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Glutathione-S-transferase-pi expression regulates sensitivity to glutathione-doxorubicin conjugate

K Tashiro1, T Asakura, C Fujiwara

  • 1Department of Biochemistry (I), Jikei University School of Medicine, Tokyo 105-8461, Japan.

Anti-Cancer Drugs
|October 18, 2001
PubMed

Insights

Glutathione-doxorubicin conjugate (GSH-DXR) efficacy depends on GST-pi levels. Overexpressing GST-pi reduces GSH-DXR

Area of Science:

  • Pharmacology and Toxicology
  • Cancer Biology
  • Enzyme Kinetics

Background:

  • Glutathione-doxorubicin conjugate (GSH-DXR) shows potent tumor cell cytotoxicity.
  • Glutathione-S-transferase (GST) enzymes are implicated in drug resistance.
  • GST-pi's role in modulating GSH-DXR efficacy requires clarification.

Purpose of the Study:

  • To investigate if GST-pi expression levels influence GSH-DXR cytotoxicity.
  • To compare the effects of GST-pi modulation on GSH-DXR and doxorubicin (DXR) sensitivity.

Main Methods:

  • Transfection of GST-pi sense cDNA into low-GST-pi HepG2 cells to enhance expression.
  • Transfection of GST-pi antisense cDNA into high-GST-pi HT29 cells to suppress expression.
  • Measurement of GST activity, drug sensitivity (IC50), and caspase-3 activation (apoptosis marker).

Main Results:

  • Enhanced GST-pi expression in HepG2 cells significantly reduced sensitivity to GSH-DXR (1/120-fold) but only slightly to DXR (1/2.6-fold).
  • Suppressed GST-pi expression in HT29 cells significantly improved sensitivity to GSH-DXR (2.9-28 nM IC50) compared to DXR (320-1020 nM IC50).
  • GST-pi modulation inversely affected caspase-3 activation, indicating an impact on apoptosis induction by GSH-DXR.

Conclusions:

  • The cytocidal efficacy of GSH-DXR is significantly controlled by the cellular level of GST-pi expression.
  • DXR sensitivity is less affected by GST-pi expression levels compared to GSH-DXR.
  • GST-pi plays a critical role in the mechanism of action and resistance to GSH-DXR.

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