Table of Contents

    Topic review

    Heme Oxygenase-1 in Central Nervous System Malignancies

    Subjects: Oncology
    View times: 155


    Central nervous system tumors are the most common pediatric solid tumors and account for 20–25% of all childhood malignancies. Several lines of evidence suggest that brain tumors show altered redox homeostasis that triggers the activation of various survival pathways, leading to disease progression and chemoresistance. Among these pathways, heme oxygenase-1 (HO-1) plays an important role. HO-1 catalyzes the enzymatic degradation of heme with the simultaneous release of carbon monoxide (CO), ferrous iron (Fe2+), and biliverdin. The biological effects of HO-1 in tumor cells have been shown to be cell-specific since, in some tumors, its upregulation promotes cell cycle arrest and cellular death, whereas, in other neoplasms, it is associated with tumor survival and progression. Since HO-1 overexpression is involved in the development and resistance of brain tumors to chemotherapy and radiotherapy, further researchers are needed to evaluate the possible use of HO -1 as strategy to improve the outcome of well-established therapeutic regimens.

    1. Introduction

    Malignancies of the central nervous system (CNS) include neoplasia developing in the brain, spinal cord, and sellar region [1][2]. Cancer cells display an altered metabolism, generally associated with an increase in reactive oxygen species (ROS) and altered redox balance resulting in cellular adaptation and proliferation [3]. Resistance to oxidative stress is one of the major adaptive advantages, allowing cancer cells to increase their metabolic rate and proliferation and to survive free radical damage. Such an adaptive response to high doses of ROS is also linked to genetic modifications, which directly or indirectly modulate ROS [4]. One of the master regulators of the antioxidant response is the nuclear factor erythroid 2 p45-related factor 2 (Nrf2) [5]. In general, the biochemical mechanism through which Nrf2 confers protection or resistance (in the case of cancer cells) provides that in response to toxic stimuli, Nrf2 is released from Keap1 in the cytosol and translocates to the nucleus where Nrf2 binds to antioxidant response elements (ARE). In this way, Nrf2 induces the expression of several antioxidant and detoxifying enzymes, i.e., γ-glutamate-cysteine ligase (γ-GCL), glutathione peroxidase (GPx), glutathione reductase (GR), NAD(P)H quinone dehydrogenase 1 (NQO1) [6], and heme oxygenase-1 (HO-1) [7][8][9].

    HO-1 is significantly increased in various human tumors both in basal condition and during different anticancer therapies contributing, together with its by-products, to the development of a resistant phenotype [10][11][12]. In this regard, it is important to take into due account the existence of a link among Nrf2, ROS, HO-1, and p53 as the main transcription factor playing a role during cell stress response, senescence, apoptosis, and carcinogenesis [13][14].

    The aim of the present review is to summarize the role of the HO system and its related proteins in brain cancer, also evaluating how these proteins can improve cancer prognosis and therapies [15]. 

    2. Biochemical Pathway of HO-1 in the Chemoresistance and Progression of Cancer

    Several studies show that HO-1 plays a protective role in chemoresistance and tumor progression through the induction of endoplasmic reticulum stress (ER stress), autophagy, activation of MAPK kinases, and through the increase of macrophage infiltration [16][17][18][19][20]. All these mechanisms offer the cell shelter from ROS damage and protein misfolding, making these cells much more resistant to damage [21]. Although it has been demonstrated that HO-1 overexpression is opposed to the therapeutic strategies implemented by proteasome inhibitors (PI), several studies demonstrated that the inhibition of HO activity significantly improved the proapoptotic effect of PI and resulted in a significant reduction of the dose of PI [16][22][23][24][25]. Indeed, the biological effect of HO-1 in cancer cells seemed to be involved both in cycle arrest and/or death and tumor survival and progression [26][27][28][29].

    3. Embryonal Tumors 

    3.1. Neuroblastoma

    Neuroblastoma (NB) is a pediatric solid cancer that often affects infants having an age between 0 to 4 years, with a median age of 23 months [30]. NBs present mass lesions in the neck, chest, abdomen, or pelvis and generally have a fatal prognosis [31][32]. In line with previous studies, our findings demonstrated that the silencing of HO-1 with a novel non-competitive inhibitor (LS1/71) makes SH-SY5Y NB cells more sensitive to carfilzomib (CFZ). Interestingly, CFZ treatment also induces the ERK and JNK signal transduction pathways, promoting cell proliferation and decreasing apoptosis rate. By contrast, LS1/71 was able to counteract these effects inhibiting ERK and JNK phosphorylation [24]. Furthermore, several studies demonstrated that miR-494, involved in HO-1 induction and cell responsive to oxidative stress, is expressed in NB cells [35]. Fest et al. tested the effect of HO-1 inhibition on NB progression in an in vivo model using A/J mice (H2-KK), which were treated with a sublethal subcutaneous dose of NXS2 cells and then ZnPPIX or sodium chloride were administered before surgery. HO-1 inhibition significantly reduced tumor growth, volume and liver metastasis, and induced apoptosis, decreasing Bcl2 and Bcl-Xl levels. Moreover, HO-1 inhibition stimulated immune cells to attack tumors promoting NXS2 cell lyse [38]. Conversely, several studies proposed HO-1 overexpression as a potential treatment for NB [39]. Accordingly, Hayama et al. demonstrated that through HO-1 induction, ferrearin-type neolignans cause apoptotic activity in human IMR-32, LA-N-1, NB-39, and SK-N- SH cell lines [40]. This effect is related to the CO produced by HO-1 that stimulates p38-MAPK and the JNK pathway, inducing BAX overexpression and apoptosis [41].

