Enhancement of etoposide (VP-16) cytotoxicity by enzymatic and photodynamically induced oxidative stress

Anticancer Drugs. 1997 Feb;8(2):164-73. doi: 10.1097/00001813-199702000-00007.


The effects of glutathione (GSH) depletion by buthionine sulfoximane (BSO) or by photosensitization-induced oxidative stress using metallo-phthalocyanines (MePcS4) on etoposide (VP-16) cytotoxicity against K562 human leukemic cells were investigated. Both treatments enhanced VP-16 toxicity in a markedly synergistic way, as revealed by combination index analysis procedure. Synergistic drug interactions were accompanied by a supra-additive induction of DNA strand breaks. The proposed role of intracellular GSH in preventing metabolic transformations of VP-16 and thus decreasing its toxicity was confirmed by electron spin resonance (ESR) monitoring of the accumulation of the VP-16 phenoxyl radical in cell cytoplasm subjected to GSH depletion. Taken together the results emphasize the beneficial effect of GSH-related oxidative stress in enhancement of etoposide toxicity and possibly in its anticancer applications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimetabolites, Antineoplastic / pharmacology
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Buthionine Sulfoximine / pharmacology
  • Cytoplasm / drug effects
  • Cytoplasm / metabolism
  • DNA Damage / drug effects
  • Drug Synergism
  • Electron Spin Resonance Spectroscopy
  • Etoposide / metabolism
  • Etoposide / pharmacokinetics
  • Etoposide / pharmacology*
  • Free Radicals / metabolism
  • Glutathione / metabolism
  • Humans
  • Indoles / pharmacology
  • Leukemia / drug therapy
  • Leukemia / pathology
  • Organometallic Compounds / pharmacology
  • Oxidative Stress / drug effects*
  • Photosensitizing Agents / pharmacology*
  • Tumor Cells, Cultured


  • Antimetabolites, Antineoplastic
  • Antineoplastic Agents, Phytogenic
  • Free Radicals
  • Indoles
  • Organometallic Compounds
  • Photosensitizing Agents
  • aluminum tetrasulfophthalocyanine
  • Buthionine Sulfoximine
  • zinc tetrasulfophthalocyanine
  • Etoposide
  • Glutathione