Ponatinib-induced cardiotoxicity: delineating the signalling mechanisms and potential rescue strategies

Singh, Anand Prakash; Glennon, Michael S; Umbarkar, Prachi; Gupte, Manisha; Galindo, Cristi L.; Zhang, Qinkun; Force, Thomas; Becker, Jason R; Lal, Hind

doi:10.1093/cvr/cvz006

Cited by 62 publications

(65 citation statements)

References 73 publications

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“…A second hypothesis would link ponatinib-induced cell necrosis to Akt inhibition. Indeed, Akt is also highly implicated in the regulation of apoptosis signaling and mediates the responses of a majority of growth factors ( Somanath et al., 2006 ), and ponatinib is known to inhibit Akt in cardiomyocytes ( Singh et al., 2019 ). These observations highlight the need of a further thorough evaluation of this pathways in the endothelial response to ponatinib.…”

Section: Discussionmentioning

confidence: 99%

The Risk of Arterial Thrombosis in Patients With Chronic Myeloid Leukemia Treated With Second and Third Generation BCR-ABL Tyrosine Kinase Inhibitors May Be Explained by Their Impact on Endothelial Cells: An In-Vitro Study

Haguet

Bouvy²,

Delvigne³

et al. 2020

Front. Pharmacol.

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BCR-ABL tyrosine kinase inhibitors (TKIs) revolutionized the treatment of chronic myeloid leukemia, inducing deep molecular responses, largely improving patient survival and rendering treatment-free remission possible. However, three of the five BCR-ABL TKIs, dasatinib, nilotinib, and ponatinib, increase the risk of developing arterial thrombosis. Prior investigations reported that nilotinib and ponatinib affect the endothelium, but the mechanisms by which they exert their toxic effects are still unclear. The impact of dasatinib and bosutinib on endothelial cells has been poorly investigated. Here, we aimed to provide an in vitro homogenous evaluation of the effects of BCR-ABL TKIs on the endothelium, with a special focus on the type of cell death to elucidate the mechanisms responsible for the potential cytotoxic effects of BCR-ABL TKIs nilotinib and ponatinib on endothelial cells. We tested the five BCR-ABL TKIs at three concentrations on human umbilical venous endothelial cells (HUVECs). This study highlights the endothelial toxicity of ponatinib and provides insights about the mechanisms by which it affects endothelial cell viability. Ponatinib induced apoptosis and necrosis of HUVECs after 72 h. Dasatinib affected endothelial cells in vitro by inhibiting their proliferation and decreased wound closure as soon as 24 h of treatment and even at infra-therapeutic dose (0.005 µM). Comparatively, imatinib, nilotinib, and bosutinib had little impact on endothelial cells at therapeutic concentrations. They did not induce apoptosis nor necrosis, even after 72 h of treatment but they inhibited HUVEC proliferation. Overall, this study reports various effects of BCR-ABL TKIs on endothelial cells and suggests that ponatinib and dasatinib induce arterial thrombosis through endothelial dysfunction.

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Section: Discussionmentioning

confidence: 99%

The Risk of Arterial Thrombosis in Patients With Chronic Myeloid Leukemia Treated With Second and Third Generation BCR-ABL Tyrosine Kinase Inhibitors May Be Explained by Their Impact on Endothelial Cells: An In-Vitro Study

Haguet

Bouvy²,

Delvigne³

et al. 2020

Front. Pharmacol.

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“…In addition, cardiomyocytes necrosis was observed during high-dose sorafenib treatment with unclear mechanism (Duran et al, 2014). The most recent study reported that ponatinib inhibited phosphorylation of Akt and ERK1/2, which contributed to the activation of pro-apoptotic caspase-3 (Singh et al, 2019). Xu et al (2018) found that dasatinib dose-dependently up-regulated intracellular HMGB1 to induce cardiomyocyte necroptosis.…”

Section: Trastuzumabmentioning

confidence: 99%

Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity

Wei

Zhang

et al. 2020

Front. Cell Dev. Biol.

101

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Homeostatic regulation of cardiomyocytes plays a crucial role in maintaining the normal physiological activity of cardiac tissue. Severe cardiotoxicity results in cardiac diseases including but not limited to arrhythmia, myocardial infarction and myocardial hypertrophy. Drug-induced cardiotoxicity limits or forbids further use of the implicated drugs. Such drugs that are currently available in the clinic include anti-tumor drugs (doxorubicin, cisplatin, trastuzumab, etc.), antidiabetic drugs (rosiglitazone and pioglitazone), and an antiviral drug (zidovudine). This review focused on cardiomyocyte death forms and related mechanisms underlying clinical drug-induced cardiotoxicity, including apoptosis, autophagy, necrosis, necroptosis, pryoptosis, and ferroptosis. The key proteins involved in cardiomyocyte death signaling were discussed and evaluated, aiming to provide a theoretical basis and target for the prevention and treatment of drug-induced cardiotoxicity in the clinical practice.

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“…One recent study evaluating the cardiotoxicity associated with ponatinib and potential rescue methods in zebrafish and isolated neonatal rat cardiomyocytes showed that ponatinib inhibits the essential cardiomyocyte prosurvival AKT/ERK signaling pathway, resulting in cardiomyocyte apoptosis [43]. Neuregulin-1β treatment prevented ponatinib-induced cardiotoxicity by supplementing this signaling pathway [45].…”

Section: Safety Profilementioning

confidence: 99%

Ponatinib in the Treatment of Chronic Myeloid Leukemia and Philadelphia Chromosome-Positive Acute Leukemia: Recommendations of a German Expert Consensus Panel with Focus on Cardiovascular Management

et al. 2019

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Treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute leukemia (Ph+ ALL) has been revolutionized with the advent of tyrosine kinase inhibitors (TKIs). Most patients with CML achieve long-term survival similar to individuals without CML due to treatment with TKIs not only in frontline but also in further lines of therapy. The third-generation TKI ponatinib has demonstrated efficacy in patients with refractory CML and Ph+ ALL. Ponatinib is currently the most potent TKI in this setting demonstrating activity against T315I mutant clones. However, ponatinib’s safety data revealed a dose-dependent, increased risk of serious cardiovascular (CV) events. Guidance is needed to evaluate the benefit–risk profile of TKIs, such as ponatinib, and safety measures to prevent treatment-associated CV events. An expert panel of German hematologists and cardiologists summarize current evidence regarding ponatinib’s efficacy and CV safety profile. We propose CV management strategies for patients who are candidates for ponatinib.

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Ponatinib-induced cardiotoxicity: delineating the signalling mechanisms and potential rescue strategies

Cited by 62 publications

References 73 publications

The Risk of Arterial Thrombosis in Patients With Chronic Myeloid Leukemia Treated With Second and Third Generation BCR-ABL Tyrosine Kinase Inhibitors May Be Explained by Their Impact on Endothelial Cells: An In-Vitro Study

The Risk of Arterial Thrombosis in Patients With Chronic Myeloid Leukemia Treated With Second and Third Generation BCR-ABL Tyrosine Kinase Inhibitors May Be Explained by Their Impact on Endothelial Cells: An In-Vitro Study

Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity

Ponatinib in the Treatment of Chronic Myeloid Leukemia and Philadelphia Chromosome-Positive Acute Leukemia: Recommendations of a German Expert Consensus Panel with Focus on Cardiovascular Management

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