    3.2. Medulloblastoma

    Medulloblastoma is characterized by a significant burden of adverse outcomes in survivors [43]. Traditional genetic analysis suggests that isochromosome 17q, which results in the loss of 17p and the gain of 17q, represents the most common aberration in medulloblastomas [44][45][46]. Therapeutic strategies for medulloblastoma include a combination of surgery, radiotherapy, and chemotherapy [45][47]. Although HO-1 and HO-2 expression also showed no significant association with the different medulloblastoma subtypes, patients with high HO-1 and low HO-2 expression have better survival [48]. Moreover, HO-1 induction played a cytoprotective role against oxidative stress in DAOY cells exposed to the CO donor, suggesting HO-1 as a pharmacological target to enhance the efficacy of radiotherapy or chemotherapy [49][50].

    3.3. Meningiomas

    Meningioma is a common tumor of the central nervous system affecting the meninges, classified as Grade I, Grade II or “atypical”, and Grade III or “anaplastic” [51][52]. Genetic alterations, such as mutation or loss of the tumor suppressor gene neurofibromatosis 2 (NF2) on chromosome 22, constitute a leading cause of about 50% of meningiomas [53][54]. Current guidelines suggested surgery followed by radiotherapy as treatment of choice for intracranial meningiomas [55][56]. A study conducted by Takahashi et al. showed that HO-1 induction in rat KMY-J cells treated with TS-PDT (photodynamic therapy using talaporfin sodium) may contribute to resistance in meningioma cells, also attenuating its therapeutic effect. In particular, the mRNA expression level of Hmox1 was significantly increased, and this effect was counteracted when TS-PDT was combined with ZnPPIX, reducing meningioma cell viability [57].

    4. Diffuse Astrocytic and Oligodendroglial Tumors

    Gliomas, the most common group of primary brain tumors, include astrocytoma, oligodendroglioma, ependymoma and glioblastoma multiforme [15].

    4.1. Astocytoma

    Astrocytomas are most frequently caused by several chromosomal alterations, such as trisomy or polysomy of chromosome 7 [58][59]. Several lines of evidence suggested that HO-1 expression was involved in a worse prognosis of patients with Grades II and III astrocytomas, suggesting a pro-tumoral role of HO-1 in glioma progression [61].

    4.2. Oligodendroglioma

    Oligodendroglial tumors- oligodendrogliomas and oligoastrocytomas- are caused by the loss of heterozygosity (LOH) for chromosome arms 1p and 19q, which, in turn, derive from a non-balanced translocation t (1:19) (q10: p10) [62][63][64]. In high-grade gliomas, HO-1-expressing macrophages are higher in areas of solid tumor growth and decrease with increasing tumor distance, suggesting HO-1 accumulation as an indicator of neoangiogenesis in hypoxic areas [19][60]. Furthermore, HO-mediated heme degradation is involved in cellular CO production, inducing angiogenesis and neoplastic growth [65].

    4.3. Glioblastoma Multiforme

    Glioblastoma multiforme (GBM) is the most aggressive glioma grade which is divided into primary and secondary subgroups according to clinical characteristics [66], most frequently caused by the amplifications of the EGFR gene on chromosome 7, or mutations in the TP53 or in the retinoblastoma (RB1) pathways [67][68][69]. Both in vitro and in vivo studies have reported the role of Nrf2 in blocking the proliferation of human glioma, confirming its role in maintaining self-renewal in GSCs [70]. Moreover, HO-1 could be considered a potential target to counteract both initial and metastatic grade tumor growth [71]. In fact, when HO-1 is not expressed, the GBM cell invasion is inhibited [72]. The expression of HO-1 was also directly correlated with FoxP3, a marker of regulatory T-cells (Treg), and tumor growth. Indeed, Treg progressively infiltrates gliomas with an increase in brain tumor grade, determining an immunosuppressive environment [19][75]. Furthermore, GBM cells display a hypoxia-dependent differential modulation of biliverdin reductase (hBVR), increasing its expression and promoting cell survival under hypoxic states [76].

