Doxorubicin plus lonidamine: in vivo metabolic effects on the rat heart

Lonidamine (LND) is a new drug that interferes with mitochondrial functions, thereby inhibiting cellular oxygen consumption and energy metabolism in both normal and neoplastic cells. These metabolic actions of LND seem to increase the cytotoxic effect of antitumor agents such as doxorubicin (Dx). Dx is a widely used antitumor agent, but the specific cardiac toxicity which develops at a critical cumulative dose is the major limiting factor in its long term use. So far, nothing is known about a possible synergic action of LND and Dx on the metabolism of cardiac cells. The purpose of this study was to verify in an experimental model in vivo, whether LND could increase the toxicity of Dx on rat heart. Groups each consisting of 10 female Wistar rats (weighing 100-150 g) were injected ip with a single dose of Dx (10 mg/kg), LDN (50 mg/kg), or Dx plus LND and dimethylsulfoxide (DMSO) (ratio LND:DMSO = 1/10). After 24 h, oxygen uptake (QO2) and intracellular concentrations of ATP and GTP indices of cardiac metabolic impairment, were measured on heart slices in Warburg apparatus and by high-pressure liquid chromatography. Dx, significantly (p less than 0.01), reduced QO2 (34%) and intracellular concentration of ATP and GTP (32-57%). LND alone only partially reduced cardiac QO2 (23%) and intracellular ATP-GTP concentration (16-31%). By contrast, the combination of the two agents did not enhance Dx-related metabolic cardiac toxicity.