Submit to Biomolecules Review for Biomolecules Propose a Special Issue

Journal Browser

► Journal Browser

Therapeutic Significance of Heme Oxygenase Induction or Inhibition

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 38650

Share This Special Issue

Special Issue Editors

Prof. Dr. Luca Vanella

E-Mail Website
Guest Editor

Department of Drug and Health Sciences, Section of Biochemistry, University of Catania, Catania, Italy
Interests: biochemistry; cell signaling; oxidative stress; nutraceuticals; antioxidants; heme oxygenase;
Special Issues, Collections and Topics in MDPI journals

Dr. Marco Raffaele

E-Mail
Guest Editor

Department of Drug Sciences, University of Catania, Catania, Italy
Interests: heme oxygenase; mesenchymal stem cells; polyphenolic compounds; diabetes; liver diseases.

Special Issue Information

Dear colleagues,

A heme oxygenase (HO) system consists of two different isoforms, HO-1, the inducible form, and HO-2, the constitutive form. Both isozymes catalyze the rate-limiting step in heme degradation, resulting in the formation of biliverdin with the concurrent release of carbon monoxide (CO) and iron. HO-1 induction by drugs, polyphenols, and a variety of stimuli, such as low-grade inflammation and oxidative stress, is mediated by the nuclear factor erythroid 2-related factor 2 (Nrf2). HO plays a key role as a cytoprotective system and as an endogenous antioxidant system by scavenging reactive oxygen species (ROS) and preventing apoptosis during stress conditions. However, recently, it has been shown that a HO system may possess important biological functions beyond its enzymatic activity. The up-regulation of HO-1 and its cellular localization could presumably reduce the efficacy of chemotherapeutic agents in the treatment of several cancers.

Prof. Luca Vanella
Dr. Marco Raffaele
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

HO-1
HO-2
antioxidants
apoptosis
cancer
Nrf2
heme oxygenase inducers
heme oxygenase inhibitors
carbon monoxide
biliverdin

Published Papers (9 papers)

Download All Papers

Research

Jump to: Review

12 pages, 2083 KiB

Open AccessArticle

Protocatechuic Acid, a Simple Plant Secondary Metabolite, Induced Apoptosis by Promoting Oxidative Stress through HO-1 Downregulation and p21 Upregulation in Colon Cancer Cells

by Rosaria Acquaviva, Barbara Tomasello, Claudia Di Giacomo, Rosa Santangelo, Alfonsina La Mantia, Irina Naletova, Maria Grazia Sarpietro, Francesco Castelli and Giuseppe Antonio Malfa

Biomolecules 2021, 11(10), 1485; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11101485 - 08 Oct 2021

Cited by 26 | Viewed by 2749

Abstract

Gastrointestinal cancers, particularly colorectal cancer, are mainly influenced by the dietary factor. A diet rich in fruits and vegetables can help to reduce the incidence of colorectal cancer thanks to the phenolic compounds, which possess antimutagenic and anticarcinogenic properties. Polyphenols, alongside their well-known antioxidant properties, also show a pro-oxidative potential, which makes it possible to sensitize tumor cells to oxidative stress. HO-1 combined with antioxidant activity, when overexpressed in cancer cells, is involved in tumor progression, and its inhibition is considered a feasible therapeutic strategy in cancer treatment. In this study, the effects of protocatechuic acid (PCA) on the viability of colon cancer cells (CaCo-2), annexin V, LDH release, reactive oxygen species levels, total thiol content, HO-1, γ-glutamylcysteine synthetase, and p21 expression were evaluated. PCA induced, in a dose-dependent manner, a significantly reduced cell viability of CaCo-2 by oxidative/antioxidant imbalance. The phenolic acid induced modifications in levels of HO-1, non-proteic thiol groups, γ-glutamylcysteine synthetase, reactive oxygen species, and p21. PCA induced a pro-oxidant effect in cancer cells, and the in vitro pro-apoptotic effect on CaCo-2 cells is mediated by the modulation of redox balance and the inhibition of the HO-1 system that led to the activation of p21. Our results suggest that PCA may represent a useful tool in prevention and/or therapy of colon cancer. Full article

(This article belongs to the Special Issue Therapeutic Significance of Heme Oxygenase Induction or Inhibition)

► Show Figures

Figure 1

10 pages, 1514 KiB

Open AccessCommunication

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

by Valeria Sorrenti, Agata Grazia D’Amico, Ignazio Barbagallo, Valeria Consoli, Salvo Grosso and Luca Vanella