    5. HO-1 Inhibitors and Their Potential Use in the Treatment of CNS Malignancies

    The promising ways of HO-1 inhibition are founded on the genetic inhibition of HMOX1 by silencing RNA, on the use of metalloporphyrins (zinc protoporphyrin-ZnPPIX, tin protoporphyrin -SnPPIX, or chromium protoporphyrin-CrPPIX) and on the use of imidazole-based compounds [78]. Many of the inhibitors used in medical research, in addition to having a competitive interaction with HO-1, are non-specific because they also inhibit HO-2, the constitutive isoform. Moreover, imidazole-based compounds- also used in combination with other chemotherapeutic drugs- are characterized by a non-competitive binding mode showing high selectivity enzymatic activity inhibition of HO-1 with respect to HO-2 [79][80].

    6. Conclusion

    Table 1 reported a list of CNS tumors in which HO-1 is associated with an arrest in cell cycle division and subsequent cellular death or tumor survival and progression. In order to confirm the role of HO-1 as a possible molecular target for brain cancer, further research should be performed. In conclusion, understanding the mechanisms related to the HO-1 system may offer an additional target for future therapies and ameliorate oncological patients’ outcomes.

    Table 1. List of studies carried out in CNS tumors in which HO-1 expression was analyzed. The table shows tissues or cell lines, HO-1 expression, treatments, and outcomes with relevant references.


    Cell line

    HO-1 Expression




















    SH-SY5Y; SK-N-BE


    ↓ Viability



    A/J Mice (H2-Kk)


    ↓ Tumor growth, volume, and metastasis



    IMR-32; SK-H-SH






    IMR-32; LA-N-1;

