Doxorubicin Cardiomyopathy

Chatterjee, Kanu; Zhang, Jianqing; Honbo, Norman; Karliner, Joel S.

doi:10.1159/000265166

Cited by 910 publications

(731 citation statements)

References 72 publications

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“…Doxorubicin (DOX) is an effective and frequently used chemotherapeutic agent for various malignancies, which causes both an acute and late-onset, dose-limiting cardiomyopathy [36][37][38] , in part, as a result of cumulative apoptotic myocyte loss 39,40 . Transduction of ILK WT and ILK R211A caused a significant reduction in DOXinduced apoptosis (Fig.…”

Section: Resultsmentioning

confidence: 99%

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

Traister

Aafaqi

et al. 2014

Nat Commun

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Human dilated cardiomyopathy (DCM) manifests as a profound reduction in biventricular cardiac function that typically progresses to death or cardiac transplantation. There is no effective mechanism-based therapy currently available for DCM, in part because the transduction of mechanical load into dynamic changes in cardiac contractility (termed mechanotransduction) remains an incompletely understood process during both normal cardiac function and in disease states. Here we show that the mechanoreceptor protein integrin-linked kinase (ILK) mediates cardiomyocyte force transduction through regulation of the key calcium regulatory protein sarcoplasmic/endoplasmic reticulum Ca 2 þ ATPase isoform 2a (SERCA-2a) and phosphorylation of phospholamban (PLN) in the human heart. A non-oncogenic ILK mutation with a synthetic point mutation in the pleckstrin homology-like domain (ILK R211A ) is shown to enhance global cardiac function through SERCA-2a/PLN. Thus, ILK serves to link mechanoreception to the dynamic modulation of cardiac contractility through a previously undiscovered interaction with the functional SERCA-2a/PLN module that can be exploited to rescue impaired mechanotransduction in DCM.

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Section: Resultsmentioning

confidence: 99%

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

Traister

Aafaqi

et al. 2014

Nat Commun

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“…Retreatment of multiply relapsed or refractory patients with aggressive NHL anthracyclines is problematic due to long‐term cardiotoxicity (Chatterjee et al , 2010). The use of anthracycline‐based regimens is associated with a 22% cumulative 10‐year risk for cardiovascular disease, notably with an excess of risk for cardiomyopathy leading to chronic heart failure (incidence ratio 5·4) and stroke (incidence ratio 1·8) (Moser et al , 2006).…”

Section: Discussionmentioning

confidence: 99%

Monotherapy with pixantrone in histologically confirmed relapsed or refractory aggressive B‐cell non‐Hodgkin lymphoma: post‐hoc analyses from a phase III trial

et al. 2016

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This post hoc analysis of a phase 3 trial explored the effect of pixantrone in patients (50 pixantrone, 47 comparator) with relapsed or refractory aggressive B‐cell non‐Hodgkin lymphoma (NHL) confirmed by centralized histological review. Patients received 28‐d cycles of 85 mg/m2 pixantrone dimaleate (equivalent to 50 mg/m2 in the approved formulation) on days 1, 8 and 15, or comparator. The population was subdivided according to previous rituximab use and whether they received the study treatment as 3rd or 4th line. Median number of cycles was 4 (range, 2–6) with pixantrone and 3 (2–6) with comparator. In 3rd or 4th line, pixantrone was associated with higher complete response (CR) (23·1% vs. 5·1% comparator, P = 0·047) and overall response rate (ORR, 43·6% vs. 12·8%, P = 0·005). In 3rd or 4th line with previous rituximab (20 pixantrone, 18 comparator), pixantrone produced better ORR (45·0% vs. 11·1%, P = 0·033), CR (30·0% vs. 5·6%, P = 0·093) and progression‐free survival (median 5·4 vs. 2·8 months, hazard ratio 0·52, 95% confidence interval 0·26–1·04) than the comparator. Similar results were found in patients without previous rituximab. There were no unexpected safety issues. Pixantrone monotherapy is more effective than comparator in relapsed or refractory aggressive B‐cell NHL in the 3rd or 4th line setting, independently of previous rituximab.

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“…Doxorubicin is also known to induce oxidative stress, which has been utilized to explain the adverse cardiotoxic effect of chemotherapy [28]. Mitochondria are a major intracellular organelle responsible for the production of reactive oxygen and nitrogen species (ROS/RNS) [29].…”

Section: Mitochondrial Oxidative Stress Induced By Doxorubicinmentioning

confidence: 99%

Monitoring Redox Dynamics in Living Cells with a Redox-Sensitive Red Fluorescent Protein

Fan

Chen

2015

Anal. Chem.

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Redox signaling and homeostasis are important for all forms of life on Earth. There has been great interest in monitoring redox dynamics in living cells and organisms as a mean to better understand redox biology in physiological and pathological conditions. Herein we report our recent results on the development of a genetically encoded redox-sensitive red fluorescent protein (rxRFP). We first identified a circularly permuted RFP (cpRFP) scaffold, which maintained its autocatalytic fluorescence, from a red fluorescent Ca2+ sensor, R-GECO1. We then introduced cysteine residue pairs to the N- and C- termini of the cpRFP scaffold, and subsequently optimized the length and composition of the sequences adjacent to the cysteine residues. From these libraries, we identified rxRFP, showing up to a 4-fold fluorescence increase in the oxidized state compared to the reduced state at pH 7.4. We thoroughly characterized rxRFP in vitro, and expressed it in living mammalian cells to monitor redox dynamics. With its excitation peak at 576 nm and emission peak at 600 nm, rxRFP is one of the first genetically encoded red fluorescent probes that can sense general redox states.

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Doxorubicin Cardiomyopathy

Cited by 910 publications

References 72 publications

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

Monotherapy with pixantrone in histologically confirmed relapsed or refractory aggressive B‐cell non‐Hodgkin lymphoma: post‐hoc analyses from a phase III trial

Monitoring Redox Dynamics in Living Cells with a Redox-Sensitive Red Fluorescent Protein

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