Biomolecules 2021, 11(6), 917; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11060917 - 21 Jun 2021

Cited by 10 | Viewed by 2778

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. Full article

(This article belongs to the Special Issue Therapeutic Significance of Heme Oxygenase Induction or Inhibition)

► Show Figures

Figure 1

23 pages, 8992 KiB

Open AccessArticle

Myxovirus Resistance Protein 1 (MX1), a Novel HO-1 Interactor, Tilts the Balance of Endoplasmic Reticulum Stress towards Pro-Death Events in Prostate Cancer

by Emiliano Ortiz, Pablo Sanchis, Juan Bizzotto, Sofia Lage-Vickers, Estefania Labanca, Nora Navone, Javier Cotignola, Elba Vazquez and Geraldine Gueron

Biomolecules 2020, 10(7), 1005; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10071005 - 06 Jul 2020

Cited by 6 | Viewed by 2859

Abstract

The inflammatory tumor microenvironment is a fertile niche accelerating prostate cancer (PCa). We have reported that heme-oxygenase (HO-1) had a strong anti-tumoral effect in PCa. We previously undertook an in-depth proteomics study to build the HO-1 interactome in PCa. In this work, we used a bioinformatics approach to address the biological significance of HO-1 interactors. Open-access PCa datasets were mined to address the clinical significance of the HO-1 interactome in human samples. HO-1 interactors were clustered into groups according to their expression profile in PCa patients. We focused on the myxovirus resistance gene (MX1) as: (1) it was significantly upregulated under HO-1 induction; (2) it was the most consistently downregulated gene in PCa vs. normal prostate; (3) its loss was associated with decreased relapse-free survival in PCa; and (4) there was a significant positive correlation between MX1 and HMOX1 in PCa patients. Further, MX1 was upregulated in response to endoplasmic reticulum stress (ERS), and this stress triggered apoptosis and autophagy in PCa cells. Strikingly, MX1 silencing reversed ERS. Altogether, we showcase MX1 as a novel HO-1 interactor and downstream target, associated with ERS in PCa and having a high impact in the clinical setting. Full article

(This article belongs to the Special Issue Therapeutic Significance of Heme Oxygenase Induction or Inhibition)

► Show Figures

Figure 1

24 pages, 7724 KiB

Open AccessArticle

HO-1 Interactors Involved in the Colonization of the Bone Niche: Role of ANXA2 in Prostate Cancer Progression

by Nicolás Anselmino, Juan Bizzotto, Pablo Sanchis, Sofia Lage-Vickers, Emiliano Ortiz, Pia Valacco, Alejandra Paez, Estefania Labanca, Roberto Meiss, Nora Navone, Javier Cotignola, Elba Vazquez and Geraldine Gueron

Biomolecules 2020, 10(3), 467; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10030467 - 18 Mar 2020

Cited by 15 | Viewed by 3838

Abstract

Background: Prostate cancer (PCa) dissemination shows a tendency to develop in the bone, where heme oxygenase 1 (HO-1) plays a critical role in bone remodeling. Previously by LC/ESI-MSMS, we screened for HO-1 interacting proteins and identified annexin 2 (ANXA2). The aim of this study was to analyze the relevance of ANXA2/HO-1 in PCa and bone metastasis. Methods: We assessed ANXA2 levels using a co-culture transwell system of PC3 cells (pre-treated or not with hemin, an HO-1 specific inducer) and the pre-osteoclastic Raw264.7 cell line. Results: Under co-culture conditions, ANXA2 mRNA levels were significantly modulated in both cell lines. Immunofluorescence analysis unveiled a clear ANXA2 reduction in cell membrane immunostaining for Raw264.7 under the same conditions. This effect was supported by the detection of a decrease in Ca²⁺ concentration in the conditioned medium. HO-1 induction in tumor cells prevented both, the ANXA2 intracellular relocation and the decrease in Ca²⁺ concentration. Further, secretome analysis revealed urokinase (uPA) as a key player in the communication between osteoclast progenitors and PC3 cells. To assess the clinical significance of ANXA2/HO-1, we performed a bioinformatics analysis and identified that low expression of each gene strongly associated with poor prognosis in PCa regardless of the clinico-pathological parameters assessed. Further, these genes appear to behave in a dependent manner. Conclusions: ANXA2/HO-1 rises as a critical axis in PCa. Full article

(This article belongs to the Special Issue Therapeutic Significance of Heme Oxygenase Induction or Inhibition)

► Show Figures

Figure 1

14 pages, 2222 KiB

Open AccessArticle

Biliverdin Reductase A (BVRA) Knockout in Adipocytes Induces Hypertrophy and Reduces Mitochondria in White Fat of Obese Mice

by David E. Stec, Darren M. Gordon, Andrea L. Nestor-Kalinoski, Matthew C. Donald, Zachary L. Mitchell, Justin F. Creeden and Terry D. Hinds, Jr.

