Human Pluripotent Stem Cells for Modeling of Anticancer Therapy-Induced Cardiotoxicity and Cardioprotective Drug Discovery

Keung, Wendy; Cheung, Yiu‐fai

doi:10.3389/fphar.2021.650039

Cited by 5 publications

(5 citation statements)

References 76 publications

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“… 45 To facilitate the detection of cardiac toxicity early in the drug discovery process, hiPSC-CMs are increasingly used as an in vitro platform for preclinical safety assessment. 13 , 46 – 48 To test the potential of hPCMs in predicting cardiotoxicity, we selected five drugs of multiple categories that had been withdrawn from the market due to cardiac side effects. We measured the dose responses of these drugs both in hPCMs and hiPSC-CMs.…”

Section: Resultsmentioning

confidence: 99%

Functional isolation, culture and cryopreservation of adult human primary cardiomyocytes

Zhou

Shi

Tang

et al. 2022

Sig Transduct Target Ther

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Cardiovascular diseases are the most common cause of death globally. Accurately modeling cardiac homeostasis, dysfunction, and drug response lies at the heart of cardiac research. Adult human primary cardiomyocytes (hPCMs) are a promising cellular model, but unstable isolation efficiency and quality, rapid cell death in culture, and unknown response to cryopreservation prevent them from becoming a reliable and flexible in vitro cardiac model. Combing the use of a reversible inhibitor of myosin II ATPase, (-)-blebbistatin (Bleb), and multiple optimization steps of the isolation procedure, we achieved a 2.74-fold increase in cell viability over traditional methods, accompanied by better cellular morphology, minimally perturbed gene expression, intact electrophysiology, and normal neurohormonal signaling. Further optimization of culture conditions established a method that was capable of maintaining optimal cell viability, morphology, and mitochondrial respiration for at least 7 days. Most importantly, we successfully cryopreserved hPCMs, which were structurally, molecularly, and functionally intact after undergoing the freeze-thaw cycle. hPCMs demonstrated greater sensitivity towards a set of cardiotoxic drugs, compared to human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Further dissection of cardiomyocyte drug response at both the population and single-cell transcriptomic level revealed that hPCM responses were more pronouncedly enriched in cardiac function, whereas hiPSC-CMs responses reflected cardiac development. Together, we established a full set of methodologies for the efficient isolation and prolonged maintenance of functional primary adult human cardiomyocytes in vitro, unlocking their potential as a cellular model for cardiovascular research, drug discovery, and safety pharmacology.

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Section: Resultsmentioning

confidence: 99%

Functional isolation, culture and cryopreservation of adult human primary cardiomyocytes

Zhou

Shi

Tang

et al. 2022

Sig Transduct Target Ther

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“…Other articles have pointed out that arrhythmias and ischemia are the most common cardiotoxic side effects in patients receiving paclitaxel, which may be related to accelerated release of calcium (2). Paclitaxel can increase NCS-1 levels in cardiomyocytes which may lead to increased InsP3R-dependent calcium release from intracellular stores of calcium.…”

Section: Paclitaxel and Cardiotoxicitymentioning

confidence: 99%

“…The clinical use of anthracyclines is influenced by the risk of cardiotoxicity (1,2), and anthracycline-based chemotherapeutic regimens can cause clinical heart failure (HF) and reduced asymptomatic left ventricular ejection fraction (LVEF) (3,4). Liposomal doxorubicin is encapsulated in polyethylene glycol liposomes, which increases the lipophilicity of the drug, changes the tissue distribution and pharmacokinetic properties of the free drug, prolongs the drug circulation time in the blood, and may reduce cardiotoxicity and other side effects at the same time (5).…”

Section: Introductionmentioning

confidence: 99%

Development of a multivariable clinical prediction model for liposomal doxorubicin-induced cardiotoxicity in adult breast cancer patients: a retrospective multicenter study