    NB-39; SK-N-SH

    Ferrearin-type neolignans




    IMR-32; LA-N-1


    G2/M cell cycle arrest, apoptosis



    Resected specimens


    Protect tumor cells





    ↑ Viability





    ↓ Viability



    Sample from Biorepository


    Worse prognosis



    rat intracranially transplanted C6 gliomas and Resected specimens


    Macrophage infiltration, tumor growth and angiogenesis



    Primary GBM cell


    Inhibits GBM cell invasion













    Resected specimens


    ↑ Treg infiltration





    Autophagy and ferroptosis


    The entry is from 10.3390/jcm9051562


    1. Ostrom, Q.T.; Gittleman, H.; Truitt, G.; Boscia, A.; Kruchko, C.; Barnholtz-Sloan, J.S. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2011–2015. Neuro Oncol. 2018, 20, iv1–iv86, doi:10.1093/neuonc/noy131.
    2. Jensen, O.M.; Estève, J.; Møller, H.; Renard, H. Cancer in the European Community and its member states. Eur. J. Cancer 1990, 26, 1167–1256, doi:10.1016/0277-5379(90)90278-2.
    3. DeBerardinis, R.J.; Chandel, N.S. Fundamentals of cancer metabolism. Sci. Adv. 2016, 2, e1600200, doi:10.1126/sciadv.1600200.
    4. Reuter, S.; Gupta, S.C.; Chaturvedi, M.M.; Aggarwal, B.B. Oxidative stress, inflammation, and cancer: How are they linked? Free Radic. Biol. Med. 2010, 49, 1603–1616, doi:10.1016/j.freeradbiomed.2010.09.006.
    5. Kensler, T.W.; Wakabayashi, N.; Biswal, S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu. Rev. Pharmacol. Toxicol. 2007, 47, 89–116, doi:10.1146/annurev.pharmtox.46.120604.141046.
    6. Uruno, A.; Motohashi, H. The Keap1-Nrf2 system as an in vivo sensor for electrophiles. Nitric Oxide 2011, 25, 153–160, doi:10.1016/j.niox.2011.02.007.
    7. Kwak, M.K.; Wakabayashi, N.; Kensler, T.W. Chemoprevention through the Keap1-Nrf2 signaling pathway by phase 2 enzyme inducers. Mutat. Res. 2004, 555, 133–148, doi:10.1016/j.mrfmmm.2004.06.041.
    8. Barone, E.; Cenini, G.; Sultana, R.; Di Domenico, F.; Fiorini, A.; Perluigi, M.; Noel, T.; Wang, C.; Mancuso, C.; St Clair, D.K.; et al. Lack of p53 decreases basal oxidative stress levels in the brain through upregulation of thioredoxin-1, biliverdin reductase-A, manganese superoxide dismutase, and nuclear factor kappa-B. Antioxid. Redox Signal. 2012, 16, 1407–1420, doi:10.1089/ars.2011.4124.
    9. Barone, E.; Cenini, G.; Di Domenico, F.; Noel, T.; Wang, C.; Perluigi, M.; St Clair, D.K.; Butterfield, D.A. Basal brain oxidative and nitrative stress levels are finely regulated by the interplay between superoxide dismutase 2 and p53. J. Neurosci. Res. 2015, 93, 1728–1739, doi:10.1002/jnr.23627.
    10. Goodman, A.I.; Choudhury, M.; da Silva, J.L.; Schwartzman, M.L.; Abraham, N.G. Overexpression of the heme oxygenase gene in renal cell carcinoma. Proc. Soc. Exp. Biol. Med. 1997, 214, 54–61, doi:10.3181/00379727-214-44069.
    11. Berberat, P.O.; Dambrauskas, Z.; Gulbinas, A.; Giese, T.; Giese, N.; Kunzli, B.; Autschbach, F.; Meuer, S.; Buchler, M.W.; Friess, H. Inhibition of heme oxygenase-1 increases responsiveness of pancreatic cancer cells to anticancer treatment. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2005, 11, 3790–3798, doi:10.1158/1078-0432.CCR-04-2159.
    12. Barbagallo, I.; Parenti, R.; Zappalà, A.; Vanella, L.; Tibullo, D.; Pepe, F.; Onni, T.; Li Volti, G. Combined inhibition of Hsp90 and heme oxygenase-1 induces apoptosis and endoplasmic reticulum stress in melanoma. Acta Histochem. 2015, 117, 705–711, doi:10.1016/j.acthis.2015.09.005.
    13. Mijit, M.; Caracciolo, V.; Melillo, A.; Amicarelli, F.; Giordano, A. Role of p53 in the Regulation of Cellular Senescence. Biomolecules 2020, 10, 420, doi:10.3390/biom10030420.
    14. Beyfuss, K.; Hood, D.A. A systematic review of p53 regulation of oxidative stress in skeletal muscle. Redox Rep. 2018, 23, 100–117, doi:10.1080/13510002.2017.1416773.
    15. Louis, D.N.; Perry, A.; Reifenberger, G.; von Deimling, A.; Figarella-Branger, D.; Cavenee, W.K.; Ohgaki, H.; Wiestler, O.D.; Kleihues, P.; Ellison, D.W. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A summary. Acta Neuropathol. 2016, 131, 803–820, doi:10.1007/s00401-016-1545-1.
