Abstract
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.
Highlights
Lung cancer is the leading cause of cancer-related deaths worldwide [1]
Many chemotherapeutics have been clinically employed to avoid the recurrence of malignancy after surgery, acquired chemotherapy resistance remains the biggest challenge to the successful treatment of patients with lung cancer [39,40]
It is important to note that the metabolic status of cancer cells may affect Heme oxygenase (HO)-1 expression that is dependent on different signal pathways and transcription factors, suggesting a possible yet unclear regulation of HO-1 [43]
Summary
Lung cancer is the leading cause of cancer-related deaths worldwide [1]. During lung tumorigenesis, cancer cells enhance their metabolic output, which in turn increases the production of reactive oxygen species (ROS). Non-small-cell lung cancer (NSCLC) increases the transcription of antioxidant genes [2]. Heme oxygenase (HO) is regulated by the Nrf2/ARE pathway and is among the family of cellular antioxidant defense and detoxification enzymes, representing an important cytoprotective system to overcome oxidative stress and inflammation [6,7,8]. HO is a microsomal enzyme, which acts as a catalyst for the first rate-limiting step in the degradation of heme and plays an important role in the recycling of iron. It cleaves the α-meso carbon bridge of heme, yielding equimolar
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
