Therapeutic potential of nitric oxide donors in the prevention and treatment of angiogenesis-inhibitor-induced hypertension

Abstract

Angiogenesis is critical to tumor growth as well as to metastases. This process is tightly regulated by pro- and anti-angiogenic growth factors and their receptors. Some of these factors are highly specific for the endothelium-e.g., vascular endothelial growth factor (VEGF). A variety of drugs that target VEGF or its receptors have been developed for the treatment of different tumor types and a number of new agents is expected to be introduced within the coming years. However, clinical experience has revealed that inhibition of VEGF induces several side effects including hypertension and renal and cardiac toxicity. Angiogenesis-inhibitor-induced hypertension represents "crux medicorum" as it is often pharmacoresistant to antihypertensive therapy. We consider two most important pathomechanisms in the development of hypertension induced by angiogenesis inhibitors. The first represents direct inhibition of NO production leading to reduced vasodilatation and the second consists in increased proliferation of vascular medial cells mediated by NO deficiency and is resulting in fixation of hypertension. Based on the results of experimental and clinical studies as well as on our clinical experience, we assume that NO donors could be successfully used not only for the treatment of developed angiogenesis-inhibitor-induced hypertension but also for preventive effects. We thoroughly documented three clinical cases of cancer patients with resistant hypertension who on receiving NO donor treatment achieved target blood pressure level and a good clinical status.

Fig. 1

Proposed pathways for the VEGF-induced induction of NO synthesis in endothelial cells and the actions in smooth muscle cells. VEGF induces immediate NO synthesis through the PLC-Ca²⁺/CaM pathway and the induction of delayed NO synthesis implies Akt/PKB and PKC activition (eNOS upregulation). In smooth muscle cells, NO increases cGMP leading to vasorelaxation and inhibits ribonucleotide reductase resulting in decreased proliferation