Developing a Beta-Lapachone Prodrug for Therapy Against NQ01-Overexpressing Breast Cancers

Abstract

We report the development of mono(arylimino) derivatives of beta-lap as potential prodrugs (Reinicke et al. 2005). They undergo hydrolytic conversion to beta-lap at rates dependent on the electron-withdrawing strength of their substituent groups and pH of the diluent. Once converted, they caused NQO1-dependent, - calpain-mediated cell death in human cancer cells identical to that caused by beta-lap. NQO1 reduces beta-lap to an unstable hydroquinone that rapidly undergoes a two-step oxidation back to the parent compound. The resultant futile cycling generates reactive oxygen species (ROS). We hypothesize that O2"- is generated by the NQO1-mediated metabolism of -lap. Comet assay analyses and measurements of disulfide glutathione levels suggest that NQO1- dependent beta-lap metabolism produces DNA damaging oxidative stress. Our data indicate that ROS formation is upstream of subsequent endoplasmic reticulum calcium store release, suggesting that beta-lap-mediated ROS formation may be necessary, but not sufficient, to induce cell death.

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Document Details

Document Type
Technical Report
Publication Date
Mar 01, 2006
Accession Number
ADA450260

Entities

People

  • David A. Boothman
  • Kathryn E. Reinicke

Organizations

  • Case Western Reserve University

Tags

DTIC Thesaurus Topics

  • Antineoplastic Agents
  • Breast Cancer
  • Cell Physiological Processes
  • Cells
  • Chemical Synthesis
  • Chemistry
  • Electrospray Ionization
  • Free Radicals
  • Ionizing Radiation
  • Liquid Chromatography
  • Mass Spectrometry
  • Measurement
  • Neoplasms
  • Organic Chemistry
  • Oxidative Stress
  • Spectra
  • Spectrometry

Fields of Study

  • Biology

Readers

  • Cellular and Molecular Pathways of Apoptosis.
  • Molecular and Cellular Biochemistry
  • Polymer Science and Technology

Technology Areas

  • Microelectronics