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Unexpected cardiotoxicity in haematological bortezomib treated patients

2007; Wiley; Volume: 138; Issue: 3 Linguagem: Inglês

10.1111/j.1365-2141.2007.06659.x

1365-2141

Enrico Orciuolo, Gabriele Buda, Nadia Cecconi, Sara Galimberti, Daniele Versari, Giulia Cervetti, Antonio Salvetti, Mario Petrini,

NF-κB Signaling Pathways

Bortezomib is an antitumor compound that inhibits proteasome activity. It is able to impair the activation of nuclear factor (NF)-κB, blocking the degradation of inhibitory κB (IκB), which is required for NF-κB translocation into the nucleus and activation of target genes. NF-κB is important for cell survival, regulating the expression of genes involved in apoptosis, such as BCL2 and BCL2L1, cell cycle progression, inflammation and angiogenesis (Richardson et al, 2003). In 2006, we treated 69 patients with bortezomib, either alone or as combination therapy. Bortezomib therapy is known to be associated with neurological side effects and thrombocytopenia (Richardson et al, 2003); however, we noticed an unexpected increase of cardiac complications, ranging from heart failure to onset of arrhythmias. Only one single case of heart failure (Voortman & Giaccone, 2006) and one asymptomatic arrhythmia (Berenson et al, 2007) following bortezomib therapy have been reported to date. All except one of our bortezomib-treated patients were receiving at least a second line therapy, and some of them had previously received anthracycline-containing regimens. Eight (11·6%) of the 69 patients developed serious cardiac side effects requiring medication, hospitalisation or the implant of a pacemaker (see Table I). All patients underwent cardiovascular screening before receiving bortezomib and no clinically significant abnormalities were present. The only conditions that were identified as common to all the patients were bortezomib administration and age >60 years. All eight patients who experienced cardiotoxicity underwent at least four cycles of bortezomib, strengthening the hypothesis of a direct connection with the drug. Each cycle included bortezomib 1·3 mg/m2 on days 1, 4, 8 and 11 and the recycling period was 3 weeks. The onset of cardiac symptoms was never recorded before a cumulative dose of 20·8 mg/m2 of bortezomib. The ubiquitin-proteasome system is responsible for non-lysosomal degradation of intracellular proteins, including key regulators of cell cycle, angiogenesis and apoptosis, and transcription factors, which regulate crucial mechanisms of plaque formation and rupture. Additionally, the presence of a reduced proteasome activity is associated with an increased rate of apoptosis in smooth muscle cells, determining atherosclerotic plaque instability by weakening of the fibrous cap and enlargement of the necrotic core (Versari et al, 2006). Furthermore, NF-κB activation plays an essential role in the intracellular signal transduction of the second window of protection of delayed ischaemic preconditioning in the myocardium, leading to myocardial cytoprotection (Jancso et al, 2005). Therefore, bortezomib may simultaneously cause atherosclerotic plaque progression and tendency to rupture, and facilitate ischaemic heart complications by reducing/abrogating myocardial preconditioning. Additionally, although bortezomib was found to reduce the onset of delayed arrhythmias following coronary ligation in the canine model by upregulating the adrenergic sensitiser GRK2 (Yu et al, 2005), in the absence of an acute ischaemic event this mechanism may rather be responsible for deleterious cardiac effects (Liu et al, 2005). Indeed, desensitisation of the adrenergic receptor, while preventing tachyarrhythmias (Liu et al, 2005) might potentially favour bradycardia, as accordingly shown in our population. Finally, there is much experimental evidence to support the crucial role of a deficient proteasome activity in impairing cardiac function by several mechanisms, the most important of which is putatively the accumulation of unfolded, damaged and undegraded proteins inside myocytes (as extensively reviewed by Willis & Patterson, 2006). We hypothesise that these combined mechanisms may lead to the cardiac complications observed in our bortezomib-treated patients.