 1136
  • Volume

  • 10
  • Issue

  • 11