Modeling trastuzumab-related cardiotoxicity in vitro using human stem cell-derived cardiomyocytes

Kurokawa, Yosuke; Shang, Michael R.; Yin, Rose T.; George, Steven C.

doi:10.1016/j.toxlet.2018.01.001

Cited by 42 publications

(26 citation statements)

References 60 publications

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“…RTK activity may also be reduced by blocking the human epidermal growth factor receptor 2 (HER2), which activation is a common feature of a subset of malignant diseases, particularly breast cancer (102). While trastuzumab (TZM), a TKi monoclonal antibody blocking HER2, greatly improves treatment against HER2 positive malignancies, inhibition of HER2 signaling was found to be detrimental for cardiac function (102)(103)(104). In a subset of breast cancer patients, treatment with TZM led to mild to severe decrease in LVEF without apparent myocardial tissue damage or cell loss.…”

Section: Hpsc-cardiomyocyte Models In Drug Screening Of Tyrosine Kinamentioning

confidence: 99%

“…Moreover, this disease phenotype could be rescued using metabolism-stimulating agents, such as AMPK (102). Additionally, HER2 activation triggered by exogenous neuregulin-1 could reduce hPSC-cardiomyocyte damage and cell loss during Doxorubicin exposure, an effect that was lost upon inhibition of the HER2 receptor by TZM (103,104). These findings indicate that hPSCcardiomyocyte 2D models may serve as a valuable tool to identify cardioprotective compounds in a high throughput system, which can be further validated in more advanced human-based 3D cardiac models.…”

Section: Hpsc-cardiomyocyte Models In Drug Screening Of Tyrosine Kinamentioning

confidence: 99%

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Human Pluripotent Stem Cell-Derived Cardiomyocytes for Assessment of Anticancer Drug-Induced Cardiotoxicity

Schwach

Slaats

Passier

2020

Front. Cardiovasc. Med.

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Cardiotoxicity is a major cause of high attrition rates among newly developed drugs. Moreover, anti-cancer treatment-induced cardiotoxicity is one of the leading reasons of mortality in cancer survivors. Cardiotoxicity screening in vitro may improve predictivity of cardiotoxicity by novel drugs, using human pluripotent stem cell (hPSC)-derived-cardiomyocytes. Anthracyclines, including Doxorubicin, are widely used and highly effective chemotherapeutic agents for the treatment of different forms of malignancies. Unfortunately, anthracyclines cause many cardiac complications early or late after therapy. Anthracyclines exhibit their potent anti-cancer effect primarily via induction of DNA damage during the DNA replication phase in proliferative cells. In contrast, studies in animals and hPSC-cardiomyocytes have revealed that cardiotoxic effects particularly arise from (1) the generation of oxidative stress inducing mitochondrial dysfunction, (2) disruption of calcium homeostasis, and (3) changes in transcriptome and proteome, triggering apoptotic cell death. To increase the therapeutic index of chemotherapeutic Doxorubicin therapy several protective strategies have been developed or are under development, such as (1) reducing toxicity through modification of Doxorubicin (analogs), (2) targeted delivery of anthracyclines specifically to the tumor tissue or (3) cardioprotective agents that can be used in combination with Doxorubicin. Despite continuous progress in the field of cardio-oncology, cardiotoxicity is still one of the major complications of anti-cancer therapy. In this review, we focus on current hPSC-cardiomyocyte models for assessing anthracycline-induced cardiotoxicity and strategies for cardioprotection. In addition, we discuss latest developments toward personalized advanced pre-clinical models that are more closely recapitulating the human heart, which are necessary to support in vitro screening platforms with higher predictivity. These advanced models have the potential to reduce the time from bench-to-bedside of novel antineoplastic drugs with reduced cardiotoxicity.

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Section: Hpsc-cardiomyocyte Models In Drug Screening Of Tyrosine Kinamentioning

confidence: 99%

Section: Hpsc-cardiomyocyte Models In Drug Screening Of Tyrosine Kinamentioning

confidence: 99%

Human Pluripotent Stem Cell-Derived Cardiomyocytes for Assessment of Anticancer Drug-Induced Cardiotoxicity

Schwach

Slaats

Passier

2020

Front. Cardiovasc. Med.