    16. Lee, G.H.; Kim, H.K.; Chae, S.W.; Kim, D.S.; Ha, K.C.; Cuddy, M.; Kress, C.; Reed, J.C.; Kim, H.R.; Chae, H.J. Bax inhibitor-1 regulates endoplasmic reticulum stress-associated reactive oxygen species and heme oxygenase-1 expression. J. Biol. Chem. 2007, 282, 21618–21628, doi:10.1074/jbc.M700053200.
    17. Vasconcellos, L.R.; Siqueira, M.S.; Moraes, R.; Carneiro, L.A.; Bozza, M.T.; Travassos, L.H. Heme Oxygenase-1 and Autophagy Linked for Cytoprotection. Curr. Pharm. Des. 2018, 24, 2311–2316, doi:10.2174/1381612824666180727100909.
    18. Pei, L.; Kong, Y.; Shao, C.; Yue, X.; Wang, Z.; Zhang, N. Heme oxygenase-1 induction mediates chemoresistance of breast cancer cells to pharmorubicin by promoting autophagy via PI3K/Akt pathway. J. Cell. Mol. Med. 2018, 22, 5311–5321, doi:10.1111/jcmm.13800.
    19. Nishie, A.; Ono, M.; Shono, T.; Fukushi, J.; Otsubo, M.; Onoue, H.; Ito, Y.; Inamura, T.; Ikezaki, K.; Fukui, M.; et al. Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas. Clin. Cancer Res. 1999, 5, 1107–1113.
    20. So, K.Y.; Kim, S.H.; Jung, K.T.; Lee, H.Y.; Oh, S.H. MAPK/JNK1 activation protects cells against cadmium-induced autophagic cell death via differential regulation of catalase and heme oxygenase-1 in oral cancer cells. Toxicol. Appl. Pharmacol. 2017, 332, 81–91, doi:10.1016/j.taap.2017.07.022.
    21. Johnson, D.E. The ubiquitin-proteasome system: Opportunities for therapeutic intervention in solid tumors. Endocr. Relat. Cancer 2015, 22, T1–T17, doi:10.1530/ERC-14-0005.
    22. Kim, Y.; Li, E.; Park, S. Insulin-like growth factor-1 inhibits 6-hydroxydopamine-mediated endoplasmic reticulum stress-induced apoptosis via regulation of heme oxygenase-1 and Nrf2 expression in PC12 cells. Int. J. Neurosci. 2012, 122, 641–649, doi:10.3109/00207454.2012.702821.
    23. Furfaro, A.L.; Piras, S.; Passalacqua, M.; Domenicotti, C.; Parodi, A.; Fenoglio, D.; Pronzato, M.A.; Marinari, U.M.; Moretta, L.; Traverso, N.; et al. HO-1 up-regulation: A key point in high-risk neuroblastoma resistance to bortezomib. Biochim. Biophys. Acta 2014, 1842, 613–622, doi:10.1016/j.bbadis.2013.12.008.
    24. Barbagallo, I.; Giallongo, C.; Volti, G.L.; Distefano, A.; Camiolo, G.; Raffaele, M.; Salerno, L.; Pittala, V.; Sorrenti, V.; Avola, R.; et al. Heme Oxygenase Inhibition Sensitizes Neuroblastoma Cells to Carfilzomib. Mol. Neurobiol. 2019, 56, 1451–1460, doi:10.1007/s12035-018-1133-6.
    25. Gulino, R.; Vicario, N.; Giunta, M.A.S.; Spoto, G.; Calabrese, G.; Vecchio, M.; Gulisano, M.; Leanza, G.; Parenti, R. Neuromuscular Plasticity in a Mouse Neurotoxic Model of Spinal Motoneuronal Loss. Int. J. Mol. Sci. 2019, 20, 1500, doi:10.3390/ijms20061500.
    26. Becker, J.C.; Fukui, H.; Imai, Y.; Sekikawa, A.; Kimura, T.; Yamagishi, H.; Yoshitake, N.; Pohle, T.; Domschke, W.; Fujimori, T. Colonic expression of heme oxygenase-1 is associated with a better long-term survival in patients with colorectal cancer. Scand. J. Gastroenterol. 2007, 42, 852–858, doi:10.1080/00365520701192383.
    27. Li Volti, G.; Tibullo, D.; Vanella, L.; Giallongo, C.; Di Raimondo, F.; Forte, S.; Di Rosa, M.; Signorelli, S.S.; Barbagallo, I. The Heme Oxygenase System in Hematological Malignancies. Antioxid. Redox Signal. 2017, 27, 363–377, doi:10.1089/ars.2016.6735.
    28. Nitti, M.; Piras, S.; Marinari, U.M.; Moretta, L.; Pronzato, M.A.; Furfaro, A.L. HO-1 Induction in Cancer Progression: A Matter of Cell Adaptation. Antioxidants 2017, 6, 29, doi:10.3390/antiox6020029.
    29. Salerno, L.; Romeo, G.; Modica, M.N.; Amata, E.; Sorrenti, V.; Barbagallo, I.; Pittala, V. Heme oxygenase-1: A new druggable target in the management of chronic and acute myeloid leukemia. Eur. J. Med. Chem. 2017, 142, 163–178, doi:10.1016/j.ejmech.2017.07.031.
    30. Park, J.R.; Eggert, A.; Caron, H. Neuroblastoma: Biology, prognosis, and treatment. Hematol. Oncol. Clin. N. Am. 2010, 24, 65–86, doi:10.1016/j.hoc.2009.11.011.
    31. Maris, J.M. Recent advances in neuroblastoma. N. Engl. J. Med. 2010, 362, 2202–2211, doi:10.1056/NEJMra0804577.
