tin-mesoporphyrin and Lung-Neoplasms

In order to maintain redox homeostasis, non-small-cell lung cancer (NSCLC) increases the activation of many antioxidant systems, including the heme-oxygenase (HO) system. The overexpression of HO-1 has been often associated with chemoresistance and tumor aggressiveness. Our results clearly showed an overexpression of the HO-1 protein in A549 NSCLC cell lines compared to that in non-cancerous cells. Thus, we hypothesized that "off-label" use of tin mesoporphyrin, a well-known HO activity inhibitor clinically used for neonatal hyperbilirubinemia, has potential use as an anti-cancer agent. The pharmacological inhibition of HO activity caused a reduction in cell proliferation and migration of A549. SnMP treatment caused an increase in oxidative stress, as demonstrated by the upregulation of reactive oxygen species (ROS) and the depletion of glutathione (GSH) content. To support these data, Western blot analysis was performed to analyze glucose-6-phosphate dehydrogenase (G6PD), TP53-induced glycolysis and the apoptosis regulator (TIGAR), and the glutamate cysteine ligase catalytic (GCLC) subunit, as they represent the main regulators of the pentose phosphate pathway (PPP) and glutathione synthesis, respectively. NCI-H292, a subtype of the NSCLC cell line, did not respond to SnMP treatment, possibly due to low basal levels of HO-1, suggesting a cellular-dependent antitumorigenic effect. Altogether, our results suggest HO activity inhibition may represent a potential target for selective chemotherapy in lung cancer subtypes.

Topics: A549 Cells; Antineoplastic Agents; Apoptosis Regulatory Proteins; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Glutamate-Cysteine Ligase; Glutathione; Heme Oxygenase-1; Humans; Lung Neoplasms; Metalloporphyrins; Phosphoric Monoester Hydrolases; Tumor Suppressor Protein p53

The human lung cell line A549 is frequently used as an in vitro model for studying lung toxicity and genotoxicity of environmental mutagens and carcinogens. Hyperbaric oxygen (HBO) treatment has been shown to be an excellent model for investigating the genetic consequences of oxidative stress in vitro and in vivo. We have now studied the genotoxic effects of and adaptive protection by HBO in A549 cells. Using the alkaline Comet assay, our results show that HBO exposure directly induces DNA damage but reduces the DNA-damaging effect of a second HBO treatment of the cells 24 h later. HBO pretreatment also reduces potassium chromate-induced genotoxicity in A549 cells. Heme oxygenase-1 (HO-1) protein level is increased 24 h after HBO exposure and inhibition of HO-1 activity by tin-mesoporphyrin increased HBO genotoxicity. These results are in accordance with previous findings suggesting an involvement of HO-1 in the adaptive protection. Our study indicates that A549 cells are an appropriate cell culture system for the evaluation of genetic effects induced by HBO in lung cells.

Topics: Animals; Cells, Cultured; Chromates; Comet Assay; Cricetinae; DNA Damage; Enzyme Inhibitors; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Humans; Hyperbaric Oxygenation; Lung; Lung Neoplasms; Male; Membrane Proteins; Metalloporphyrins; Middle Aged; Oxygen; Potassium Compounds; Protective Agents