Molecular mechanisms of carfilzomib-induced cardiotoxicity in mice and the emerging cardioprotective role of metformin

Abstract

Carfilzomib (Cfz), an irreversible proteasome inhibitor licensed for relapsed/refractory myeloma, is associated with cardiotoxicity in humans. We sought to establish the optimal protocol of Cfz-induced cardiac dysfunction, to investigate the underlying molecular-signaling and, based on the findings, to evaluate the cardioprotective potency of metformin (Met). Mice were randomized into protocols 1 and 2 (control and Cfz for 1 and 2 consecutive days, respectively); protocols 3 and 4 (control and alternate doses of Cfz for 6 and 14 days, respectively); protocols 5A and 5B (control and Cfz, intermittent doses on days 0, 1 [5A] and 0, 1, 7, and 8 [5B] for 13 days); protocols 6A and 6B (pharmacological intervention; control, Cfz, Cfz+Met and Met for 2 and 6 days, respectively); and protocol 7 (bortezomib). Cfz was administered at 8 mg/kg (IP) and Met at 140 mg/kg (per os). Cfz resulted in significant reduction of proteasomal activity in heart and peripheral blood mononuclear cells in all protocols except protocols 5A and 5B. Echocardiography demonstrated that Cfz led to a significant fractional shortening (FS) depression in protocols 2 and 3, a borderline dysfunction in protocols 1 and 4, and had no detrimental effect on protocols 5A and 5B. Molecular analysis revealed that Cfz inhibited AMPKα/mTORC1 pathways derived from increased PP2A activity in protocol 2, whereas it additionally inhibited phosphatidylinositol 3-kinase/Akt/endothelial nitric oxide synthase pathway in protocol 3. Coadministration of Met prevented Cfz-induced FS reduction and restored AMPKα phosphorylation and autophagic signaling. Conclusively, Cfz decreased left ventricular function through increased PP2A activity and inhibition of AMPKα and its downstream autophagic targets, whereas Met represents a novel promising intervention against Cfz-induced cardiotoxicity.

Proteasome Inhibitors for the Treatment of Multiple Myeloma

“…In particular, the agent is associated with cardiovascular AEs. Recently, Efentakis et al demonstrated that cardiotoxicity by carfilzomib is associated with the autophagy pathway and upregulation of protein phosphatase (PP)-2A phosphatase activity but not the inhibition of the proteasome function [60]. Selected carfilzomib-containing regimens for relapsed and/or refractory MM patients are shown in Table 4.…”

Prevention, monitoring and treatment of cardiovascular adverse events in myeloma patients receiving carfilzomib A consensus paper by the European Myeloma Network and the Italian Society of Arterial Hypertension

“…However, speculations can be made on its irreversible and highly potent proteasome inhibition activity that could differentiate its safety profile from that of bortezomib . Cardiac stress produces misfolded proteins; proteasome‐mediated degradation of these toxic products is pivotal to preserve cellular function in some patients . Moreover, the levels of nitric oxide, an important mediator of endothelial function, could also be modulated by proteasome activity, and decreased nitric oxide levels could impair vasodilatation, inducing hypertension and cardiac dysfunction .…”

Oncocardiology: new challenges, new opportunities

“…Although the underlying pathomechanism has not been elucidated, proteasome inhibitor-associated perturbation of endothelial nitric oxide synthase (eNOS) has been hypothesized to facilitate cardiovascular dysfunction [21]. Additionally, a direct effect on cardiac protein homeostasis has been demonstrated in a preclinical model [22]. Risk factors for cardiotoxicity (e.g., diabetes mellitus, poorly controlled arterial hypertension, known history of heart failure) should be assessed at baseline.…”

“…Elevation of BNP (>400 pg/ml) is associated with higher rates of hospitalization for cardiovascular adverse events [21]. Metformin may exhibit a preventive effect, but prospective clinical data are still warranted [22].…”