3α-Hydroxymasticadienonic acid as an antiproliferative agent that impairs mitochondrial functions

Previous investigations on the biological effects of 3α-hydroxymasticadienonic acid (1) have demonstrated both anti-inflammatory and cytotoxic activities. However, neither the molecular mechanism of cytotoxic action nor the possible intracellular target(s) have been reported so far for this compound. The crucial role played by mitochondria on both cell survival and death, due to production of ATP and intrinsic apoptosis, respectively, prompted a study of the effect of 1 on isolated rat liver mitochondria. It was found that 1 causes a dose-dependent impairment of mitochondrial bioenergetic parameters, such as the respiratory control index and transmembrane electrical potential. Moreover, in the presence of Ca(2+), at a 10 μM concentration, 1 resulted in the induction of membrane permeability transition by oxidative stress, leading to the release of pro-apoptotic factors. At a 100 μM concentration, compound 1 affected mitochondrial Ca(2+) transport by inhibiting the accumulation of the cation in the mitochondrial matrix. Altogether, it was demonstrated that 1 induces an impairment of mitochondrial functions that may account for the cytotoxicity exhibited by this compound.