Lonidamine as a modulator of taxol activity in human ovarian cancer cells: effects on cell cycle and induction of apoptosis

Int J Cancer. 1998 Oct 29;78(3):377-84. doi: 10.1002/(SICI)1097-0215(19981029)78:3<377::AID-IJC20>3.0.CO;2-2.

Abstract

The ability of lonidamine (LND), an energolytic derivative of indazole-carboxylic acid, to modulate the cytotoxicity of Taxol (TX) was investigated in the A2780 human ovarian cancer cell line. Different cytotoxicity results were obtained as a function of treatment schedule. Specifically, TX followed by LND produced synergistic effects. Conversely, antagonistic effects were recorded when drugs were given simultaneously or according to the opposite sequence. TX induced an oligonucleosomal DNA fragmentation typical of the apoptotic process. The extent and the kinetics of DNA cleavage in samples treated with the taxane alone were similar to those of samples treated with the TX-LND sequence. Activation of Yama protease and degradation of poly (ADP-ribose) polymerase were not observed after individual or combined treatment. LND did not appreciably modify the effect exerted by TX on proteins involved in cell cycle progression (i.e., inhibition of p34cdc2 expression) and apoptosis (i.e., upregulation of wt p53 and transactivation of p21waf1), and only caused a slight induction of the Bax protein. LND alone did not affect tubulin polymerization in A2780 cells and, when administered after a 24 hr TX exposure, did not appreciably alter the extent of tubulin polymerization induced by the taxane. Although additional studies are needed to define the molecular basis of the TX-LND interaction, our results suggest that LND can positively modulate the antitumor activity of TX in ovarian cancer cells and indicate that the energolytic is potentially useful in combination therapy including the taxane in ovarian cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / toxicity*
  • Apoptosis / drug effects*
  • Caspase 3
  • Caspases / metabolism
  • Cell Cycle / drug effects*
  • Cell Survival / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / biosynthesis
  • Cyclins / genetics
  • Drug Synergism
  • Enzyme Inhibitors / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Indazoles / toxicity*
  • Mitotic Index / drug effects
  • Ovarian Neoplasms
  • Paclitaxel / toxicity*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protamine Kinase / metabolism
  • Tubulin / chemistry
  • Tubulin / drug effects
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / biosynthesis
  • Tumor Suppressor Protein p53 / genetics

Substances

  • Antineoplastic Agents
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Enzyme Inhibitors
  • Indazoles
  • Tubulin
  • Tumor Suppressor Protein p53
  • Poly(ADP-ribose) Polymerases
  • Protamine Kinase
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • Paclitaxel
  • lonidamine