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.