Sun¹,

Ping²,

Miao³

et al. 2022

Ann Transl Med

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Background: The clinical use of anthracyclines is limited by the risk of cardiotoxicity. So, we aim to develop a clinical prediction model for liposomal doxorubicin-induced cardiotoxicity in adult breast cancer patients. Methods:We designed a multicenter retrospective cohort study. A total of 257 hospitalized breast cancer patients treated with doxorubicin liposomes were finally enrolled in the study, including 58 patients from Beijing Friendship Hospital and 199 from Beijing Cancer Hospital. In all, 32 cases developed cardiotoxicity, including 4 at the Beijing Friendship Hospital and 28 at the Beijing Cancer Hospital. The study involved breast cancer patients with no pre-existing heart disease, whose clinical data were collected from their medical records. All patients underwent electrocardiogram (ECG) and/or left ventricular ejection fraction (LVEF) measurements prior to treatment with doxorubicin liposomes. Patients were clinically assessed after each cycle of treatment, and ECG and/or LVEF measurements were performed at least once after treatment.Liposomal doxorubicin-induced cardiotoxicity was defined when one of the following three conditions was met: (I) a reduction in LVEF of at least 5% from the baseline and the absolute value was less than 55%, accompanied by congestive heart failure (CHF) symptoms or signs; (II) a reduction in LVEF of at least 10% to an absolute value of less than 55%, without CHF symptoms or signs; (III) the definite diagnosis of CHF.Variables associated with cardiotoxicity were identified by univariate and multivariate logistic regression, and the consistency and differentiation of the final model were evaluated.

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“…During the past few years, although chemotherapies have improved long-term survival rates, there is, unfortunately, an additional increased risk of cardiac complications because of underlying long-term adverse effects of these anti-cancer agents [ 42 , 43 , 44 ]. The primary application area of hiPSC-CM assays has focused on cardiotoxicity screening of several anti-cancer agents [ 45 , 46 , 47 , 48 , 49 , 50 ]. In the last several decades, there have been tremendous advances in anticancer drug discovery and research, with more than 100 anticancer drugs that have been approved by the FDA [ 51 , 52 , 53 ].…”

Section: Assessing Chemotherapy-induced Chronic Cardiotoxicity Using ...mentioning

confidence: 99%

Chronic Cardiotoxicity Assays Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs)

Narkar

Willard

Blinova

2022

IJMS

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Cardiomyocytes (CMs) differentiated from human induced pluripotent stem cells (hiPSCs) are increasingly used in cardiac safety assessment, disease modeling and regenerative medicine. A vast majority of cardiotoxicity studies in the past have tested acute effects of compounds and drugs; however, these studies lack information on the morphological or physiological responses that may occur after prolonged exposure to a cardiotoxic compound. In this review, we focus on recent advances in chronic cardiotoxicity assays using hiPSC-CMs. We summarize recently published literature on hiPSC-CMs assays applied to chronic cardiotoxicity induced by anticancer agents, as well as non-cancer classes of drugs, including antibiotics, anti-hepatitis C virus (HCV) and antidiabetic drugs. We then review publications on the implementation of hiPSC-CMs-based assays to investigate the effects of non-pharmaceutical cardiotoxicants, such as environmental chemicals or chronic alcohol consumption. We also highlight studies demonstrating the chronic effects of smoking and implementation of hiPSC-CMs to perform genomic screens and metabolomics-based biomarker assay development. The acceptance and wide implementation of hiPSC-CMs-based assays for chronic cardiotoxicity assessment will require multi-site standardization of assay protocols, chronic cardiac maturity marker reproducibility, time points optimization, minimal cellular variation (commercial vs. lab reprogrammed), stringent and matched controls and close clinical setting resemblance. A comprehensive investigation of long-term repeated exposure-induced effects on both the structure and function of cardiomyocytes can provide mechanistic insights and recapitulate drug and environmental cardiotoxicity.

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Human Pluripotent Stem Cells for Modeling of Anticancer Therapy-Induced Cardiotoxicity and Cardioprotective Drug Discovery

Cited by 5 publications

References 76 publications

Functional isolation, culture and cryopreservation of adult human primary cardiomyocytes

Functional isolation, culture and cryopreservation of adult human primary cardiomyocytes

Development of a multivariable clinical prediction model for liposomal doxorubicin-induced cardiotoxicity in adult breast cancer patients: a retrospective multicenter study

Chronic Cardiotoxicity Assays Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs)

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