Around 60-80% of all
breast tumors are
estrogen receptor-positive. One of the several therapeutic approaches used for this type of
cancers is the use of
aromatase inhibitors.
Exemestane is a third-generation steroidal
aromatase inhibitor that undergoes a complex and extensive metabolism, being catalytically converted into chemically active metabolites. Recently, our group showed that the major
exemestane metabolites, 17β-hydroxy-6-methylenandrosta-1,4-dien-3-one and 6-(hydroxymethyl)androsta-1,4,6-triene-3,17-dione, as well as, the intermediary metabolite 6β-Spirooxiranandrosta-1,4-diene-3,17-dione, are potent
aromatase inhibitors in
breast cancer cells. In this work, in order to better understand the
biological mechanisms of
exemestane in
breast cancer and the effectiveness of its metabolites, it was investigated their effects in sensitive and acquired-resistant
estrogen receptor-positive
breast cancer cells. Our results indicate that metabolites induced, in sensitive
breast cancer cells, cell cycle arrest and apoptosis via mitochondrial pathway, involving
caspase-8 activation. Moreover, metabolites also induced autophagy as a promoter mechanism of apoptosis. In addition, it was demonstrated that metabolites can sensitize
aromatase inhibitors-resistant
cancer cells, by inducing apoptosis. Therefore, this study indicates that
exemestane after metabolization originates active metabolites that suppress the growth of sensitive and resistant
breast cancer cells. It was also concluded that, in both cell lines, the
biological effects of metabolites are different from the ones of
exemestane, which suggests that
exemestane efficacy in
breast cancer treatment may also be dependent on its metabolites.