Nitric oxide modulates proapoptotic and antiapoptotic properties of chemotherapy agents: the case of NO‐pegylated epirubicin

Abstract

The use of the anthracycline epirubicin (EPI) is limited by the risk of a dilatory congestive heart failure that develops as a consequence of induction of a mitochondrial-dependent cardiomyocyte and endothelial cell apoptosis. Nitric oxide (NO) increases the antitumoral activity of several chemotherapics, while it provides protection against apoptosis induced by oxidative stress both in endothelial cells and cardiomyocytes. The aim of the present study was to investigate whether the addition of an NO-releasing moiety to a pegylated derivative of EPI (p-EPI-NO) confers to the drug a different cytotoxic profile against tumoral and normal cells. The cytotoxic profile of the drugs was investigated in Caco-2 cell line, in embryonic rat heart-derived myoblasts (H9c2), in adult cardiomyocytes, and in endothelial cells (HUVEC). p-EPI-NO was more efficient than EPI in inducing Caco-2 cell apoptosis, while it spared HUVEC, H9c2 cells and adult cardiomyocytes from EPI-induced toxicity. Exposure of cells to p-EPI-NO resulted in a NO-mediated inhibition of cellular respiration followed by mitochondrial membrane depolarization and cell death in Caco-2 cells but not in HUVEC and H9c2 cells in which mitochondrial membrane polarization was maintained at the expense of glycolytically generated ATP. These findings indicate that addition of an NO-releasing moiety to p-EPI increases the anti-neoplastic activity of the drug, while it reduces its cytotoxicity against nonneoplastic cells.

Drug and protein delivery by polymer conjugation

“…An example is a heterobifunctional PEG dendron bearing the anticancer drug epirubicin and up to eight nitric oxidereleasing molecules that increase drug activity in tumour cells while preventing anthracycline cardiotoxicity [86]. The conjugate was first extensively studied in vitro; those studies found enhanced antitumor activity and reduced toxicity against cardiomyocytes and endothelial cells following the addition of a NO-releasing moiety [18,86].…”

Atlas of Genetics and Cytogenetics in Oncology and Haematology, 2009, n°1 - Full issue

“…This is what happens in some infectious diseases such as AIDS, where lymphocyte polarization may be induced by both HIV-1 cell-to-cell infection (Fais et al, 1995) and gp120 stimulation without infection (Luciani et al, 2004), but also following stimulation with HIV-1-induced cytokines, such as IL-7 (Fluur et al, 2007). As previously mentioned, it is very hard to distinctly and sharply draw boundaries between the various forms of programmed cell death that cells utilise during the variety of challenges to which they are constantly exposed such as: embryonic development, neurodegeneration, AIDS, carcino-genesis and chemotherapic drugs (Santucci et al, 2006). As far as apotosis is concerned though, mounting evidence, culminating in in vivo beyond doubt results, highlights clear cut differences in the death programs undertaken by type I and type II cells (Lacronique et al, 1996).…”

Polymer conjugates as therapeutics: future trends, challenges and opportunities

“…Research originated in Veronese's group showed the design of a series of new polymeric conjugates bearing on the same PEG chain epirubicine (EPI) and a nitric oxide (NO) releasing molecule [154] . As both compounds suffer the same cellular fate, NO is able to increase the antitumoural activity of EPI while it provides protection against apoptosis induced by oxidative stress, both in endothelial cells and in cardiomyocytes, preventing anthracycline-related cardiotoxicity [154] .…”