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.
Highlights
Heme oxygenase-1 (HO-1) is the inducible isoform of heme oxygenase, the first rate-limiting enzyme in the degradation of heme to free iron, carbon monoxide (CO), and biliverdin [1].HO-1 is present at low levels in many tissues and is highly upregulated by numerous stimuli, such as heme, heavy metals, UV irradiation, reactive oxygen species (ROS), polyphenols, and inflammatory cytokines [2,3]
MET works by targeting the enzyme AMPK (AMP activated protein kinase), which induces muscles to take up glucose from the blood
A recent breakthrough has found the upstream regulator of AMPK to be a protein kinase known as LKB1, a well-recognized tumor suppressor [52]
Summary
Heme oxygenase-1 (HO-1) is the inducible isoform of heme oxygenase, the first rate-limiting enzyme in the degradation of heme to free iron, carbon monoxide (CO), and biliverdin [1]. The anti-proliferative effects of metformin, reported in several cancers including breast, colon, glioma, ovarian, pancreatic, and prostate cancer [27,28,29], have been mainly associated with the capacity of MET to inhibit mitochondrial respiration and increasing glycolysis rates [30] and to arrest cell cycle and inducing caspase-dependent apoptosis [31,32]. It has been shown that metformin significantly decreases the intracellular glutathione levels and enhanced sensitivity of esophageal squamous cell carcinoma to cisplatin [46], suggesting that regulation of the antioxidant defenses represents a key target for cancer therapy In this regard, new evidence has shown the involvement of TIGAR (TP53-induced glycolysis and apoptosis regulator) in glutathione restoration [47].
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