Autophagic dysregulation in doxorubicin cardiomyopathy

Bartlett, Jordan; Trivedi, Purvi; Pulinilkunnil, Thomas

doi:10.1016/j.yjmcc.2017.01.007

Cited by 173 publications

(156 citation statements)

References 88 publications

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“…73 Specifically autophagy suppresses cellular senescence by removing damaged macromolecules or organelles, or promotes cellular senescence by facilitating the synthesis of senescence-associated secretory proteins. 76 The interference of anthracyclines with TFEB activity can also impair autophagy of peroxisomes, pexophagy, which may contribute to neurotoxicity, cognitive dysfunction, and accelerated brain aging in cancer patients and survivors. This would preserve the integrity of tissue structure and function.…”

Section: Autophagy Regulates Cell and Tissue Homeostasismentioning

confidence: 99%

“…75 Drugs that interfere with the activation of TFEB, such as anthracyclines, impair autophagy and cause cardiomyopathy. 76 The interference of anthracyclines with TFEB activity can also impair autophagy of peroxisomes, pexophagy, which may contribute to neurotoxicity, cognitive dysfunction, and accelerated brain aging in cancer patients and survivors. 77 Autophagy has crucial roles in vertebrate development from the pre-implantation stage to organogenesis.…”

Section: Autophagy Regulates Cell and Tissue Homeostasismentioning

confidence: 99%

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Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

2019

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Chloroquines are 4-aminoquinoline-based drugs mainly used to treat malaria. At pharmacological concentrations, they have significant effects on tissue homeostasis, targeting diverse signaling pathways in mammalian cells. A key target pathway is autophagy, which regulates macromolecule turnover in the cell. In addition to affecting cellular metabolism and bioenergetic flow equilibrium, autophagy plays a pivotal role at the interface between inflammation and cancer progression. Chloroquines consequently have critical effects in tissue metabolic activity and importantly, in key functions of the immune system. In this article, we will review the work addressing the role of chloroquines in the homeostasis of mammalian tissue, and the potential strengths and weaknesses concerning their use in cancer therapy.

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Section: Autophagy Regulates Cell and Tissue Homeostasismentioning

confidence: 99%

Section: Autophagy Regulates Cell and Tissue Homeostasismentioning

confidence: 99%

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

2019

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“…[8][9][10][11][12][13][14][15][16] Therefore, inhibiting ROS accumulation and calcium overload may be an effective strategy to control THP-induced cardiotoxicity. Studies in recent years have demonstrated that anthracyclines trigger excessive mitochondrial reactive oxygen species (ROS) production in cardiomyocytes, subsequently inducing calcium overload, mitochondrial dysfunction, autophagy dysregulation, and eventually apoptotic and autophagic cell death.…”

Section: Introductionmentioning

confidence: 99%

“…Studies in recent years have demonstrated that anthracyclines trigger excessive mitochondrial reactive oxygen species (ROS) production in cardiomyocytes, subsequently inducing calcium overload, mitochondrial dysfunction, autophagy dysregulation, and eventually apoptotic and autophagic cell death. [8][9][10][11][12][13][14][15][16] Therefore, inhibiting ROS accumulation and calcium overload may be an effective strategy to control THP-induced cardiotoxicity.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‐129‐1‐3p protects cardiomyocytes from pirarubicin‐induced apoptosis by down‐regulating the GRIN2D‐mediated Ca²⁺ signalling pathway