Biomolecules 2020, 10(3), 387; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10030387 - 02 Mar 2020

Cited by 38 | Viewed by 3695

Abstract

Biliverdin reductase (BVR) is an enzymatic and signaling protein that has multifaceted roles in physiological systems. Despite the wealth of knowledge about BVR, no data exist regarding its actions in adipocytes. Here, we generated an adipose-specific deletion of biliverdin reductase-A (BVRA) (Blvra^FatKO) in mice to determine the function of BVRA in adipocytes and how it may impact adipose tissue expansion. The Blvra^FatKO and littermate control (Blvra^Flox) mice were placed on a high-fat diet (HFD) for 12 weeks. Body weights were measured weekly and body composition, fasting blood glucose and insulin levels were quantitated at the end of the 12 weeks. The data showed that the percent body fat and body weights did not differ between the groups; however, Blvra^FatKO mice had significantly higher visceral fat as compared to the Blvra^Flox. The loss of adipocyte BVRA decreased the mitochondrial number in white adipose tissue (WAT), and increased inflammation and adipocyte size, but this was not observed in brown adipose tissue (BAT). There were genes significantly reduced in WAT that induce the browning effect such as Ppara and Adrb3, indicating that BVRA improves mitochondria function and beige-type white adipocytes. The Blvra^FatKO mice also had significantly higher fasting blood glucose levels and no changes in plasma insulin levels, which is indicative of decreased insulin signaling in WAT, as evidenced by reduced levels of phosphorylated AKT (pAKT) and Glut4 mRNA. These results demonstrate the essential role of BVRA in WAT in insulin signaling and adipocyte hypertrophy. Full article

(This article belongs to the Special Issue Therapeutic Significance of Heme Oxygenase Induction or Inhibition)

► Show Figures

Figure 1

15 pages, 2159 KiB

Open AccessArticle

Synthetically Lethal Interactions of Heme Oxygenase-1 and Fumarate Hydratase Genes

by Paulina Podkalicka, Olga Mucha, Szczepan Kruczek, Anna Biela, Kalina Andrysiak, Jacek Stępniewski, Maciej Mikulski, Michał Gałęzowski, Kamil Sitarz, Krzysztof Brzózka, Alicja Józkowicz, Józef Dulak and Agnieszka Łoboda

Biomolecules 2020, 10(1), 143; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10010143 - 16 Jan 2020

Cited by 12 | Viewed by 3866

Abstract

Elevated expression of heme oxygenase-1 (HO-1, encoded by HMOX1) is observed in various types of tumors. Hence, it is suggested that HO-1 may serve as a potential target in anticancer therapies. A novel approach to inhibit HO-1 is related to the synthetic lethality of this enzyme and fumarate hydratase (FH). In the current study, we aimed to validate the effect of genetic and pharmacological inhibition of HO-1 in cells isolated from patients suffering from hereditary leiomyomatosis and renal cell carcinoma (HLRCC)—an inherited cancer syndrome, caused by FH deficiency. Initially, we confirmed that UOK 262, UOK 268, and NCCFH1 cell lines are characterized by non-active FH enzyme, high expression of Nrf2 transcription factor-regulated genes, including HMOX1 and attenuated oxidative phosphorylation. Later, we demonstrated that shRNA-mediated genetic inhibition of HMOX1 resulted in diminished viability and proliferation of cancer cells. Chemical inhibition of HO activity using commercially available inhibitors, zinc and tin metalloporphyrins as well as recently described new imidazole-based compounds, especially SLV-11199, led to decreased cancer cell viability and clonogenic potential. In conclusion, the current study points out the possible relevance of HO-1 inhibition as a potential anti-cancer treatment in HLRCC. However, further studies revealing the molecular mechanisms are still needed. Full article

(This article belongs to the Special Issue Therapeutic Significance of Heme Oxygenase Induction or Inhibition)

► Show Figures

Figure 1

Review

Jump to: Research

23 pages, 5198 KiB

Open AccessReview

Heme Oxygenase-1 Signaling and Redox Homeostasis in Physiopathological Conditions

by Valeria Consoli, Valeria Sorrenti, Salvo Grosso and Luca Vanella

Biomolecules 2021, 11(4), 589; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11040589 - 16 Apr 2021