    32. Castel Sánchez, V.; Melero Moreno, C.; García-Miguel García-Rosados, P.; Navajas Gutiérrez, A.; Ruiz Jiménez, J.I.; Navarro Fos, S.; Garín Valle, J.C.; Galbe Sada, M. [Neuroblastoma in children under than 1 year of age]. An. Esp. Pediatr. 1997, 47, 584–590.
    33. Furfaro, A.L.; Piras, S.; Domenicotti, C.; Fenoglio, D.; De Luigi, A.; Salmona, M.; Moretta, L.; Marinari, U.M.; Pronzato, M.A.; Traverso, N.; et al. Role of Nrf2, HO-1 and GSH in Neuroblastoma Cell Resistance to Bortezomib. PLoS ONE 2016, 11, e0152465, doi:10.1371/journal.pone.0152465.
    34. Furfaro, A.L.; Macay, J.R.; Marengo, B.; Nitti, M.; Parodi, A.; Fenoglio, D.; Marinari, U.M.; Pronzato, M.A.; Domenicotti, C.; Traverso, N. Resistance of neuroblastoma GI-ME-N cell line to glutathione depletion involves Nrf2 and heme oxygenase-1. Free Radic. Biol. Med. 2012, 52, 488–496, doi:10.1016/j.freeradbiomed.2011.11.007.
    35. Piras, S.; Furfaro, A.L.; Caggiano, R.; Brondolo, L.; Garibaldi, S.; Ivaldo, C.; Marinari, U.M.; Pronzato, M.A.; Faraonio, R.; Nitti, M. microRNA-494 Favors HO-1 Expression in Neuroblastoma Cells Exposed to Oxidative Stress in a Bach1-Independent Way. Front. Oncol. 2018, 8, 199, doi:10.3389/fonc.2018.00199.
    36. Yao, P.L.; Chen, L.; Dobrzański, T.P.; Zhu, B.; Kang, B.H.; Müller, R.; Gonzalez, F.J.; Peters, J.M. Peroxisome proliferator-activated receptor-β/δ inhibits human neuroblastoma cell tumorigenesis by inducing p53- and SOX2-mediated cell differentiation. Mol. Carcinog. 2017, 56, 1472–1483, doi:10.1002/mc.22607.
    37. Piras, S.; Furfaro, A.L.; Brondolo, L.; Passalacqua, M.; Marinari, U.M.; Pronzato, M.A.; Nitti, M. Differentiation impairs Bach1 dependent HO-1 activation and increases sensitivity to oxidative stress in SH-SY5Y neuroblastoma cells. Sci. Rep. 2017, 7, 7568, doi:10.1038/s41598-017-08095-7.
    38. Fest, S.; Soldati, R.; Christiansen, N.M.; Zenclussen, M.L.; Kilz, J.; Berger, E.; Starke, S.; Lode, H.N.; Engel, C.; Zenclussen, A.C.; et al. Targeting of heme oxygenase-1 as a novel immune regulator of neuroblastoma. Int. J. Cancer 2016, 138, 2030–2042, doi:10.1002/ijc.29933.
    39. Hassannia, B.; Wiernicki, B.; Ingold, I.; Qu, F.; Van Herck, S.; Tyurina, Y.Y.; Bayır, H.; Abhari, B.A.; Angeli, J.P.F.; Choi, S.M.; et al. Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. J. Clin. Investig. 2018, 128, 3341–3355, doi:10.1172/JCI99032.
    40. Hayama, T.; Tabata, K.; Uchiyama, T.; Fujimoto, Y.; Suzuki, T. Ferrearin C induces apoptosis via heme oxygenase-1 (HO-1) induction in neuroblastoma. J. Nat. Med. 2011, 65, 431–439, doi:10.1007/s11418-011-0514-1.
    41. Kim, B.J.; Ryu, S.W.; Song, B.J. JNK- and p38 kinase-mediated phosphorylation of Bax leads to its activation and mitochondrial translocation and to apoptosis of human hepatoma HepG2 cells. J. Biol. Chem. 2006, 281, 21256–21265, doi:10.1074/jbc.M510644200.
    42. Kitano, T.; Yoda, H.; Tabata, K.; Miura, M.; Toriyama, M.; Motohashi, S.; Suzuki, T. Vitamin K3 analogs induce selective tumor cytotoxicity in neuroblastoma. Biol. Pharm. Bull. 2012, 35, 617–623, doi:10.1248/bpb.35.617.
    43. Aref, D.; Croul, S. Medulloblastoma: Recurrence and metastasis. CNS Oncol. 2013, 2, 377–385, doi:10.2217/cns.13.30.
    44. Kool, M.; Korshunov, A.; Remke, M.; Jones, D.T.; Schlanstein, M.; Northcott, P.A.; Cho, Y.J.; Koster, J.; Schouten-van Meeteren, A.; van Vuurden, D.; et al. Molecular subgroups of medulloblastoma: An international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol. 2012, 123, 473–484, doi:10.1007/s00401-012-0958-8.
    45. Millard, N.E.; De Braganca, K.C. Medulloblastoma. J. Child Neurol. 2016, 31, 1341–1353, doi:10.1177/0883073815600866.
    46. Griffin, C.A.; Hawkins, A.L.; Packer, R.J.; Rorke, L.B.; Emanuel, B.S. Chromosome abnormalities in pediatric brain tumors. Cancer Res. 1988, 48, 175–180.
    47. Rossi, A.; Caracciolo, V.; Russo, G.; Reiss, K.; Giordano, A. Medulloblastoma: From molecular pathology to therapy. Clin. Cancer Res. 2008, 14, 971–976, doi:10.1158/1078-0432.CCR-07-2072.