Qin

Tan

et al. 2020

J Cellular Molecular Medi

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Pirarubicin (THP), an anthracycline anticancer drug, is a first-line therapy for various solid tumours and haematologic malignancies. However, THP can cause dosedependent cumulative cardiac damage, which limits its therapeutic window. The mechanisms underlying THP cardiotoxicity are not fully understood. We previously showed that MiR-129-1-3p, a potential biomarker of cardiovascular disease, was down-regulated in a rat model of THP-induced cardiac injury. In this study, we used Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analyses to determine the pathways affected by miR-129-1-3p expression. The results linked miR-129-1-3p to the Ca 2+ signalling pathway. TargetScan database screening identified a tentative miR-129-1-3p-binding site at the 3′-UTR of GRIN2D, a subunit of the N-methyl-D-aspartate receptor calcium channel. A luciferase reporter assay confirmed that miR-129-1-3p directly regulates GRIN2D. In H9C2 (rat) and HL-1 (mouse) cardiomyocytes, THP caused oxidative stress, calcium overload and apoptotic cell death. These THP-induced changes were ameliorated by miR-129-1-3p overexpression, but exacerbated by miR-129-1-3p knock-down. In addition, miR-129-1-3p overexpression in cardiomyocytes prevented THP-induced changes in the expression of proteins that are either key components of Ca 2+ signalling or important regulators of intracellular calcium trafficking/balance in cardiomyocytes including GRIN2D, CALM1, CaMKⅡδ, RyR2-pS2814, SERCA2a and NCX1.Together, these bioinformatics and cell-based experiments indicate that miR-129-1-3p protects against THP-induced cardiomyocyte apoptosis by down-regulating the GRIN2D-mediated Ca 2+ pathway. Our results reveal a novel mechanism underlying the pathogenesis of THP-induced cardiotoxicity. The miR-129-1-3p/Ca 2+ signalling pathway could serve as a target for the development of new cardioprotective agents to control THP-induced cardiotoxicity. K E Y W O R D Sapoptosis, Ca 2+ signalling pathway, cardiomyocytes, GRIN2D, miR-129-1-3p, pirarubicin | 2261 LI et aL.

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“…Doxorubicin is a widely used chemotherapeutic agent but has long been associated with cardiac dysfunction in cancer patients (Bartlett et al, 2017). Doxorubicin acts directly on cardiomyocytes (CMCs), generating reactive oxygen species and reactive nitrogen species (Cappetta et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Doxorubicin‐induced cardiomyocyte toxicity – protective effects of endothelial cells in a tri‐culture model system

Alias

Parikh

Hidalgo‐Bastida

et al. 2018

J of Interdiscip Nanomed

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Doxorubicin-induced cardiomyopathy is a clinically prevalent pathology, occurring as a sequelae following chemotherapy for cancer patients. In particular, the "first dose" effect has been particularly challenging, given the heterogeneous and multifactorial nature of this pathophysiology. Here, we describe the development of a physiologically relevant in vitro model for cardiotoxicity testing, using human cells. Primary cardiomyocytes, endothelial, and smooth muscle cells were tri-cultured in 2D, or within nano-fibrous scaffolds in a 3D environment, under dynamic nutrient flow, using the Quasi Vivo® system. State-ofthe-art sensor chips were used to detect troponin I levels, 2 h after acute exposure to doxorubicin. We demonstrate a significant improvement in cardiomyocyte viability when grown in a 3D tri-culture environment over a 5-day period and a 10-fold reduction in doxorubicin-induced toxicity. Our tri-culture model can be used as a valuable tool for physiologically relevant assessment of drug-induced cardiotoxicity in vitro.

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Autophagic dysregulation in doxorubicin cardiomyopathy

Cited by 173 publications

References 88 publications

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

MicroRNA‐129‐1‐3p protects cardiomyocytes from pirarubicin‐induced apoptosis by down‐regulating the GRIN2D‐mediated Ca²⁺ signalling pathway

Doxorubicin‐induced cardiomyocyte toxicity – protective effects of endothelial cells in a tri‐culture model system

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Autophagic dysregulation in doxorubicin cardiomyopathy

Cited by 173 publications

References 88 publications

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

MicroRNA‐129‐1‐3p protects cardiomyocytes from pirarubicin‐induced apoptosis by down‐regulating the GRIN2D‐mediated Ca2+ signalling pathway

Doxorubicin‐induced cardiomyocyte toxicity – protective effects of endothelial cells in a tri‐culture model system

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MicroRNA‐129‐1‐3p protects cardiomyocytes from pirarubicin‐induced apoptosis by down‐regulating the GRIN2D‐mediated Ca²⁺ signalling pathway