Discussion
non-cancer, mitochondrial dysfunction, consequent decline, breast cancer
BREAST CANCER, DRUG WITHDRAWAL, SECONDARY, MITOCHONDRIAL DYSFUNCTION, ADVERSE DRUG REACTIONS
To the best of our knowledge, this study is the first RCT to investigate the potential cardioprotective effects of metformin and donepezil in breast cancer patients receiving doxorubicin. Co-treatment with either metformin or donepezil did not reduce the incidence of hsTnI elevation post-doxorubicin therapy. In the placebo group, the level of hsTnI increased significantly after receiving doxorubicin, with consequent decline in LVEF and GLS. However, neither metformin nor donepezil attenuated these effects. The secondary analysis of mitochondrial respiration in PBMCs showed that only metformin could preserve maximal mitochondrial respiration and spare respiratory capacity during doxorubicin treatment.Previous in vitro and in vivo models suggested that metformin prevented doxorubicin-induced cardiotoxicitySecondary analysis of mitochondrial respiration in the PBMCs showed an impaired maximal mitochondrial respiration and spare respiratory capacity in the placebo group. These findings supported the hypothesis that mitochondrial dysfunction is one of the main mechanisms of doxorubicin-induced cardiotoxicityThe incidence of troponin-I elevation in our study was higher, compared to previous clinical trialsOur study showed higher discontinuation rates in patients taking donepezil (61.5%) compared to those taking metformin (18.6%) and placebo (10.4%), which was attributed to the adverse drug reactions. The rate of drug withdrawal in the donepezil group in our study was higher, compared to previous clinical trials of donepezil in non-cancer patients