Tin Mesoporphyrin Selectively Reduces Non-Small-Cell Lung Cancer Cell Line A549 Proliferation by Interfering with Heme Oxygenase and Glutathione Systems

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.

Heme Oxygenase Modulation Drives Ferroptosis in TNBC Cells

“…Taken together, these results highlight the role of HO as one of the many factors that are able to sustain ferroptosis. Thus, it is worth remarking on the difference between the two pharmacological strategies used by us and other research groups [ 29 , 37 , 53 ], exploiting either the induction or inhibition of the HO system in order to understand their effectiveness in different cellular and animal models. Low basal HO-1 levels appear to be critical to predict cells’ sensitivity to ferroptosis, suggesting its potential targeting as a novel therapeutic approach for BC.…”

“…Subsequently HO-2, GPX4 and FHC levels were evaluated after treatment with erastin, hemin, an erastin/hemin combination and curcumin. Samples were processed as previously described by Sorrenti et al, [ 37 ]. Membranes were incubated overnight with HO-1 (GTX101147, diluted 1:1000, GeneTex, Irvine, CA, USA), HO-2 (SPA897, diluted 1:2000, Enzo Life Sciences, Farmingdale, NY, USA), GPX4 (ab125066, diluted 1:1000, Abcam, Cambridge, UK), ACSL4 (PA5–27137, diluted 1:1000, Thermo Fisher Scientific, Rodano, MI, Italy), FHC (ab81444, diluted 1:1000) and β-actin (GTX109639, diluted 1:7000, GeneTex) primary antibodies.…”

“…On the basis of these observations, HO-1 inhibition has been widely exploited as a valid therapeutic strategy for cancer treatment [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. However, recent findings seem to propose a different approach for pharmacological modulation of HO-1 in cancer therapy, displaying a reduction in cancerous cell proliferation following enzyme induction [ 36 , 37 ]. Hence, the emerging correlation between modulation of the HO system and ferroptosis can be considered as a potential new path to pursue for treating specific cancers.…”

Deciphering the Effects and Mechanisms of Yi-Fei-San-Jie-pill on Non-Small Cell Lung Cancer With Integrating Network Target Analysis and Experimental Validation

“…As it is known to all that cancer cells need more energy and rely on enhanced glycolysis. Nonetheless, mitochondria were corroborated to promote aerobic oxidation for lung cancer survival and metastasis ( Li F. et al, 2020 ; Sorrenti et al, 2021 ). The latest review also shows that the combination of traditional therapies and autophagy inhibitors including 3-MA can improve the efficacy of lung cancer ( Wang Z. et al, 2021 ), and even intervention in specific autophagy genes can improve the response rate of immunotherapy ( Lawson et al, 2020 ).…”

The Expression of TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) Can Be Controlled by the Antioxidant Orchestrator NRF2 in Human Carcinoma Cells

“…Consequently, the downregulation of TIGAR in tumors has been proposed as an appropriate strategy to increase the effectiveness of antineoplastic therapies based on ROS-mediated cell death [8,9]. Recently, the cytotoxic effects of the DNA methyltransferase inhibitor decitabine and the inhibitor of heme-oxygenase tin mesoporphyrin have been linked to decreased expression of TIGAR and reduced PPP in myeloid leukemia and non-small cell lung carcinoma (NSCLC), respectively [10,11].…”