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Cardiac Toxicity of Targeted Therapies Used in the Treatment for Solid Tumours: A Review

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Abstract

Cardiotoxicity associated with conventional cytostatics is a known phenomenon and is related to their general cytotoxic effects. This damage to the myocardium is usually irreversible. Despite the attempts to optimize safety profile of targeted anticancer drugs during their development, evidence shows that these new treatment modalities also have cardiotoxic potential or may adversely affect vascular system. Over the last years, a significant number of these agents have been introduced in medical practice. Arterial hypertension, arrhythmias, left ventricular dysfunction and a heart failure are the most frequent cardiovascular adverse effects of targeted anticancer agents, but this toxicity seems to be reversible. To enable early interventions and to minimize these cardiovascular adverse effects, health care professionals have to be well-informed and familiar with the safety profiles of the drugs they administered, the patient’s cardiovascular condition and co-morbidities, and they must regularly monitor their patients for potential adverse effects. The aim of this paper is to provide an overview of cardiotoxic effects caused by targeted anticancer drugs used in the treatment of solid tumours. We discuss pathophysiological mechanisms, diagnostics and treatment, risk factors and options for prevention.

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Abbreviations

Abl:

abelson tyrosine kinase

ALL:

acute lymphoblastic leukaemia

Akt:

murine thymoma viral oncogene homolog 1 (alternative title: PKB protein kinase B)

ALK:

anaplastic lymphoma kinase

ASK:

activator of S-phase kinase

Bad:

Bcl-2 antagonist of cell death

Bak-1:

Bcl-2 antagonist killer

Bax:

Bcl-2 associated × protein

Bcl-2:

B-cell lymphoma 2

Bcl-xL:

Bcl-2-related protein, long isoform

Bcr-Abl:

breakpoint cluster region-abelson tyrosine kinase fusion protein

B-Raf:

v-Raf murine sarcoma viral oncogene homolog B1

CaM-kinase:

Ca(2+)/calmodulin kinase

cAMP:

cyclic adenosine monophosphate

CBP:

CREB-binding protein

CDK:

cyclin-dependent kinase

Cdc42:

cell division cycle 42

CREB:

cAMP response element-binding protein 1

c-Jun:

v-Jun avian sarcoma virus 17 oncogene homolog (JUN oncogene)

c-Kit:

v-Kit Hardy– Zuckerman 4 feline sarcoma viral oncogene homolog (KIT oncogene)

CML:

chronic myeloid leukaemia

CTLA-4:

cytotoxic T-lymphocyte antigen-4

DAG:

diacylglycerol

EGF:

epidermal growth factor

EGFR:

epidermal growth factor receptor

eIF-4E:

eukaryotic translation initiation factor 4E

Elk1:

ELK1 member of ETS oncogene family (oncogene ELK1)

EpCAM:

epithelial cellular adhesion molecule

ERK1:

mitogen-activated protein kinase 3 (MAPK3)

ERK2:

mitogen-activated protein kinase 1 (MAPK1)

FAK:

focal adhesion kinase

FGF:

fibroblast growth factor

FGFR4:

fibroblast growth factor receptor 4

Flt-3:

FMS-related tyrosine kinase 3

FOXO3A:

forkhead box O3A

GATA4:

GATA-binding protein 4

GCN2:

eukaryotic translation initiation factor 2-alpha kinase 4

GIST:

gastrointestinal stromal tumour

GMEB1:

glucocorticoid modulatory element-binding protein 1

Grb2:

growth factor receptor-bound protein 2

GSK-3b:

glycogen synthase kinase 3-beta

HDAC:

histone deacetylase

HER2:

v-ERB-B2 avian erythroblastic leukaemia viral oncogene homolog 2 (ERBB2, oncogene HER2, human epidermal growth receptor 2)

HER4:

v-ERB-B2 avian erythroblastic leukaemia viral oncogene homolog 4 (ERBB4, oncogene HER4)

