Heme Oxygenase-1 Inhibition Sensitizes Human Prostate Cancer Cells towards Glucose Deprivation and Metformin-Mediated Cell Death

Abstract

High levels of heme oxygenase (HO)-1 have been frequently reported in different human cancers, playing a major role in drug resistance and regulation of cancer cell redox homeostasis. Metformin (MET), a drug widely used for type 2 diabetes, has recently gained interest for treating several cancers. Recent studies indicated that the anti-proliferative effects of metformin in cancer cells are highly dependent on glucose concentration. The present work was directed to determine whether use of a specific inhibitor of HO-1 activity, alone or in combination with metformin, affected metastatic prostate cancer cell viability under different concentrations of glucose. MTT assay and the xCELLigence system were used to evaluate cell viability and cell proliferation in DU145 human prostate cancer cells. Cell apoptosis and reactive oxygen species were analyzed by flow cytometry. The activity of HO-1 was inhibited using a selective imidazole-based inhibitor; genes associated with antioxidant systems and cell death were evaluated by qRT-PCR. Our study demonstrates that metformin suppressed prostate cancer growth in vitro and increased oxidative stress. Disrupting the antioxidant HO-1 activity, especially under low glucose concentration, could be an attractive approach to potentiate metformin antineoplastic effects and could provide a biochemical basis for developing HO-1-targeting drugs against solid tumors.

Mild exacerbation of obesity- and age-dependent liver disease progression by senolytic cocktail dasatinib + quercetin

“…RNA extraction and qRT-PCR methods were previously described [ 29 , 30 ]. Murine primer sequences were listed in Table 3 .…”

Expression of heme oxygenase-1 in type II pneumocytes protects against heatstroke-induced lung damage

“…genes (Amorim et al 2015;Wang et al 2015;Bruchim et al 2019). Heme oxygenase (HO)-1, also known as HSP32, is a stress-responsive enzyme that catabolizes heme into carbon monoxide (CO), biliverdin, and iron (Raffaele et al 2019;Aziz et al 2020). HO-1 expression prevents a pulmonary inflammatory response to hypoxia, cardiac ischemia/reperfusion injury, and polycystic kidney disease (Minamino et al 2001;Nath 2006;He et al 2013).…”

Role of Heme Oxygenase as a Modulator of Heme-Mediated Pathways

“…Recently it has been shown that HO-1 overexpression and nuclear translocation, a mechanism occurring preferentially under pathological conditions, is associated with transcription regulating roles of HO-1, which are independent of the generation of HO products [57]. Together with the anti-oxidative and anti-apoptotic action of the HO products BR and CO exploited by tumor cells, these findings suggest HO-1 inhibition as a suitable therapy against different cancer types [55], such as melanoma [58], prostate cancer cells [59], as well as various leukemia malignancies [60,61]. In contrast to normal cells, many tumor cells are particularly vulnerable to inhibition of HO, because they possess reduced levels of other anti-oxidative enzyme systems, such as catalase, superoxide dismutase and glutathione peroxidase [62,63,64,65].…”