In Journal of Internal Medicine, Halle et al.  reviewed the way the transcription factor nuclear factor kappa-B (NF-κB) could be implicated in the radiotherapy-induced cardiotoxicity. In this high-quality study, authors have concluded that preventive strategies focusing on NF-κB could reduce vascular inflammation and consequently the risk of future adverse cardiovascular events. We subsequently highlight other promising approach to minimize treatment-related cardiotoxicity.
Pentoxifylline (PTXF) is a phosphodiesterase inhibitor that has been first developed as a rheological agent. Preclinical studies have brought evidence that PTXF reduces radiation fibrosis when administered alone or in combination with α-tocopherol (vitamin E). The efficacy on radiation side effects of a combined PTXF treatment was confirmed in a randomized clinical trial, but it remains necessary to improve our understanding of the underlying mechanistic pathways . Because the NF-κB inhibition is generally associated with downregulation of pro-inflammatory factors and cell apoptosis, it is possible that the activation of NF-κB may be implicated in heart injury models. PTXF was first described to block the translocation of NF-κB in vascular smooth muscle cells . Then, PTXF has been reported to produce beneficial effects in heart failure by promoting oxygenation of ischaemic areas . The drug also modulates deposition of collagen and reduces radiation-related increases in left ventricular diastolic pressures . The dose-dependent cardioprotective effects of PTXF may be partially explained by the downregulation of pro-inflammatory cytokines (TNF-α and IL-6) mediated by inhibiting NF-κB activation [4, 6].
Halle et al.  also described that a slowly progressive vasculopathy is involved in cardiac toxicity through chronic inflammatory response. Tissular dysfunctions observed after radiotherapy share several common pathways with processes associated with fibrotic diseases, mediated by an inappropriate increase in extracellular matrix. Transforming growth factor-beta 1 (TGFβ1) is one of the numerous secreted factors involved in fibrosis. A wide range of cells produces it, including inflammatory, mesenchymal and epithelial cells. It acts by converting fibroblasts and other cell types into matrix-producing myofibroblasts. As reported in several animals’ models, oxidative damage attributed reactive oxygen species (ROS) contribute to fibrosis after exposure to high-dose ionizing radiation. ROS generated by radiotherapy activate TGF-β1-dependent intracellular signaling pathways, which contributes to upregulating collagen synthesis . Interestingly, PTXF and vitamin E have been described to have antioxidant properties  and to downregulate the expression of TGFβ1 mRNA and in a heart model, . In a randomized, double-blind, placebo-controlled trial, 6 months’ treatment of combined PTXF–vitamin E significantly reduced superficial radiation-induced fibrosis . Therefore, it is proposed that changes in NF-κB and TGFβ1 may be an important factor involved in the mechanism of the cardioprotective effects of PTXF [4, 6]. Including such biologic data could permit better to better understand the underlying mechanism of radiation-induced toxicity and developing protective strategies to avoid normal tissue toxicity.