Targeting endothelial cell metabolism for cardio-protection from the toxicity of antitumor agents

Abstract

The vascular endothelium plays a fundamental role in the maintenance of tissue homeostasis, regulating local blood flow and other physiological processes. Chemotherapeutic drugs and target therapies, including antiangiogenic drugs targeting vascular endothelial growth factor (VEGF) or its receptors, not only efficiently act against tumor growth, but may also induce endothelial dysfunction and cardiovascular toxicity. Continued research efforts aim to better understand, prevent and mitigate these chemotherapy associated cardiovascular diseases. Conventional chemotherapeutic agents, such as anthracyclines, platinum compounds, and taxanes, and newer targeted agents, such as bevacizumab, trastuzumab, and tyrosine kinase inhibitors, have known risk of cardiovascular toxicity, which can limit their effectiveness by promoting increased morbidity and/or mortality. This review describes a) the activity of anticancer agents in inducing endothelial dysfunction, b) the metabolic pathways and signalling cascades which may be targeted by protective agents able to maintain or restore endothelial cell function, such as endothelial nitric oxide synthase/fibroblast growth factor-2 (eNOS-FGF-2) pathway, and c) the drugs/strategies reported to improve endothelial function and to reduce the risks of cardiovascular diseases such as angiotensin converting enzyme inhibitors (ACEi) and beta blockers, that are fundamental therapies in chronic heart failure (HF), as well as non-standard HF treatments such ad nitric oxide donors and antioxidant strategies. There is increasing interest in whether ACEi, beta-blockers, and/or statins might prevent and/or therapeutically control cardiotoxic effects in cancer patients. Maintaining endothelial function during or following treatments with chemotherapeutic agents, without affecting anti-tumor drug-effectiveness, is essential for preserving or recovering cardiovascular homeostasis. In this respect, the early detection and immediate therapy of cardiovascular toxicity appear crucial for substantial recovery of cardiac function in cancer patients.

Keywords: Nitric Oxide; Sorafenib; Sunitinib; Trastuzumab; Vascular Endothelial Growth Factor.

Fig. 1

Quiescent endothelial cells (ECs) participate to the physiological maintenance of cardiovascular tissue homeostasis through the control of vessel tone, permeability and intima thickness, coagulation and fibrinolysis, vessel remodelling and angiogenesis. Growth factors as VEGF, or peptides as BK and SP modulate the production/release of vasoactive molecules from ECs, including NO, PGI2, AngII and ET, which, in turn, activate intracellular signalling pathways as MAPK and cGMP pathways, and/or FGF2 production, involved in contractile function and EC survival and proliferation. Endothelial loss-of-function/dysfunction following exposure to conventional chemoterapeutic drugs or target therapies, including VEGF/VEGFR inhibitors. Cancer therapies damage essential signaling cascades that promote undesired cancer cell proliferation, but also protect endothelial cells, especially in response to stress. Endothelial dysfunction is regarded as a decrease of NO released from ECs, an increase of vessel permeability, an increase of platelet adhesion and aggregation, and transmigration of inflammatory cells, which in turn sustain atherosclerosis, vasoconstriction and reduced EC trofism and survival. Endothelial dysfunction is crucial in heart damage. Different categories of drugs have been shown to improve endothelial function and to reduce the risk of cardiovascular diseases associated to treatment with chemotherapeutic agents. Among these, there are ACEi, ARBs, renin and β1 antagonist, NO donor drugs, PKCε agonist and ALDH2 activators. (VEGF: vascular endothelial growth factor; BK: bradykinin; SP: substance P; NO: nitric oxide; ET: endothelin; PGI2: prostacyclin; AngII: angiotensin II; MAPK: Mitogen activated proteine kinase; cGMP: cyclic guanosine monophosphate; FGF2: fibroblast growth factor; VSMCs: vascular smooth muscle cells)

Fig. 2

Molecular mechanisms of doxorubicin induced endothelial damage and reversion by the SH-containing ACEi zofenoprilat. Exposure of bovine coronary post-capillary venular endothelial cells to doxorubicin (D) impaired cell survival by promoting their apoptosis (evaluated as cleaved caspase-3: Cl. Caspase 3). ERK1/2 related p53 activation was responsible for doxorubicin induced caspase-3 cleavage. pERK1/2 and p53 were evaluated by western blot in EC treated with 0.5 μM doxorubicin (D) for 1 h, while the cleavage of caspase-3 was monitored by western blotting in EC exposed to doxorubicin for 6 h. P53 mediated-apoptosis and impairment of survival were reverted by treatment with zofenoprilat (Z), added at 1–100 μM concentration together with doxorubicin. The previously described prosurvival signaling pathway (activation of PI-3K dependent eNOS and upregulation of endogenous FGF-2 and telomease reverse transcriptase TERT) [77] was not involved in the protective effect of doxorubicin induced damage, which, instead, could be ascribed to cystathionine gamma lyase (CSE) dependent availability of H₂S from zofenoprilat. Indeed the levels of CSE protein were upregulated by zofenoprilat treatment (10 μM, 4 h) [78]

Fig. 3

Metabolic pathways preserving EC function. ECs maintain a prosurvival phenotype through the upregulation of eNOS, the activation of cGMP, Akt and MAPK pathways, and the transcription of FGF-2. ACEi, PKCε activators, novel NO donor drugs, VEGF mimetic peptides and ALDH2 activator have been reported to modulate eNOS activity and/or FGF-2 expression, suggesting a potential application of these drugs in association with chemotherapeutic drugs to preserve EC function and to reduce the risk for CVDs in long-term cancer survivors

Fig. 4

Molecular mechanisms of zofenoprilat-induced protective effects on vascular ECs. Zofenoprilat induces a constant H₂S production through CSE upregulation in vascular endothelium. On its turn H₂S maintains ECs survival and stimulates the angiogenic process through a sequential pathway involving K_ATP channel/Akt/eNOS/ERK1/2 pathway (for details see [104])