IGF:

insulin-like growth factor I

ILK:

integrin-linked kinase

IP3:

inositol triphosphate

IRAK3:

interleukin 1 receptor-associated kinase 3

JAK (1, 2):

janus kinase (1, 2)

JNK:

c-Jun N-terminal kinases

KRAS:

v-KI-RAS2 Kirsten rat sarcoma viral oncogene homolog (oncogene KRAS)

MAPK:

mitogen-activated protein kinase

MARK (1–4):

MAP/microtubule affinity-regulating kinase 1–4

MEF2 (A–D):

MADS box transcription enhancer factor 2 (A-D)

MEK (1–6):

MAPK/ERK kinase 1–6

MEKK (1/2):

MAP/ERK kinase 1/2 (MEK kinase)

mTOR:

mammalian target of rapamycin

MURF2:

muscle-specific ring finger protein 2

Nbr1:

neighbour of BRCA1 gene

NFAT:

nuclear factor of activated T cells

NF-kB:

nuclear factor kappa-B

NSCLC:

non-small-cell lung cancer

p38:

p38 MAP kinase (mitogen-activated protein kinase 14—MAPK14)

p62:

ubiquitin-binding protein p62

PAK (2, 3):

p21 protein-activated kinase 2–3

PDGFR (α, β):

platelet-derived growth factor receptor (alpha–beta)

PDK1:

pyruvate dehydrogenase kinase isoenzyme 1

Ph+:

Philadelphia chromosome-positive leukaemia

PI3K:

phosphatidylinositol 3-kinase

PIP3:

phosphatidylinositol (3, 4, 5)- triphosphate

PKA:

protein kinase alpha

PKC:

protein kinase C

PLC:

phospholipase C

PLK:

polo-like kinase

PNET:

neuroendocrine tumours of pancreatic origin

PRKCQ:

protein kinase C–theta

PKI:

protein kinase inhibitors

Raf:

v-raf-1 murine leukaemia viral oncogene homolog 1 (oncogene RAF1, c-Raf)

Ras:

v-ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS, p21)

Ret:

rearranged during transfection protooncogene

RyR:

ryanodine receptors

S6K:

ribosome S6 kinase (p70S6K)

SCF–MGF:

stem cell factor (Kit ligand)

SERCA:

sarcoplasmic reticulum Ca(2+)-ATPase

Shc:

Shc transforming protein

SOS:

son of sevenless drosophila homolog 1

Src:

v-src avian sarcoma (Schmidt– Ruppin A-2) viral oncogene homolog

STAT (3/5):

signal transducer and activator of transcription 3/5

TGF-β:

transforming growth factor beta-1

TRAF (2/6):

TNF receptor-associated factor 2/6

Tyk 2:

tyrosine kinase 2

VEGF:

vascular endothelial growth factor A

VEGFR (1, 2, 3):

vascular endothelial growth factor receptor 1–3

β1AR:

β1-adrenergic receptor

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Acknowledgments

This work was supported by the Czech Ministry of Health, project No. MZ0MOU2005, and by the IGA MZ CR, project No. NS/10357-3. We thank R. Lakomy, R. Nemecek, O. Slaby and J. Vyskocil for their helpful discussions and their constructive critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Zluty kopec 7, 65653, Brno, The Czech Republic

    Marek Svoboda, Alexandr Poprach, Igor Kiss & Rostislav Vyzula

  2. Clinic of Cardiovascular Diseases, Masaryk Memorial Cancer Institute, Zluty kopec 7, 65653, Brno, The Czech Republic

    Svatopluk Dobes

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  1. Marek Svoboda
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Correspondence to Marek Svoboda.

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Svoboda, M., Poprach, A., Dobes, S. et al. Cardiac Toxicity of Targeted Therapies Used in the Treatment for Solid Tumours: A Review. Cardiovasc Toxicol 12, 191–207 (2012). https://doi.org/10.1007/s12012-012-9164-0

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