Supervisors info:
Ιωάννα Ανδρεάδου, Καθηγήτρια, Τμήμα Φαρμακευτικής, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Summary:
Introduction: Multiple myeloma is the most common hematological dyscrasia and is primarily manifested in the elderly patients who also suffer from cardiovascular comorbidities. Carfilzomib is used as a first-line treatment for relapsed/refractory multiple myeloma, but exhibits a significant cardiovascular toxicity. Taking under consideration that hyperlipidemia is a common comorbidity in patients treated with carfilzomib and stands as an independent risk factor for cardiovascular events manifestation, the aim of the present study was to investigate (i) the effect of hyperlipidemia-atherosclerosis in terms of carfilzomib-induced cardiotoxicity (ii) the cardioprotective effect of metformin (Met) which has been recently suggested as a potential prophylactic treatment act (iii) the potential cardioprotective effect of atorvastatin in the observed phenotype in vivo.
Methods: Male ApoE -/- mice were randomized as follows: Acute protocol: ApoE -/- 5 months of age: 1. Control (N/S 0.9%) 2. Cfz for 2 days. Sub-aute protocol: ApoE -/- 5 months of age: 1. Control (N / S 0.9%) 2. Cfz for 6 days. The sub-acute protocol was then repeated in ApoE -/- mice fed with Western diet (HFD), and the cardioprotective potential of metformin was evaluated in the presence or absence of atorvastatin. Thus, ApoE -/- mice were randomized as follows: ApoE -/- HFD: 1. Control (N/S 0.9%) 2. Cfz 3. Cfz + Met for 6 days, ApoE -/- HFD + atorvastatin: 1. Control (N/S 0.9%) 2. Cfz 3. Cfz + Met for 6 days. Cfz (8 mg / kg, intraperitoneally) in the two-dose protocol was administered daily, while in the sub-acute setting Cfz was administered on alternate days. Met (140 mg / kg, per os) and atorvastatin (20mg/kg per os) were administered every 24 hours. At the baseline and at the end of the experiments, ultrasound evaluation was performed and mice were sacrificed for blood and heart tissue collection. Plasma lipids were determined, proteasome activity was measured in both polymorphonuclear cells of the blood (PBMCs) and myocardium, and a part of the myocardium was subjected to Western Blot analysis.
Results: Cfz reduced proteasome activity as well as the fractional shortening (FS%) in all protocols. Cfz+Met co-administration led to a restoration of cardiac contractily. In ApoE -/- mice, Cfz decreased eNOS and Raptor phosphorylation after 2 doses, while 4 doses of Cfz reduced Akt phosphorylation and inhibited the AMPKα / Raptor axis. In ApoE -/- mice on HFD, Cfz inhibited the Akt/eNOS axis, while co-administration of Cfz + Met resulted in increased AMPKα phosphorylation and LC3B expression. In addition, ApoE -/- showed impaired lipid homeostasis, which was exacerbated by HFD as indicated by elevated levels of total cholesterol and low-density lipoprotein (LDL). Metformin co-administration increased plasma HDL levels. Finally, atorvastatin improved the lipid profile of experimental animals without providing cardioprotection against Cfz-induced cardiotoxicity.
Conclusions: Cfz administration induces cardiotoxicity in all the above models in compliance with our previous findings. Met retains its cardioprotective action despite hyperlipidemia and is superior to atorvastatin possibly through its metabolic action on the myocardium.
Keywords:
Proteasome inhibitors, carfilzomib, cardiotoxicity, hylerlipidemia, atherosclerosis, comorbidity, metformin, atorvastatin
