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Cardiotoxicity is a well-established complication of oncology therapies. Cardiomyopathy resulting from anthracyclines is a classic example. In the past decade, an explosion of novel cancer therapies, often targeted and more specific than traditional therapies, has revolutionized oncology therapy and dramatically changed cancer prognosis. However, some of these therapies have introduced an assortment of cardiovascular (CV) complications. At times, these devastating outcomes have only become apparent after drug approval and have limited the use of potent therapies. There is a growing need for better testing platforms, both for CV toxicity screening, as well as for elucidating mechanisms of cardiotoxicities of approved cancer therapies. This review discusses the utility of nonclinical models (in vitro, in vivo, & in silico) available and highlights recent advancements in modalities like human stem cell-derived cardiomyocytes for developing more comprehensive cardiotoxicity testing and new means of cardioprotection with targeted anticancer therapies.

The cardiovascular care of cancer patients (cardio-oncology) has emerged as a new discipline in clinical medicine, given recent advances in cancer therapy, and is driven by the cardiovascular complications that occur as a direct result of cancer therapy. Traditional therapies such as anthracyclines and radiation have been recognized for years to have cardiovascular complications. Less expected were the cardiovascular effects of targeted cancer therapies, which were initially thought to be specific to cancer cells and would spare any adverse effects on the heart. Cancers are typically driven by mutations, translocations, or overexpression of protein kinases. The majority of these mutated kinases are tyrosine kinases, though serine/threonine kinases also play key roles in some malignancies. Several agents were developed to target these kinases, but many more are in development. Major successes have been largely restricted to agents targeting human epidermal growth factor receptor-2 (mutated or overexpressed in breast cancer), BCR-ABL (chronic myelogenous leukemia and some cases of acute lymphoblastic leukemia), and c-Kit (gastrointestinal stromal tumor). Other agents targeting more complex malignancies, such as advanced solid tumors, have had successes, but have not extended life to the degree seen with chronic myelogenous leukemia. Years before the first targeted therapy, Judah Folkman correctly proposed that to address solid tumors one had to target the inherent neoangiogenesis. Unfortunately, emerging evidence confirms that angiogenesis inhibitors cause cardiac complications, including hypertension, thrombosis, and heart failure. And therein lies the catch-22. Nevertheless, cardio-oncology has the potential to be transformative as the human cardiomyopathies that arise from targeted therapies can provide insights into the normal function of the heart.

Cancer therapy has progressed remarkably in recent years. In no area has this been more apparent than in the development of "targeted therapies", particularly those using drugs that inhibit the activity of certain tyrosine kinases, activating mutations or amplifications of which are causal, or strongly contributory, to tumorigenesis. However, some of these therapies have been associated with toxicity to the heart. Here we summarize what is known about the cardiotoxicity of cancer drugs that target tyrosine kinases. We focus on basic mechanisms through which interruption of specific signalling pathways leads to cardiomyocyte dysfunction and/or death, and contrast this with therapeutic responses in cancer cells.

Imatinib mesylate (Gleevec) is a small-molecule inhibitor of the fusion protein Bcr-Abl, the causal agent in chronic myelogenous leukemia. Here we report ten individuals who developed severe congestive heart failure while on imatinib and we show that imatinib-treated mice develop left ventricular contractile dysfunction. Transmission electron micrographs from humans and mice treated with imatinib show mitochondrial abnormalities and accumulation of membrane whorls in both vacuoles and the sarco- (endo-) plasmic reticulum, findings suggestive of a toxic myopathy. With imatinib treatment, cardiomyocytes in culture show activation of the endoplasmic reticulum (ER) stress response, collapse of the mitochondrial membrane potential, release of cytochrome c into the cytosol, reduction in cellular ATP content and cell death. Retroviral gene transfer of an imatinib-resistant mutant of c-Abl, alleviation of ER stress or inhibition of Jun amino-terminal kinases, which are activated as a consequence of ER stress, largely rescues cardiomyocytes from imatinib-induced death. Thus, cardiotoxicity is an unanticipated side effect of inhibition of c-Abl by imatinib.

Aging is regulated by conserved signaling pathways. The glycogen synthase kinase-3 (GSK-3) family of serine/threonine kinases regulates several of these pathways, but the role of GSK-3 in aging is unknown. [...]