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“…Trastuzumab (Herceptin) is a monoclonal antibody used in the treatment of metastatic breast cancer (Fleck, Garratt, Haass, & Willem, ). ErbB2 (HER2), an orphan co‐receptor for Neuregulin‐1 (NRG1), is the target of Trastuzumab (Kurokawa, Shang, Yin, & George, ). In NCCs, many variants of Nrg1 are produced via alternative splicing and usage of distinct promoters.…”

Section: Chemical Agentsmentioning

confidence: 99%

The role of teratogens in neural crest development

Cerrizuela

Vega-Lopez

Aybar

2020

Birth Defects Research

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The neural crest (NC), discovered by Wilhelm His 150 years ago, gives rise to a multipotent migratory embryonic cell population that generates a remarkably diverse and important array of cell types during the development of the vertebrate embryo. These cells originate in the neural plate border (NPB), which is the ectoderm between the neural plate and the epidermis. They give rise to the neurons and glia of the peripheral nervous system, melanocytes, chondrocytes, smooth muscle cells, odontoblasts and neuroendocrine cells, among others. Neurocristopathies are a class of congenital diseases resulting from the abnormal induction, specification, migration, differentiation or death of NC cells (NCCs) during embryonic development and have an important medical and societal impact. In general, congenital defects affect an appreciable percentage of newborns worldwide. Some of these defects are caused by teratogens, which are agents that negatively impact the formation of tissues and organs during development. In this review, we will discuss the teratogens linked to the development of many birth defects, with a strong focus on those that specifically affect the development of the NC, thereby producing neurocristopathies.Although increasing attention is being paid to the effect of teratogens on embryonic development in general, there is a strong need to critically evaluate the specific role of these agents in NC development. Therefore, increased understanding of the role of these factors in NC development will contribute to the planning of strategies aimed at the prevention and treatment of human neurocristopathies, whose etiology was previously not considered.

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“…Compared with animal models, hiPSC‐CMs are more representative of human cardiac physiology in terms of ion channel expression, heart rate, and myofilament composition . Several studies exploring the cardiotoxicity of different chemotherapy agents using stem cell models have been described in the past few years (summarized in Table ).…”

Section: Modeling Anticancer Therapy Mediated Cardiotoxicity In Vitromentioning

confidence: 99%

“…A recent study demonstrated that trastuzumab induces cardiotoxicity in hiPSC‐CMs that was dependent on the activation of the erythroblastic oncogene B2/B4 (ErbB2/B4) by either neuregulin (NRG‐1) or heparin‐binding epidermal growth factor, suggesting that trastuzumab is blocking the cardioprotective effects of the ErbB2/4 pathway . In contrast, two other studies showed that trastuzumab‐mediated cardiotoxicity on hiPSC‐CMs is independent of the ErbB2/B4 pathway activation , highlighting the need to develop standardized cell culture conditions to improve the validity of hiPSC‐CMs in trastuzumab‐toxicity screening.…”

Section: Modeling Anticancer Therapy Mediated Cardiotoxicity In Vitromentioning

confidence: 99%

Concise Review: Precision Matchmaking: Induced Pluripotent Stem Cells Meet Cardio-Oncology

Nair

Prado

Perea‐Gil

et al. 2019

Stem Cells Translational Medicine

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As common chemotherapeutic agents are associated with an increased risk of acute and chronic cardiovascular complications, a new clinical discipline, cardio‐oncology, has recently emerged. At the same time, the development of preclinical human stem cell‐derived cardiovascular models holds promise as a more faithful platform to predict the cardiovascular toxicity of common cancer therapies and advance our understanding of the underlying mechanisms contributing to the cardiotoxicity. In this article, we review the recent advances in preclinical cancer‐related cardiotoxicity testing, focusing on new technologies, such as human induced pluripotent stem cell‐derived cardiomyocytes and tissue engineering. We further discuss some of the limitations of these technologies and present future directions. Stem Cells Translational Medicine 2019;8:758&767

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Modeling trastuzumab-related cardiotoxicity in vitro using human stem cell-derived cardiomyocytes

Cited by 42 publications

References 60 publications

Human Pluripotent Stem Cell-Derived Cardiomyocytes for Assessment of Anticancer Drug-Induced Cardiotoxicity

Human Pluripotent Stem Cell-Derived Cardiomyocytes for Assessment of Anticancer Drug-Induced Cardiotoxicity

The role of teratogens in neural crest development

Concise Review: Precision Matchmaking: Induced Pluripotent Stem Cells Meet Cardio-Oncology

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