Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sunitinib malate, an oral multitargeted tyrosine kinase inhibitor (TKI), has been approved for the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumors. It is supposed that this targeted approach improves antitumor activity with less toxicity than traditional chemotherapy. However, unanticipated cardiotoxicity related to TKIs has been reported. Less well described are the treatment and prognosis of patients with sunitinib-related cardiogenic shock. Here, we report a successfully treated case. In contrast to previous case reports, the shock status did not allow for standard heart failure treatment with angiotensin-converting enzyme inhibitor or beta-blocker. We used intra-aortic balloon counterpulsation, and the patient survived. Twenty-four days after onset, the patient's left ventricular ejection fraction had improved from 20% to 48%. To the best of our knowledge, this is the first case report of severe heart failure after sunitinib treatment in Taiwan. As the clinical application of TKIs expands, cardiologists and oncologists should be alert to the possible adverse cardiovascular effects and be ready to institute prompt treatment.
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PMID:Cardiac magnetic resonance imaging in sunitinib malate-related cardiomyopathy: no late gadolinium enhancement. 1954 68

Tyrosine kinase inhibitors (TKIs) are transforming the treatment of patients with malignancies. One such agent, sunitinib (Sutent, Pfizer), has demonstrated activity against a variety of solid tumors. Sunitinib is "multi-targeted," inhibiting growth factor receptors that regulate both tumor angiogenesis and tumor cell survival. However cardiac dysfunction has been associated with its use. Identification of the target of sunitinib associated cardiac dysfunction could guide future drug design to reduce toxicity while preserving anti-cancer activity. Herein we identify severe mitochondrial structural abnormalities in the heart of a patient with sunitinib-induced heart failure. In cultured cardiomyocytes, sunitinib induces loss of mitochondrial membrane potential and energy rundown. Despite the latter, AMPK activity, which should be increased in the setting of energy compromise, is reduced in hearts of sunitinib-treated mice and cardiomyocytes in culture and this is due to direct inhibition of AMPK by sunitinib. Critically, we find that adenovirus-mediated gene transfer of an actived mutant of AMPK reduces sunitinib-induced cell death. Our findings suggest AMPK inhibition plays a central role in sunitinib cardiomyocyte toxicity, highlighting the potential of off-target effects of TKIs contributing to cardiotoxicity. While multi-targeting can enhance tumor cell killing, this must be balanced against the potential increased risk of cardiac dysfunction.
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PMID:Sunitinib-induced cardiotoxicity is mediated by off-target inhibition of AMP-activated protein kinase. 2037 35

Cancer growth and metastasis are often driven by activating mutations in, or gene amplications of, specific tyrosine or serine/threonine kinases. Kinase inhibitors (KIs) promised to provide targeted therapy-specifically inhibiting the causal or contributory kinases driving tumor progression while leaving function of other kinases intact. These inhibitors are of 2 general classes: (1) monoclonal antibodies that are typically directed against receptor tyrosine kinases or their ligands and (2) small molecules targeting specific kinases. The latter will be the focus of this review. This class of therapeutics has had some remarkable successes, including revolutionizing the treatment of some malignancies (eg, imatinib [Gleevec] in the management of chronic myeloid leukemia) and adding significantly to the management of other difficult to treat cancers (eg, sunitinib [Sutent] and sorafenib [Nexavar] in the management of renal cell carcinoma). But in some instances, cardiotoxicity, often manifest as left ventricular dysfunction and/or heart failure, has ensued after the use of KIs in patients. Herein we will explore the mechanisms underlying the cardiotoxicity of small-molecule KIs, hoping to explain how and why this happens, and will further examine strategies to deal with the problem.
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PMID:Why do kinase inhibitors cause cardiotoxicity and what can be done about it? 2072 98

Kinase inhibitors have emerged as an important new class of agents for the treatment of diverse tumors. Sunitinib malate is a small-molecule, oral, multi-kinase inhibitor approved for use in treating renal cell carcinoma and gastrointestinal stromal tumor. It has also demonstrated efficacy in treating pancreatic neuroendocrine tumors and is being evaluated for the treatment of other cancers. Initially developed for its inhibition of the vascular endothelial growth factor (VEGF) signaling pathway, sunitinib has been associated with hypertension and heart failure. This review examines the incidence and severity of these adverse events, relevant findings from other agents that inhibit VEGF signaling, the mechanisms underlying these effects, and suggestions for their clinical management. Hypertension is a common adverse effect that is usually easily managed. The associated heart failure is less common; it can be reversible but must be actively monitored and managed. Mechanistic insights suggest that an attentive clinical strategy for hypertension could prevent severe cardiotoxicity.
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PMID:Sunitinib, hypertension, and heart failure: a model for kinase inhibitor-mediated cardiotoxicity. 2193 79