Molecular mechanisms in the antiproliferative action of taxol and tiazofurin

Anticancer Res. Sep-Oct 1996;16(5A):2469-77.

Abstract

The molecular antiproliferative effects of taxol and tiazofurin were studied in human K562 leukemia, and in MCF-7 breast and OVCAR-5 ovarian carcinoma cell cultures. A single treatment with taxol (2 to 100 nM) or tiazofurin (5 to 20 microM) on K562 leukemia cells resulted in both a differentiation program and apoptosis in the same cell culture. Tiazofurin proved to be the most potent inducer of differentiation among the inducers, however, taxol had a major impact on induction of the alterations characteristic of apoptosis. The antiproliferative effect of tiazofurin was mediated by 37 to 85% inhibition of IMP dehydrogenase activity. Both the differentiation and apoptosis induced by tiazofurin were dependent on GTP supply. The induction of differentiation and/or apoptosis was mediated by downregulation of c-myc and Ki-ras oncogenes in all three cell lines treated with tiazofurin (by 2 hr) or taxol (by 24 hr). Combined treatments with tiazofurin and taxol exerted a schedule-dependent, antiproliferative interaction in the cell lines studied. Synergistic inhibition of cell proliferation was observed when cells were pretreated with tiazofurin (10 to 15 microM) for at least 12 hr, then taxol (5 to 15 nM) was added.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Differentiation / drug effects*
  • Cell Division / drug effects
  • Cell Nucleus / drug effects
  • DNA Fragmentation
  • DNA, Neoplasm / drug effects
  • Down-Regulation
  • Drug Synergism
  • Erythrocytes / drug effects
  • Female
  • Genes, myc / drug effects
  • Genes, ras / drug effects
  • Humans
  • IMP Dehydrogenase / metabolism*
  • Leukemia / enzymology
  • Leukemia / genetics
  • Leukemia / pathology
  • Ovarian Neoplasms / enzymology
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology
  • Paclitaxel / pharmacology*
  • Ribavirin / analogs & derivatives*
  • Ribavirin / pharmacology
  • Tumor Cells, Cultured
  • Tumor Stem Cell Assay

Substances

  • Antineoplastic Agents
  • DNA, Neoplasm
  • Ribavirin
  • IMP Dehydrogenase
  • Paclitaxel
  • tiazofurin