    48. Li, T.; Yu, L. Clinicopathological significance of HO-1 and HO-2 expression in medulloblastoma. In Advanced Materials Research: 2014; Trans Tech Publications, Ltd.; Volume 881–883; pp. 469–472.
    49. Al-Owais, M.M.; Scragg, J.L.; Dallas, M.L.; Boycott, H.E.; Warburton, P.; Chakrabarty, A.; Boyle, J.P.; Peers, C. Carbon monoxide mediates the anti-apoptotic effects of heme oxygenase-1 in medulloblastoma DAOY cells via K+ channel inhibition. J. Biol. Chem. 2012, 287, 24754–24764, doi:10.1074/jbc.M112.357012.
    50. Al-Owais, M.M.; Dallas, M.L.; Boyle, J.P.; Scragg, J.L.; Peers, C. Heme Oxygenase-1 Influences Apoptosis via CO-mediated Inhibition of K+ Channels. Adv. Exp. Med. Biol. 2015, 860, 343–351, doi:10.1007/978-3-319-18440-1_39.
    51. Buerki, R.A.; Horbinski, C.M.; Kruser, T.; Horowitz, P.M.; James, C.D.; Lukas, R.V. An overview of meningiomas. Future Oncol. 2018, 14, 2161–2177, doi:10.2217/fon-2018-0006.
    52. Dumanski, J.P.; Carlbom, E.; Collins, V.P.; Nordenskjöld, M. Deletion mapping of a locus on human chromosome 22 involved in the oncogenesis of meningioma. Proc. Natl. Acad. Sci. USA 1987, 84, 9275–9279, doi:10.1073/pnas.84.24.9275.
    53. Ruttledge, M.H.; Sarrazin, J.; Rangaratnam, S.; Phelan, C.M.; Twist, E.; Merel, P.; Delattre, O.; Thomas, G.; Nordenskjöld, M.; Collins, V.P. Evidence for the complete inactivation of the NF2 gene in the majority of sporadic meningiomas. Nat. Genet. 1994, 6, 180–184, doi:10.1038/ng0294-180.
    54. Rouleau, G.A.; Merel, P.; Lutchman, M.; Sanson, M.; Zucman, J.; Marineau, C.; Hoang-Xuan, K.; Demczuk, S.; Desmaze, C.; Plougastel, B. Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature 1993, 363, 515–521, doi:10.1038/363515a0.
    55. Simpson, D. The recurrence of intracranial meningiomas after surgical treatment. J. Neurol. Neurosurg. Psychiatry 1957, 20, 22–39, doi:10.1136/jnnp.20.1.22.
    56. Euskirchen, P.; Peyre, M. Management of meningioma. Presse Med. 2018, 47, e245–e252, doi:10.1016/j.lpm.2018.05.016.
    57. Takahashi, T.; Suzuki, S.; Misawa, S.; Akimoto, J.; Shinoda, Y.; Fujiwara, Y. Photodynamic therapy using talaporfin sodium induces heme oxygenase-1 expression in rat malignant meningioma KMY-J cells. J. Toxicol. Sci. 2018, 43, 353–358, doi:10.2131/jts.43.353.
    58. Wessels, P.H.; Twijnstra, A.; Kessels, A.G.; Krijne-Kubat, B.; Theunissen, P.H.; Ummelen, M.I.; Ramaekers, F.C.; Hopman, A.H. Gain of chromosome 7, as detected by in situ hybridization, strongly correlates with shorter survival in astrocytoma grade 2. Genes Chromosomes Cancer 2002, 33, 279–284.
    59. Reifenberger, G.; Collins, V.P. Pathology and molecular genetics of astrocytic gliomas. J. Mol. Med. 2004, 82, 656–670, doi:10.1007/s00109-004-0564-x.
    60. Deininger, M.H.; Meyermann, R.; Trautmann, K.; Duffner, F.; Grote, E.H.; Wickboldt, J.; Schluesener, H.J. Heme oxygenase (HO)-1 expressing macrophages/microglial cells accumulate during oligodendroglioma progression. Brain Res. 2000, 882, 1–8, doi:10.1016/s0006-8993(00)02594-4.
    61. Gandini, N.A.; Fermento, M.E.; Salomón, D.G.; Obiol, D.J.; Andrés, N.C.; Zenklusen, J.C.; Arevalo, J.; Blasco, J.; López Romero, A.; Facchinetti, M.M.; et al. Heme oxygenase-1 expression in human gliomas and its correlation with poor prognosis in patients with astrocytoma. Tumour Biol. 2014, 35, 2803–2815, doi:10.1007/s13277-013-1373-z.
    62. Wesseling, P.; van den Bent, M.; Perry, A. Oligodendroglioma: Pathology, molecular mechanisms and markers. Acta Neuropathol. 2015, 129, 809–827, doi:10.1007/s00401-015-1424-1.
    63. van den Bent, M.J.; Chang, S.M. Grade II and III Oligodendroglioma and Astrocytoma. Neurol. Clin. 2018, 36, 467–484, doi:10.1016/j.ncl.2018.04.005.
    64. Griffin, C.A.; Burger, P.; Morsberger, L.; Yonescu, R.; Swierczynski, S.; Weingart, J.D.; Murphy, K.M. Identification of der(1;19)(q10;p10) in five oligodendrogliomas suggests mechanism of concurrent 1p and 19q loss. J. Neuropathol. Exp. Neurol. 2006, 65, 988–994, doi:10.1097/01.jnen.0000235122.98052.8f.
