Bortezomib and heart failure: case‐report and review of the French <scp>P</scp>harmacovigilance database

Honton, Benjamin; Despas, Fabien; Dumonteil, Nicolas; Rouvellat, Caroline; Roussel, Murielle; Carrié, Didier; Galinier, Michel; Montastruc, J. L.; Pathak, Atul

doi:10.1111/fcp.12039

Cited by 36 publications

(29 citation statements)

References 10 publications

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“…This represents one major step closer to identification of specific Ub ligases for targeted degradation of toxic misfolded proteins; on the other hand, this also cautions that NAE inhibition may potentially exert cardiotoxicity, just like proteasome inhibitors. 16, 17 …”

Section: Discussionmentioning

confidence: 99%

“…12–15 These experimental demonstrations are corroborated by clinical observations that a significant portion of cancer patients receiving proteasome inhibitors in their chemotherapy develop cardiac dysfunction or even heart failure. 16, 17 A significant role of UPS malfunction in cardiac pathogenesis is further underscored by the identification of dominant negative mutations in TRIM63 , the gene encodes a Ub ligase (muscle ring finger 1), as a cause of human familial hypertrophic cardiomyopathy. 18 Hence, a better understanding of the molecular underpinnings of cardiac PQC is of paramount significance to developing strategies to improve cardiac PQC and thereby more effectively to treat a large subset of heart diseases.…”

Section: Introductionmentioning

confidence: 99%

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COP9 Signalosome Controls the Degradation of Cytosolic Misfolded Proteins and Protects Against Cardiac Proteotoxicity

Zhang

et al. 2015

Circulation Research

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Rationale Impaired degradation of misfolded proteins is associated with a large subset of heart diseases. Misfolded proteins are degraded primarily by the ubiquitin-proteasome system (UPS) but the ubiquitin ligases responsible for the degradation remain largely unidentified. The cullin deneddylation activity of the COP9 signalosome (CSN) requires all 8 CSN subunits (CSN1 through CSN8) and regulates cullin-RING ligases (CRLs), thereby controlling ubiquitination of a large number of proteins; however, neither CSN nor CRLs are known to regulate the degradation of cytosolic misfolded proteins. Objective We sought to investigate the role of CSN8/CSN in misfolded protein degradation and cardiac proteinopathy. Methods and Results Cardiac CSN8 knockout causes mouse premature death; hence, CSN8 haploinsufficiency (CSN8hypo) mice were used. Myocardial neddylated forms of cullins were markedly increased and myocardial capacity of degrading a surrogate misfolded protein was significantly reduced by CSN8hypo. When introduced into proteinopathic mice in which a bona fide misfolded protein CryABR120G is overexpressed in the heart, CSN8hypo aggravated CryABR120G-induced restrictive cardiomyopathy and shortened the lifespan of CryABR120G mice, which was associated with augmented accumulation of protein aggregates, increased neddylated proteins, and reduced levels of total ubiquitinated proteins and LC3-II in the heart. In cultured cardiomyocytes, both CSN8 knockdown and CRL inactivation suppressed the ubiquitination and degradation of CryABR120G but not native CryAB, resulting in accumulation of protein aggregates and exacerbation of CryABR120G cytotoxicity. Conclusions (1) CSN8/CSN promotes the ubiquitination and degradation of misfolded proteins and protects against cardiac proteotoxicity and (2) CRLs participate in degradation of cytosolic misfolded proteins.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

COP9 Signalosome Controls the Degradation of Cytosolic Misfolded Proteins and Protects Against Cardiac Proteotoxicity

Zhang

et al. 2015

Circulation Research

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“…These carfilzomib-associated toxicities were confirmed to occur at a higher incidence compared to bortezomib in the ENDEAVOR trial [11]. While a strong signal for cardiac toxicity has not been associated with bortezomib use, several case reports [12][13][14][15][16] have described CAEs in patients receiving this agent.…”

Section: Introductionmentioning

confidence: 89%

Cardiac events during treatment with proteasome inhibitor therapy for multiple myeloma

