Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity

Ma, Wanjun; Wei, Shanshan; Zhang, Bikui; Li, Wenqun

doi:10.3389/fcell.2020.00434

Cited by 101 publications

(76 citation statements)

References 190 publications

(194 reference statements)

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“…Pyroptosis was first demonstrated in 2001 60 and is now widely recognized to play a crucial role in the pathogenesis of cardiovascular diseases 61 . Pyroptosis is characterized by increased inflammation and activation of caspase -1, caspase-3, caspase-4, and caspase-11 as well as NLR family pyrin domain containing 3 (NLRP3) leading to the cleavage of Gasdermin D (GSDMD) or GSDME and to the rupture of the plasma membrane that allows the release of interleukin-1beta (IL-1β) and IL-18 62 – 64 .…”

Section: Pyroptosismentioning

confidence: 99%

Regulated cell death pathways in doxorubicin-induced cardiotoxicity

2021

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Doxorubicin is a chemotherapeutic drug used for the treatment of various malignancies; however, patients can experience cardiotoxic effects and this has limited the use of this potent drug. The mechanisms by which doxorubicin kills cardiomyocytes has been elusive and despite extensive research the exact mechanisms remain unknown. This review focuses on recent advances in our understanding of doxorubicin induced regulated cardiomyocyte death pathways including autophagy, ferroptosis, necroptosis, pyroptosis and apoptosis. Understanding the mechanisms by which doxorubicin leads to cardiomyocyte death may help identify novel therapeutic agents and lead to more targeted approaches to cardiotoxicity testing.

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Section: Pyroptosismentioning

confidence: 99%

Regulated cell death pathways in doxorubicin-induced cardiotoxicity

2021

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“…Doxorubicin may induce cardiotoxicity through inhibition of topoisomerase II, oxidative stress, dysregulation of intracellular calcium signaling, mitochondrial impairment, and apoptosis ( 5 , 6 ). Our lab has recently shown that death receptor signaling driven by p53 is an additional critical component of doxorubicin-induced cardiotoxicity ( 7 , 8 ).…”

Section: Introductionmentioning

confidence: 99%

Anthracycline-Induced Cardiotoxicity: Molecular Insights Obtained from Human-Induced Pluripotent Stem Cell–Derived Cardiomyocytes (hiPSC-CMs)

Bozza

Takeda

Alterovitz

et al. 2021

AAPS J

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Anthracyclines are a class of chemotherapy drugs that are highly effective for the treatment of human cancers, but their clinical use is limited by associated dose-dependent cardiotoxicity. The precise mechanisms by which individual anthracycline induces cardiotoxicity are not fully understood. Human-induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) are emerging as a physiologically relevant model to assess drugs cardiotoxicity. Here, we describe an assay platform by coupling hiPSC-CMs and impedance measurement, which allows real-time monitoring of cardiomyocyte cellular index, beating amplitude, and beating rate. Using this approach, we have performed comparative studies on a panel of four anthracycline drugs (doxorubicin, epirubicin, idarubicin, and daunorubicin) which share a high degree of structural similarity but are associated with distinct cardiotoxicity profiles and maximum cumulative dose limits. Notably, results from our hiPSC-CMs impedance model (dose-dependent responses and EC50 values) agree well with the recommended clinical dose limits for these drugs. Using time-lapse imaging and RNAseq, we found that the differences in anthracycline cardiotoxicity are closely linked to extent of cardiomyocyte uptake and magnitude of activation/inhibition of several cellular pathways such as death receptor signaling, ROS production, and dysregulation of calcium signaling. The results provide molecular insights into anthracycline cardiac interactions and offer a novel assay system to more robustly assess potential cardiotoxicity during drug development.

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“…Protection against cancer treatment-induced cardiotoxicity is challenging, because shared mechanistic pathways may contribute to both the tumor suppressive and the cardiotoxic effects of cancer treatments. For instance, anthracycline-induced apoptotic cell death is a shared pathway for the anti-cancer and cardiotoxic effects of anthracyclines [ 6 ]. Cardioprotective agents that have non-selective anti-apoptotic effects will likely inhibit the anti-cancer effects of anthracyclines.…”

Section: Introductionmentioning

confidence: 99%

CYP1B1 as a therapeutic target in cardio-oncology

2020

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Cardiovascular complications have been frequently reported in cancer patients and survivors, mainly because of various cardiotoxic cancer treatments. Despite the known cardiovascular toxic effects of these treatments, they are still clinically used because of their effectiveness as anti-cancer agents. In this review, we discuss the growing body of evidence suggesting that inhibition of the cytochrome P450 1B1 enzyme (CYP1B1) can be a promising therapeutic strategy that has the potential to prevent cancer treatment-induced cardiovascular complications without reducing their anti-cancer effects. CYP1B1 is an extrahepatic enzyme that is expressed in cardiovascular tissues and overexpressed in different types of cancers. A growing body of evidence is demonstrating a detrimental role of CYP1B1 in both cardiovascular diseases and cancer, via perturbed metabolism of endogenous compounds, production of carcinogenic metabolites, DNA adduct formation, and generation of reactive oxygen species (ROS). Several chemotherapeutic agents have been shown to induce CYP1B1 in cardiovascular and cancer cells, possibly via activating the Aryl hydrocarbon Receptor (AhR), ROS generation, and inflammatory cytokines. Induction of CYP1B1 is detrimental in many ways. First, it can induce or exacerbate cancer treatment-induced cardiovascular complications. Second, it may lead to significant chemo/radio-resistance, undermining both the safety and effectiveness of cancer treatments. Therefore, numerous preclinical studies demonstrate that inhibition of CYP1B1 protects against chemotherapy-induced cardiotoxicity and prevents chemo- and radio-resistance. Most of these studies have utilized phytochemicals to inhibit CYP1B1. Since phytochemicals have multiple targets, future studies are needed to discern the specific contribution of CYP1B1 to the cardioprotective and chemo/radio-sensitizing effects of these phytochemicals.

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Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity

Cited by 101 publications

References 190 publications

Regulated cell death pathways in doxorubicin-induced cardiotoxicity

Regulated cell death pathways in doxorubicin-induced cardiotoxicity

Anthracycline-Induced Cardiotoxicity: Molecular Insights Obtained from Human-Induced Pluripotent Stem Cell–Derived Cardiomyocytes (hiPSC-CMs)

CYP1B1 as a therapeutic target in cardio-oncology

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