Deglycosylated bleomycin has the antitumor activity of bleomycin without pulmonary toxicity

Abstract

Bleomycin (BLM) is a potent anticancer drug used to treat different malignancies, mainly lymphomas, germ cell tumors, and melanomas. Unfortunately, BLM has major, dose-dependent, pulmonary toxicity that affects 20% of treated individuals. The most severe form of BLM-induced pulmonary toxicity is lung fibrosis. Deglyco-BLM is a molecule derived from BLM in which the sugar residue d-mannosyl-l-glucose disaccharide has been deleted. The objective of this study was to assess the anticancer activity and lung toxicity of deglyco-BLM. We compared the antitumor activity and pulmonary toxicity of intraperitoneally administrated deglyco-BLM and BLM in three rodent models. Pulmonary toxicity was examined in depth after intratracheal administration of both chemotherapeutic agents. The effect of both drugs was further studied in epithelial alveolar cells in vitro. We demonstrated in rodent cancer models, including a human Hodgkin's lymphoma xenograft and a syngeneic melanoma model, that intraperitoneal deglyco-BLM is as effective as BLM in inducing tumor regression. Whereas the antitumor effect of BLM was accompanied by a loss of body weight and the development of pulmonary toxicity, deglyco-BLM did not affect body weight and did not engender lung injury. Both molecules induced lung epithelial cell apoptosis after intratracheal administration, but deglyco-BLM lost the ability to induce caspase-1 activation and the production of ROS (reactive oxygen species), transforming growth factor-β1, and other profibrotic and inflammatory cytokines in the lungs of mice and in vitro. Deglyco-BLM should be considered for clinical testing as a less toxic alternative to BLM in cancer therapy.

Supercritical-Carbon Dioxide Fluid Extract from Chrysanthemum indicum Enhances Anti-Tumor Effect and Reduces Toxicity of Bleomycin in Tumor-Bearing Mice

“…The pro-inflammatory cytokines are known to play a significant role in the processing of pulmonary fibrosis, including TNF-α and IL-6. Furthermore, the excessive free radicals will result in oxidative stress or chronic inflammation [1,2,35], the related enzymes have a significant function in the processing of lung fibrosis, and thus, the activities of the oxidant enzymes (MPO and MDA) were also measured in this study. The results showed that CI SCFE combined with BLM could distinctly decrease the levels of inflammatory cytokines (TNF-α, IL-6) and oxidant enzymes (MPO, MDA).…”

“…However, BLM exhibits the main side effect of dose-dependent pulmonary toxicity, which affects 20% of treated individuals. Pulmonary fibrosis is a severe form of lung toxicity, which was induced by BLM [2]. However, the etiology and mechanism of pulmonary fibrosis have not yet been elucidated.…”

Pleural inhibition of the caspase-1/IL-1β pathway diminishes profibrotic lung toxicity of bleomycin

“…The involvement of caspase-1/IL-1β in BLM-induced lung toxicity has already been reported in animal models [16, 17]. Recently, structural cells have been reported to be involved in capsase-1 activation and IL-1β secretion in the lung following different profibrotic stimuli [18, 19]. Mesothelial cells have already been shown to be involved in the initiation of the inflammatory response in a model of talc-induced pleurodesis [28].…”

“…For Il-1β assessment in supernatant, cells were treated with BLM in serum-free medium. When indicated, caspase-1 was blocked using YVAD (Bachem AG) as previously described [19]. …”

“…Mice deficient for inflammasome components such as the NOD-like receptor NLRP3 and thereby unable to activate caspase-1 and thus produce active IL-1β develop less severe fibrosis after BLM challenge [17]. Even though most studies on IL-1β/caspase-1 signaling focused on immune cells, some studies highlighted the involvement of this signaling pathway in structural cells [18, 19]. The role of caspase-1 on lung structural cells and its involvement during fibrotic processes is still poorly understood.…”