Chen

Lenihan²,

Phillips

et al. 2017

Cardio-Oncology

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Background: Proteasome inhibitors (PI) bortezomib and carfilzomib are cornerstone therapies for multiple myeloma. Higher incidence of cardiac adverse events (CAEs) has been reported in patients receiving carfilzomib. However, risk factors for cardiac toxicity remain unclear. Our objective was to evaluate the incidence of CAEs associated with PI and recognize risk factors for developing events.Methods: This was a descriptive analysis of 96 patients with multiple myeloma who received bortezomib (n = 44) or carfilzomib (n = 52). We compared the cumulative incidence of CAEs using a log rank test. Patient-related characteristics were assessed and multivariate analysis was used to identify risk factors for developing CAEs. Results: PI-related CAEs occurred in 21 (22%) patients. Bortezomib-associated CAEs occurred in 7 (16%) patients while carfilzomib-associated cardiac events occurred in 14 (27%) patients. The cumulative incidence of CAEs was not significantly different between agents. Events occurred after a median of 67.5 days on PI therapy. Heart failure was the most prevalent event type. More patients receiving carfilzomib were monitored by a cardiologist. By multivariate analysis, a history of prior cardiac events and longer duration of PI therapy were identified as independent risk factors for developing CAEs. Conclusions: AEs were common in patients receiving PIs. Choice of PI did not impact the cumulative incidence of CAEs. Early involvement by a cardiologist in patients at high risk for CAEs may help to mitigate the frequency and severity of CAEs.

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“…In sTAC, the intrinsic UPS functional inadequacy occurs much earlier, therefore the same moderate CR-PsmI can now achieve enough inhibition at an early time point to suppress cardiac protein synthesis (i.e., cardiac growth) but by the same mechanism this also quickly impairs PQC in cardiomyocytes, leading to cardiomyocyte malfunction, increased cell death and ultimately heart failure. Supporting our contention, intermittent primary PsmI caused restrictive cardiomyopathy in pigs [14] and cardiotoxicity including heart failure was frequently reported for PsmI used in clinical chemotherapy, especially in patients with preexisting cardiovascular conditions [36, 37]. …”

Section: Discussionmentioning

confidence: 52%

Genetically induced moderate inhibition of 20S proteasomes in cardiomyocytes facilitates heart failure in mice during systolic overload

Ranek

Zheng

Huang

et al. 2015

Journal of Molecular and Cellular Cardiology

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The in vivo function status of the ubiquitin-proteasome system (UPS) in pressure overloaded hearts remains undefined. Cardiotoxicity was observed during proteasome inhibitor chemotherapy, especially in those with preexisting cardiovascular conditions; however, proteasome inhibition (PsmI) was also suggested by some experimental studies as a potential therapeutic strategy to curtail cardiac hypertrophy. Here we used genetic approaches to probe cardiac UPS performance and determine the impact of cardiomyocyte-restricted PsmI (CR-PsmI) on cardiac responses to systolic overload. Transgenic mice expressing an inverse reporter of the UPS (GFPdgn) were subject to transverse aortic constriction (TAC) to probe myocardial UPS performance during systolic overload. Mice with or without moderate CR-PsmI were subject to TAC and temporally characterized for cardiac responses to moderate and severe systolic overload. After moderate TAC (pressure gradient: ~40mmHg), cardiac UPS function was upregulated during the first two weeks but turned to functional insufficiency between 6 and 12 weeks as evidenced by the dynamic changes in GFPdgn protein levels, proteasome peptidase activities, and total ubiquitin conjugates. Severe TAC (pressure gradients >60mmHg) led to UPS functional insufficiency within a week. Moderate TAC elicited comparable hypertrophic responses between mice with and without genetic CR-PsmI but caused cardiac malfunction in CR-PsmI mice significantly earlier than those without CR-PsmI. In mice subject to severe TAC, CR-PsmI inhibited cardiac hypertrophy but led to rapidly progressed heart failure and premature death, associated with a pronounced increase in cardiomyocyte death. It is concluded that cardiac UPS function is dynamically altered, with the initial brief upregulation of proteasome function being adaptive; and CR-PsmI facilitates cardiac malfunction during systolic overload.

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Bortezomib and heart failure: case‐report and review of the French Pharmacovigilance database

Cited by 36 publications

References 10 publications

COP9 Signalosome Controls the Degradation of Cytosolic Misfolded Proteins and Protects Against Cardiac Proteotoxicity

COP9 Signalosome Controls the Degradation of Cytosolic Misfolded Proteins and Protects Against Cardiac Proteotoxicity

Cardiac events during treatment with proteasome inhibitor therapy for multiple myeloma

Genetically induced moderate inhibition of 20S proteasomes in cardiomyocytes facilitates heart failure in mice during systolic overload

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