Supervisors info:
Ιωάννα Ανδρεάδου, Αναπληρώτρια Καθηγήτρια, Τμήμα Φαρμακευτικής, ΕΚΠΑ
Summary:
Introduction: Carfilzomib (Cfz) is an irreversible proteasome inhibitor indicated for the treatment of relapsed/refractory multiple myeloma, which has been associated with severe cardiotoxicity. The aim of this study was to i) establish a protocol evaluating the cardiac dysfunction, ii) investigate the molecular mechanisms of Cfz-induced cardiotoxicity and identify molecular targets, and iii) based on the results of the cardiotoxicity mechanism, investigate the potential cardioprotective mechanisms of metformin (Met).
Materials and Methods: Mice were randomized into: Protocol 1 (acute): Control (n=7); Cfz (n=8), for 6 days. Protocol 2 (sub-chronic): Control (n=5); Cfz (n=8), for 14 days. Protocol 3 (intermittent, acute and sub-chronic): Control (n=6); Cfz (n=5), consecutive doses on days 0, 1 and 7, 8 for 13 days. Protocol 4 (pharmacological intervention): Control (n=8); Cfz (n=8); Cfz+Met (n=8); Met (n=4), for 6 days. Cfz (8 mg/kg, ip) was administered every 48h (Protocols 1, 2, 4) and Met (140 mg/kg, po) every 24h. Cardiac function was assessed in all protocols. Myocardial tissue samples were obtained for the analysis of proteasome peptidases activity, PP2A activity and molecular mechanisms focused in Akt/eNOS axis, AMPΚα pathway and autophagy.
Results: Cfz (8 mg/kg) resulted in significant reduction of proteasome activity in heart and peripheral blood mononuclear cells. Echocardiography demonstrated FS% reduction in Cfz group following Protocol 1. Sub-chronic administration resulted in moderate left ventricular dilation and borderline reduction of FS. Cfz did not impair cardiac function after intermittent acute and sub-chronic administration. Molecular mechanisms were investigated in Protocol 1: Cfz inhibited PI3K/Akt/eNOS pathway and AMPKα/mTORC1-mediated autophagy by increasing PP2A activity. Based on the above results, Met an AMPKα activator, when co-administered with Cfz prevented FS% reduction, increased phosphorylation of Akt and AMPKα, and restored autophagy. Additionally, Met co-administration with Cfz resulted in significant reduction of proteasome activity in heart and peripheral blood mononuclear cells.
Conclusion: Cfz induced cardiac dysfunction through increased PP2A activity and inhibition of PI3K/Akt/eNOS and AMPKα-mediated autophagy. Met prevented cardiac dysfunction, emerging as a potent pharmacological intervention for the management of Cfz-induced cardiotoxicity.
Keywords:
carfilzomib, cardiotoxicity, metformin, molecular mechanism