Cited by 95 | Viewed by 8889

Abstract

Heme-oxygenase is the enzyme responsible for degradation of endogenous iron protoporphyirin heme; it catalyzes the reaction’s rate-limiting step, resulting in the release of carbon monoxide (CO), ferrous ions, and biliverdin (BV), which is successively reduced in bilirubin (BR) by biliverdin reductase. Several studies have drawn attention to the controversial role of HO-1, the enzyme inducible isoform, pointing out its implications in cancer and other diseases development, but also underlining the importance of its antioxidant activity. The contribution of HO-1 in redox homeostasis leads to a relevant decrease in cells oxidative damage, which can be reconducted to its cytoprotective effects explicated alongside other endogenous mechanisms involving genes like TIGAR (TP53-induced glycolysis and apoptosis regulator), but also to the therapeutic functions of heme main transformation products, especially carbon monoxide (CO), which has been shown to be effective on GSH levels implementation sustaining body’s antioxidant response to oxidative stress. The aim of this review was to collect most of the knowledge on HO-1 from literature, analyzing different perspectives to try and put forward a hypothesis on revealing yet unknown HO-1-involved pathways that could be useful to promote development of new therapeutical strategies, and lay the foundation for further investigation to fully understand this important antioxidant system. Full article

(This article belongs to the Special Issue Therapeutic Significance of Heme Oxygenase Induction or Inhibition)

► Show Figures

Figure 1

16 pages, 5668 KiB

Open AccessReview

Heme-Oxygenase and Kidney Transplantation: A Potential for Target Therapy?

by Daniela Corona, Burcin Ekser, Rossella Gioco, Massimo Caruso, Chiara Schipa, Pierfrancesco Veroux, Alessia Giaquinta, Antonio Granata and Massimiliano Veroux

Biomolecules 2020, 10(6), 840; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10060840 - 30 May 2020

Cited by 11 | Viewed by 2919

Abstract

Kidney transplantation is a well-established therapy for patients with end-stage renal disease. While a significant improvement of short-term results has been achieved in the short-term, similar results were not reported in the long-term. Heme-oxygenase (HO) is the rate-limiting enzyme in heme catabolism, converting heme to iron, carbon monoxide, and biliverdin. Heme-oxygenase overexpression may be observed in all phases of transplant processes, including brain death, recipient management, and acute and chronic rejection. HO induction has been proved to provide a significant reduction of inflammatory response and a reduction of ischemia and reperfusion injury in organ transplantation, as well as providing a reduction of incidence of acute rejection. In this review, we will summarize data on HO and kidney transplantation, suggesting possible clinical applications in the near future to improve the long-term outcomes. Full article

(This article belongs to the Special Issue Therapeutic Significance of Heme Oxygenase Induction or Inhibition)

► Show Figures

Figure 1

9 pages, 884 KiB

Open AccessReview

Distinct Approaches of Raloxifene: Its Far-Reaching Beneficial Effects Implicating the HO-System

by Denise Börzsei, Renáta Szabó, Alexandra Hoffmann, Médea Veszelka, Imre Pávó, Zsolt Turcsán, Csaba Viczián, Krisztina Kupai, Csaba Varga and Anikó Pósa

Biomolecules 2020, 10(3), 375; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10030375 - 28 Feb 2020

Cited by 3 | Viewed by 6001

Abstract

Selective estrogen receptor modulators (SERMs) were discovered in the mid-1900s in connection with estrogen-related pathological conditions. They were developed to antagonize the adverse effects of estrogen and have been shown to be effective against postmenopausal disorders manifested by estrogen deficiency. Raloxifene (RAL), one of the most widely used SERMs, expresses estrogen-like effects on bones, while it is found to be an antagonist on breast and uterus. RAL has multiple beneficial effects throughout the body, including antioxidant and anti-inflammatory properties, because of which it gains particular attention. Additionally, previous studies have revealed that RAL is an efficient modulator of heme-oxygenase (HO) expression. HO, through its general activity, participates in comprehensive cell defense processes, thus the induction of HO by RAL administration indicates a major role in its therapeutic efficacy. In this review, we compile the current knowledge about the overall metabolic, neurocognitive, and cardiovascular effects of RAL involving the cytoprotective HO-system. Full article

(This article belongs to the Special Issue Therapeutic Significance of Heme Oxygenase Induction or Inhibition)

► Show Figures