Cardiovascular safety of VEGF-targeting therapies: current evidence and handling strategies

Abstract

Treatment with the angiogenesis inhibitors bevacizumab, sunitinib, and sorafenib as single agents or in combination with conventional chemotherapy is becoming a cornerstone of modern anticancer therapy. However, the potential toxicity of these drugs, mainly to the cardiovascular system, is still being investigated. Patient assessment at baseline, of crucial importance in candidates for treatment, involves the evaluation of risk factors and screening for past or present cardiovascular disease. Strict monitoring of treatment-related adverse effects must be conducted in order to allow the early detection of cardiovascular toxicities and their prompt medication. In the present paper, the most frequent cardiovascular toxicities and their underlying mechanisms are investigated, with a view to providing indications for effective patient management.

Figure 1.

Signaling pathways of sunitinib and sorafenib cardiotoxicity. Sunitinib, by inhibiting the ribosomal S6 kinase (RSK), allows the release of the proapoptotic factor BCL2-associated death promoter (BAD) from RSK inactivation; BAD interacts with BCL2 associated X protein (BAX), which, in turn, causes the release of cytochrome c (Cyt C), leading to caspase activation and cell death. Moreover, sunitinib, counteracting adenosine monophosphate activated protein kinase (AMPK), fosters protein translation and lipid biosynthesis through eukaryotic elongation factor 2 (EEF2), mammalian target of rapamycin (mTOR), and acetyl coenzyme A carboxylase (ACC). Sorafenib, preventing v-raf-1 murine leukemia viral oncogene homolog 1 (RAF1)/extracellular signal regulated kinase (ERK) formation, disrupts the ERK-mediated prosurvival pathway; furthermore, sorafenib, inhibiting the proapoptotic kinases apoptosis signal-regulating kinase 1 (ASK1) and mammalian sterile 20 kinase 2 (MST2), through RAF1, triggers cell death.