Circulating Levels of Epirubicin Cause Endothelial Senescence While Compromising Metabolic Activity and Vascular Function

Abstract

Anthracycline-based chemotherapy is a common treatment for cancer patients. Because it is delivered intravenously, endothelial cells are exposed first and to the highest concentrations, prior to diffusion to target cells. Not surprisingly, vascular dysfunction is a consequence of anthracycline therapy. While chemotherapy-induced endothelial damage at administration sites has been investigated, the effects of lower doses encountered by distant microvascular networks has not. The aim of this study was to investigate the impact of epirubicin, a widely used anthracycline, on healthy endothelial cells to elucidate its effects on microvascular physiology. Here, endothelial cells were briefly exposed to low doses of epirubicin to recapitulate levels in circulation following dilution in the blood and compound half-life in circulation. Both immediate and prolonged responses to treatment were assessed to determine changes in endothelial function. Epirubicin caused a decrease in proliferation and viability in hUVEC, with lower doses resulting in a senescent phenotype in a large proportion of cells, accompanied by a significant increase in pro-inflammatory cytokines and a significant decrease in metabolic activity. Epirubicin exposure also impaired endothelial function with delayed wound closure, reduced angiogenic potential and increased monolayer permeability downstream of VE-cadherin internalization. Primary lung endothelial cells obtained from epirubicin-treated mice similarly demonstrated reduced viability and functional impairment. In vivo, epirubicin treatment resulted in persistent reduction in lung vascular density and significantly increased infiltration of myeloid cells. Modulation of endothelial status and inflammatory tissue microenvironment observed in response to low doses of epirubicin may predict risk for long-term secondary pathologies associated with chemotherapy.

Life after Cell Death—Survival and Survivorship Following Chemotherapy

“…Given that most chemotherapy is administered intravenously, endothelial cells (EC) are the first to come into contact with drugs, and the effects on the vascular system are manifold [36][37][38]; predictably, vascular damage is a major consequence of chemotherapy. Exposure to chemotherapy leads to endothelial activation [48,49] and progenitor-mediated regeneration [14], as well as decreased barrier function due to cell death and/or changes in adherens and intercellular junctions [16,36,48]. EC form a continuous but very heterogeneous organ, with unique functional and metabolic profiles, which responds to stress and inflammation in an organ-specific manner [50]; this may actually underlie therapy-driven metastatic organotropism.…”

“…While microvascular cell plasticity ensures that metabolic demands are met at specific organs and in specific contexts [64], their adaptive responses to stress can involve structural, angiogenic, intercellular communication and metabolic changes likely to favour dissemination and proliferation of circulating tumour cells (CTC) [48,51,[65][66][67]. In turn, CTC have been shown to more efficiently evade cytotoxic treatments, as a result of enhanced DNA repair mechanisms [68].…”

“…A significant number of EC undergo apoptosis following chemotherapy exposure, particularly the ones found at sites of injection [36,48,[88][89][90]. Microvascular EC treated with cisplatin display increased caspase activity with induction of apoptosis and necrosis in the 24 h following treatment [91].…”

“…Most somatic cells will not, and this is the key aspect of the success and reliability of classical chemotherapy [1,9]. Somatic cells are exposed to varying degrees of circulating drugs, and their survival requires that they respond to that stimulus; one of the most common consequences of exposure to chemotherapy (and radiotherapy) is senescence [48,93,98,99].…”

“…While associated with age-related diseases, the stable arrest of proliferation brought upon by the process of senescence can be desirable when induced in cancer cells themselves [103], but is associated with relapse when triggered in somatic cells, such as fibroblasts [104] or endothelial cells [48,52,98,105]. Senescent mesenchymal stem cells promote breast cancer proliferation and invasive behaviour via secretion of IL-6 [106].…”