Cyclophilin D (which is encoded by the Ppif gene) is a mitochondrial matrix peptidyl-prolyl isomerase known to modulate opening of the mitochondrial permeability transition pore (MPTP). Apart from regulating necrotic cell death, the physiologic function of the MPTP is largely unknown. Here we have shown that [Ppif.sup.[-/-]] mice exhibit substantially greater cardiac hypertrophy, fibrosis, and reduction in myocardial function in response to pressure overload stimulation than control mice. In addition, [Ppif.sup.[-/-]] mice showed greater hypertrophy and lung edema as well as reduced survival in response to sustained exercise stimulation. Cardiomyocyte-specific transgene expression of cyclophilin D in [Ppif.sup.[-/-]] mice rescued the enhanced hypertrophy, reduction in cardiac function, and rapid onset of heart failure following pressure overload stimulation. Mechanistically, the maladaptive phenotype in the hearts of [Ppif.sup.[-/-]] mice was associated with an alteration in MPTP-mediated [Ca.sup.2+] efflux resulting in elevated levels of mitochondrial matrix [Ca.sup.2+] and enhanced activation of [Ca.sup.2+]-dependent dehydrogenases. Elevated matrix [Ca.sup.2+] led to increased glucose oxidation relative to fatty acids, thereby limiting the metabolic flexibility of the heart that is critically involved in compensation during stress. These findings suggest that the MPTP maintains homeostatic mitochondrial [Ca.sup.2+] levels to match metabolism with alterations in myocardial workload, thereby suggesting a physiologic function for the MPTP., Introduction Opening of the mitochondrial permeability transition pore (MPTP) is critically involved in regulating cell death by inducing a sustained and irreversible loss of inner mitochondrial membrane potential, coinciding with [...]

The glycogen synthase kinase-3 (GSK-3) family of serine/threonine kinases consists of 2 highly related isoforms, a and β. Although GSK-3β has an important role in cardiac development, much remains unknown about the function of either GSK-3 isoform in the postnatal heart. Herein, we present what we believe to be the first studies defining the role of GSK-3α in the mouse heart using gene targeting. [Gsk3a.sup.[-/-]] mice over 2 months of age developed progressive cardiomyocyte and cardiac hypertrophy and contractile dysfunction. Following thoracic aortic constriction in young mice, we observed enhanced hypertrophy that rapidly transitioned to ventricular dilatation and contractile dysfunction. Surprisingly, markedly impaired β-adrenergic responsiveness was found at both the organ and cellular level. This phenotype was reproduced by acute treatment of WT cardiomyocytes with a small molecule GSK-3 inhibitor, confirming that the response was not due to a chronic adaptation to LV dysfunction. Thus, GSK-3α appears to be the central regulator of a striking range of essential processes, including acute and direct positive regulation of β-adrenergic responsiveness. In the absence of GSK-3α, the heart cannot respond effectively to hemodynamic stress and rapidly fails. Our findings identify what we believe to be a new paradigm of regulation of β-adrenergic signaling and raise concerns given the rapid expansion of drug development targeting GSK-3., Introduction The glycogen synthase kinase-3 (GSK-3) family consists of 2 isoforms, α and β, which are 98% identical within their kinase domains but differ substantially in their N- and C-terminal [...]

Based on extensive preclinical data, glycogen synthase kinase-3 (GSK-3) has been proposed to be a viable drug target for a wide variety of disease states, ranging from diabetes to bipolar disorder. Since these new drugs, which will be more powerful GSK-3 inhibitors than lithium, may potentially be given to women of childbearing potential, and since it has controversially been suggested that lithium therapy might be linked to congenital cardiac defects, we asked whether GSK-3 family members are required for normal heart development in mice. We report that terminal cardiomyocyte differentiation was substantially blunted in Gsk3b-/- embryoid bodies. While GSK-3[alpha]--deficient mice were born without a cardiac phenotype, no live-born Gsk3b-/- pups were recovered. The Gsk3b-/- embryos had a double outlet RV, ventricular septal defects, and hypertrophic myopathy, with near obliteration of the ventricular cavities. The hypertrophic myopathy was caused by cardiomyocyte hyperproliferation without hypertrophy and was associated with increased expression and nuclear localization of three regulators of proliferation--GATA4, cyclin D1, and c-Myc. These studies, which we believe are the first in mammals to examine the role of GSK-3[alpha] and GSK-3[beta] in the heart using loss-of-function approaches, implicate GSK-3[beta] as a central regulator of embryonic cardiomyocyte proliferation and differentiation, as well as of outflow tract development. Although controversy over the teratogenic effects of lithium remains, our studies suggest that caution should be exercised in the use of newer, more potent drugs targeting GSK-3 in women of childbearing age., Introduction The factors regulating proliferation of cardiomyocytes during development have been the focus of many investigations in the past decade. These studies have identified several growth factors, acting in a [...]

