Correlation between nuclear action of anthracycline anticancer agents and their binding affinity to the proteasome

Int J Oncol. 2002 Nov;21(5):1081-5.

Abstract

4'-O-tetrahydropyranyladriamycin (THP) showed an approximately 10-fold greater inhibitory effect on DNA synthesis in L1210 mouse leukemia cells than adriamycin (ADM). The intracellular transfer rate and nuclear accumulation of THP were approximately 5-fold higher than those of ADM. The intensity of in vitro inhibition of topoisomerase II activity by ADM was almost the same as that by THP. There were no significant differences between the uptake of either of these agents by the isolated nuclei of L1210 cells. The nuclear uptake of both agents in the presence of the cytosolic fraction of L1210 cells consisted of both simple diffusion and carrier-mediated components, and the carrier-mediated component of THP was approximately 2-fold higher than that of ADM. THP showed approximately 5-fold higher affinity to the proteasome than ADM, and interfered with ADM binding in a competitive manner. These results suggest that the binding affinity of these anticancer agents to the proteasome is an important factor in their transport to the nucleus and determines their specificity of action for the nuclear DNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Antibiotics, Antineoplastic / pharmacology*
  • Cell Nucleus / drug effects*
  • Cell Nucleus / metabolism
  • Cysteine Endopeptidases / metabolism*
  • DNA / drug effects
  • DNA Damage
  • Doxorubicin / analogs & derivatives*
  • Doxorubicin / metabolism
  • Doxorubicin / pharmacology*
  • Leukemia L1210 / metabolism
  • Leukemia L1210 / pathology
  • Mice
  • Multienzyme Complexes / metabolism*
  • Proteasome Endopeptidase Complex
  • Thymidine / metabolism

Substances

  • Antibiotics, Antineoplastic
  • Multienzyme Complexes
  • Doxorubicin
  • DNA
  • pirarubicin
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Thymidine