The Heme Oxygenase System in Hematological Malignancies

Volti, Giovanni Li; Tibullo, Daniele; Vanella, Luca; Giallongo, Cesarina; Raimondo, Francesco Di; Forte, Stefano; Rosa, Michelino Di; Signorelli, Salvatore Santo; Barbagallo, Ignazio

doi:10.1089/ars.2016.6735

Cited by 34 publications

(31 citation statements)

References 112 publications

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“…In agreement with previous results, showing the ability of carnosine to indirectly counteract oxidative stress by enhancing the expression of members of the endogenous antioxidant system, including HO-1 and Nrf2 [56][57][58], under our experimental conditions we found that carnosine up-regulated both Nrf2 and, particularly, its downstream product HO-1 (Figure 8). Since the activity of HO-1 has been addressed as one of the main actors in the defense system towards oxidative/nitrosative stress [10,[59][60][61][62], it is presumable that the carnosine-mediated positive HO-1 modulation contributes in part to the generalized decrease in metabolic indicators of sustained oxidative/nitrosative stress (sum of nitrite + nitrate, MDA; Figures 2 and 6). On the other hand, carnosine effects on Nrf2 might have led stimulated macrophages to have lower expressions of Nox-2 and Cox-2 and concomitant higher expressions in canonical scavenger enzymes (Gpx, Cat, and SOD-2; Figure 5).…”

Section: Discussionmentioning

confidence: 99%

Modulation of Pro-Oxidant and Pro-Inflammatory Activities of M1 Macrophages by the Natural Dipeptide Carnosine

Fresta

Fidilio

Lazzarino

et al. 2020

IJMS

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Carnosine is a natural endogenous dipeptide widely distributed in mammalian tissues, existing at particularly high concentrations in the muscles and brain and possesses well-characterized antioxidant and anti-inflammatory activities. In an in vitro model of macrophage activation, induced by lipopolysaccharide + interferon-gamma (LPS + IFN-γ), we here report the ability of carnosine to modulate pro-oxidant and pro-inflammatory activities of macrophages, representing the primary cell type that is activated as a part of the immune response. An ample set of parameters aimed to evaluate cytotoxicity (MTT assay), energy metabolism (HPLC), gene expressions (high-throughput real-time PCR (qRT-PCR)), protein expressions (western blot) and nitric oxide production (qRT-PCR and HPLC), was used to assess the effects of carnosine on activated macrophages challenged with a non cytotoxic LPS (100 ng/mL) + IFN-γ (600 U/mL) concentration. In our experimental model, main carnosine beneficial effects were: (1) the modulation of nitric oxide production and metabolism; (2) the amelioration of the macrophage energy state; (3) the decrease of the expressions of pro-oxidant enzymes (Nox-2, Cox-2) and of the lipid peroxidation product malondialdehyde; (4) the restoration and/or increase of the expressions of antioxidant enzymes (Gpx1, SOD-2 and Cat); (5) the increase of the transforming growth factor-β1 (TGF-β1) and the down-regulation of the expressions of interleukins 1β and 6 (IL-1β and IL-6) and 6) the increase of the expressions of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1). According to these results carnosine is worth being tested in the treatment of diseases characterized by elevated levels of oxidative stress and inflammation (atherosclerosis, cancer, depression, metabolic syndrome, and neurodegenerative diseases).

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Section: Discussionmentioning

confidence: 99%

Modulation of Pro-Oxidant and Pro-Inflammatory Activities of M1 Macrophages by the Natural Dipeptide Carnosine

Fresta

Fidilio

Lazzarino

et al. 2020

IJMS

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“…Under oxidative stress, HO-1 expression is induced by the NRF2 transcription factor as part of the cellular antioxidant defence response. HO-1 is upregulated in some leukaemic cells [ 190 ], which could be a compensatory mechanism to cope with oxidative stress [ 95 ]. It is noteworthy that HO-1 overexpression has been related to drug resistance [ 191 ].…”

Section: The Use Of Ros As a Therapeutic Target In Haematological Malmentioning

confidence: 99%

Reactive oxygen species in haematopoiesis: leukaemic cells take a walk on the wild side

Prieto-Bermejo

Romo-González

Pérez-Fernández

et al. 2018

J Exp Clin Cancer Res

103

115

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Oxidative stress is related to ageing and degenerative diseases, including cancer. However, a moderate amount of reactive oxygen species (ROS) is required for the regulation of cellular signalling and gene expression. A low level of ROS is important for maintaining quiescence and the differentiation potential of haematopoietic stem cells (HSCs), whereas the level of ROS increases during haematopoietic differentiation; thus, suggesting the importance of redox signalling in haematopoiesis. Here, we will analyse the importance of ROS for haematopoiesis and include evidence showing that cells from leukaemia patients live under oxidative stress. The potential sources of ROS will be described. Finally, the level of oxidative stress in leukaemic cells can also be harnessed for therapeutic purposes. In this regard, the reliance of front-line anti-leukaemia chemotherapeutics on increased levels of ROS for their mechanism of action, as well as the active search for novel compounds that modulate the redox state of leukaemic cells, will be analysed.

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“…In these cases, HO-1 acts as survival molecule and its up-regulation protects cells from apoptosis, induces cell proliferation, metastasis, angiogenesis by promoting vascular endothelial growth factor (VEGF) expression, and resistance to therapy [71]. Numerous papers describe the involvement of HO-1 in the progression of blood malignancies and in the mechanisms leading to chemo-resistance in leukemia, but also in the progression of solid tumors, such as human renal cell carcinoma, melanoma, and prostate-and pancreatic cancer [72]. Particularly, different studies show that HO-1 is expressed in cytoplasm and also in nucleus of cancer cells in lung, prostate and oral tumor tissues.…”

Section: Hemeoxygenase-1 Induction In Cancer Progressionmentioning

confidence: 99%

Iron Metabolism in Cancer Progression

Forciniti

Greco

Grizzi

et al. 2020

IJMS

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Iron is indispensable for cell metabolism of both normal and cancer cells. In the latter, several disruptions of its metabolism occur at the steps of tumor initiation, progression and metastasis. Noticeably, cancer cells require a large amount of iron, and exhibit a strong dependence on it for their proliferation. Numerous iron metabolism-related proteins and signaling pathways are altered by iron in malignancies, displaying the pivotal role of iron in cancer. Iron homeostasis is regulated at several levels, from absorption by enterocytes to recycling by macrophages and storage in hepatocytes. Mutations in HFE gene alter iron homeostasis leading to hereditary hemochromatosis and to an increased cancer risk because the accumulation of iron induces oxidative DNA damage and free radical activity. Additionally, the iron capability to modulate immune responses is pivotal in cancer progression. Macrophages show an iron release phenotype and potentially deliver iron to cancer cells, resulting in tumor promotion. Overall, alterations in iron metabolism are among the metabolic and immunological hallmarks of cancer, and further studies are required to dissect how perturbations of this element relate to tumor development and progression.

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The Heme Oxygenase System in Hematological Malignancies

Cited by 34 publications

References 112 publications

Modulation of Pro-Oxidant and Pro-Inflammatory Activities of M1 Macrophages by the Natural Dipeptide Carnosine

Modulation of Pro-Oxidant and Pro-Inflammatory Activities of M1 Macrophages by the Natural Dipeptide Carnosine

Reactive oxygen species in haematopoiesis: leukaemic cells take a walk on the wild side

Iron Metabolism in Cancer Progression

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