Positive pressure ventilation with large tidal volumes has been shown to cause release of cytokines, including interleukin (IL)-8. The mechanisms regulating lung stretch-induced cytokine production are unclear. We hypothesized that stretch-induced IL-8 production is dependent on the activation of the mitogen-activated protein kinases, c-Jun N[H.sub.2]-terminal kinases (JNK), p38, and/or extracellular signal-regulated kinase (ERK) 1/2. We exposed A549 cells, a type II-like alveolar epithelial cell line, to cyclic stretch at 20 cycles/min for 5 min-2 h. Cyclic stretch induced IL-8 protein production, IL-8 mRNA expression, and JNK activation, but only transient activation of p38 and ERK1/2. Inhibition of stretch-induced JNK activation by adenovirus-mediated gene transfer of stress-activated protein kinase (SEK-1), a dominant-negative mutant of SEK-1, the immediate upstream activator of the JNKs, and pharmacological JNK inhibitor II SP-600125 blocked IL-8 mRNA expression and attenuated IL-8 production. Inhibition of p38 and ERK1/2 did not affect stretch-induced IL-8 production. Stretch-induced activation NF-KB and activator protein (AP)-1 was blocked by NF-[kappa]B inhibitor and JNK inhibitor, respectively. An NF-IL-6 site was not essential for cyclic stretch-induced IL-8 promoter activity. Stretch also induced NF-[kappa]B-inducing kinase (NIK) activation, and inhibition of NF-[kappa]B attenuated IL-8 mRNA expression and IL-8 production. We conclude that stretch-induced transcriptional regulation of IL-8 mRNA and IL-8 production was via activation of AP-1 and NF-[kappa]B and was dependent on JNK and NIK activation, respectively. A549 cells; mitogen-activated protein kinase; ventilation

Generation of arachidonic acid by the ubiquitously expressed cytosolic phospholipase A[sub.2] (PLA[sub.2]) has a fundamental role in the regulation of cellular homeostasis, inflammation and tumorigenesis. Here we report that cytosolic PLA[sub.2] is a negative regulator of growth, specifically of striated muscle. We find that normal growth of skeletal muscle, as well as normal and pathologic stress-induced hypertrophic growth of the heart, are exaggerated in Pla2g4a[sup.-/-] mice, which lack the gene encoding cytosolic PLA[sub.2]. The mechanism underlying this phenotype is that cytosolic PLA[sub.2] negatively regulates insulin-like growth factor (IGF)-1 signaling. Absence of cytosolic PLA[sub.2] leads to sustained activation of the IGF-1 pathway, which results from the failure of 3-phosphoinositide-dependent protein kinase (PDK)-1 to recruit and phosphorylate protein kinase C (PKC)-[zeta], a negative regulator of IGF-1 signaling. Arachidonic acid restores activation of PKC-[zeta], correcting the exaggerated IGF-1 signaling. These results indicate that cytosolic PLA[sub.2] and arachidonic acid regulate striated muscle growth by modulating multiple growth-regulatory pathways., Author(s): Syed Haq (corresponding author) [1, 7]; Heiko Kilter [1, 7]; Ashour Michael [1, 7]; Jingzang Tao [2]; Eileen O'Leary [2]; Xio Ming Sun [2]; Brian Walters [1]; Kausik Bhattacharya [...]

[beta]-Catenin is a transcriptional activator that regulates embryonic development as part of the Wnt pathway and also plays a role in tumorigenesis. The mechanisms leading to Wnt-induced stabilization of [beta]-catenin, which results in its translocation to the nucleus and activation of transcription, have been an area of intense interest. However, it is not clear whether stimuli other than Wnts can lead to important stabilization of [beta]-catenin and, if so, what factors mediate that stabilization and what biologic processes might be regulated. Herein we report that [beta]-catenin is stabilized in cardiomyocytes after these cells have been exposed to hypertrophic stimuli in culture or in vivo. The mechanism by which [beta]-catenin is stabilized is distinctly different from that used by Wnt signaling. Although, as with Wnt signaling, inhibition of glycogen synthase kinase-3 remains central to hypertrophic stimulus-induced stabilization of [beta]-catenin, the mechanism by which this occurs involves the recruitment of activated PKB to the [beta]-catenin-degradation complex. PKB stabilizes the complex and phosphorylates glycogen synthase kinase-3 within the complex, inhibiting its activity directed at [beta]-catenin. Finally, we demonstrate via adenoviral gene transfer that [beta]-catenin is both sufficient to induce growth in cardiomyocytes in culture and in vivo and necessary for hypertrophic stimulus-induced growth. Thus, in these terminally differentiated cells, [beta]-catenin is stabilized by hypertrophic stimuli acting via heterotrimeric G protein-coupled receptors. The stabilization occurs via a unique Wnt-independent mechanism and results in cellular growth.