    65. Kuroki, M.; Voest, E.E.; Amano, S.; Beerepoot, L.V.; Takashima, S.; Tolentino, M.; Kim, R.Y.; Rohan, R.M.; Colby, K.A.; Yeo, K.T.; et al. Reactive oxygen intermediates increase vascular endothelial growth factor expression in vitro and in vivo. J. Clin. Investig. 1996, 98, 1667–1675, doi:10.1172/JCI118962.
    66. Furnari, F.B.; Fenton, T.; Bachoo, R.M.; Mukasa, A.; Stommel, J.M.; Stegh, A.; Hahn, W.C.; Ligon, K.L.; Louis, D.N.; Brennan, C.; et al. Malignant astrocytic glioma: Genetics, biology, and paths to treatment. Genes Dev. 2007, 21, 2683–2710, doi:10.1101/gad.1596707.
    67. Shinojima, N.; Tada, K.; Shiraishi, S.; Kamiryo, T.; Kochi, M.; Nakamura, H.; Makino, K.; Saya, H.; Hirano, H.; Kuratsu, J.; et al. Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme. Cancer Res. 2003, 63, 6962–6970.
    68. Fulci, G.; Labuhn, M.; Maier, D.; Lachat, Y.; Hausmann, O.; Hegi, M.E.; Janzer, R.C.; Merlo, A.; Van Meir, E.G. p53 gene mutation and ink4a-arf deletion appear to be two mutually exclusive events in human glioblastoma. Oncogene 2000, 19, 3816–3822, doi:10.1038/sj.onc.1203700.
    69. Ishii, N.; Maier, D.; Merlo, A.; Tada, M.; Sawamura, Y.; Diserens, A.C.; Van Meir, E.G. Frequent co-alterations of TP53, p16/CDKN2A, p14ARF, PTEN tumor suppressor genes in human glioma cell lines. Brain Pathol. 1999, 9, 469–479.
    70. Zhu, J.; Wang, H.; Sun, Q.; Ji, X.; Zhu, L.; Cong, Z.; Zhou, Y.; Liu, H.; Zhou, M. Nrf2 is required to maintain the self-renewal of glioma stem cells. BMC Cancer 2013, 13, 380, doi:10.1186/1471-2407-13-380.
    71. Dey, S.; Sayers, C.M.; Verginadis, I.I.; Lehman, S.L.; Cheng, Y.; Cerniglia, G.J.; Tuttle, S.W.; Feldman, M.D.; Zhang, P.J.; Fuchs, S.Y.; et al. ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis. J. Clin. Investig. 2015, 125, 2592–2608, doi:10.1172/JCI78031.
    72. Ghosh, D.; Ulasov, I.V.; Chen, L.; Harkins, L.E.; Wallenborg, K.; Hothi, P.; Rostad, S.; Hood, L.; Cobbs, C.S. TGFβ-Responsive HMOX1 Expression Is Associated with Stemness and Invasion in Glioblastoma Multiforme. Stem Cells 2016, 34, 2276–2289, doi:10.1002/stem.2411.
    73. Pan, H.; Wang, H.; Zhu, L.; Wang, X.; Cong, Z.; Sun, K.; Fan, Y. The involvement of Nrf2-ARE pathway in regulation of apoptosis in human glioblastoma cell U251. Neurol. Res. 2013, 35, 71–78, doi:10.1179/1743132812Y.0000000094.
    74. Liu, Y.; Liang, Y.; Zheng, T.; Yang, G.; Zhang, X.; Sun, Z.; Shi, C.; Zhao, S. Inhibition of heme oxygenase-1 enhances anti-cancer effects of arsenic trioxide on glioma cells. J. Neurooncol. 2011, 104, 449–458, doi:10.1007/s11060-010-0513-1.
    75. El Andaloussi, A.; Lesniak, M.S. CD4+ CD25+ FoxP3+ T-cell infiltration and heme oxygenase-1 expression correlate with tumor grade in human gliomas. J. Neurooncol. 2007, 83, 145–152, doi:10.1007/s11060-006-9314-y.
    76. Kim, S.S.; Seong, S.; Lim, S.H.; Kim, S.Y. Biliverdin reductase plays a crucial role in hypoxia-induced chemoresistance in human glioblastoma. Biochem. Biophys. Res. Commun. 2013, 440, 658–663, doi:10.1016/j.bbrc.2013.09.120.
    77. Kyani, A.; Tamura, S.; Yang, S.; Shergalis, A.; Samanta, S.; Kuang, Y.; Ljungman, M.; Neamati, N. Discovery and Mechanistic Elucidation of a Class of Protein Disulfide Isomerase Inhibitors for the Treatment of Glioblastoma. ChemMedChem 2018, 13, 164–177, doi:10.1002/cmdc.201700629.
    78. Podkalicka, P.; Mucha, O.; Jozkowicz, A.; Dulak, J.; Loboda, A. Heme oxygenase inhibition in cancers: Possible tools and targets. Contemp. Oncol. 2018, 22, 23–32, doi:10.5114/wo.2018.73879.
    79. Sorrenti, V.; Guccione, S.; Di Giacomo, C.; Modica, M.N.; Pittala, V.; Acquaviva, R.; Basile, L.; Pappalardo, M.; Salerno, L. Evaluation of imidazole-based compounds as heme oxygenase-1 inhibitors. Chem. Biol. Drug Des. 2012, 80, 876–886, doi:10.1111/cbdd.12015.
    80. Salerno, L.; Amata, E.; Romeo, G.; Marrazzo, A.; Prezzavento, O.; Floresta, G.; Sorrenti, V.; Barbagallo, I.; Rescifina, A.; Pittala, V. Potholing of the hydrophobic heme oxygenase-1 western region for the search of potent and selective imidazole-based inhibitors. Eur. J. Med. Chem. 2018, 148, 54–62, doi:10.1016/j.ejmech.2018.02.007.