Nitric oxide-elicited resistance to anti-glioblastoma photodynamic therapy

Abstract

Glioblastoma multiforme is a highly aggressive primary brain malignancy that resists most conventional chemo- and radiotherapeutic interventions. Nitric oxide (NO), a short lived free radical molecule produced by inducible NO synthase (iNOS) in glioblastomas and other tumors, is known to play a key role in tumor persistence, progression, and chemo/radiotherapy resistance. Site-specific and minimally invasive photodynamic therapy (PDT), based on oxidative damage resulting from non-ionizing photoactivation of a sensitizing agent, is highly effective against glioblastoma, but resistance also exists in this case. Studies in the authors’ laboratory have shown that much of the latter is mediated by iNOS/NO. For example, when glioblastoma U87 or U251 cells sensitized in mitochondria with 5-aminolevulinic acid -induced protoporphyrin IX were exposed to a moderate dose of visible light, the observed apoptosis was strongly enhanced by an iNOS activity inhibitor or NO scavenger, indicating that iNOS/NO had increased cell resistance to photokilling. Moreover, cells that survived the photochallenge proliferated, migrated, and invaded more aggressively than controls, and these responses were also driven predominantly by iNOS/NO. Photostress-upregulated iNOS rather than basal enzyme was found to be responsible for all the negative effects described. Recognition of NO-mediated hyper-resistance/hyper-aggression in PDT-stressed glioblastoma has stimulated interest in how these responses can be prevented or at least minimized by pharmacologic adjuvants such as inhibitors of iNOS activity or transcription. Recent developments along these lines and their clinical potential for improving anti-glioblastoma PDT are discussed.

Keywords

Glioblastoma / photodynamic therapy / nitric oxide / inducible nitric oxide synthase / nitric oxide-mediated photodynamic therapy resistance / anti-nitric oxide adjuvants

References

[1] Behin A,Carpentier AF.Primary brain tumours in adults..Lancet2003;361:323-31

[2] Wen PY.Malignant gliomas in adults..New England J Med2008;359:492-507

[3] Miranda A,Sousa J,Vitorino C.Breaching barriers in glioblastoma. Part 1: molecular pathways and novel treatment approaches..Int J Pharm2017;531:372-88

[4] Stewart DJ,Eapen L,Goel R.Cisplatin and radiation in the treatment of tumors of the central nervous system: pharmacological considerations and results of early studies..Int J Radiat Oncol Biol Phys1994;28:531-42

[5] Yang LJ,Lin ZX.Temozolomide and radiotherapy for newly diagnosed glioblastoma multiforme: a systematic review..Cancer Investig2014;32:31-6

[6] Bouzinab K,Zhang J,Moody CJ.In search of effective therapies to overcome resistance to temozolomide in brain tumors..Cancer Drug Resist2019;2:1018-31

[7] Quirk BJ,Donlon S,Mang TS.Photodynamic therapy (PDT) for brain tumors: where do we stand?.Photodiagn Photodyn Ther2012;12:530-44

[8] Bechet D,Guillemin F.Photodynamic therapy of malignant brain tumours: a complementary approach to conventional therapies..Cancer Treat Rev2014;40:229-41

[9] Cramer SW.Photodynamic therapy for the treatment of glioblastoma..Front Surg2020;6:81 PMCID:PMC6985206

[10] Girotti AW.Upregulation of nitric oxide in tumor cells as a negative adaptation to photodynamic therapy..Lasers in Surg Med2018;50:590-8

[11] Alderton WK,Knowles RG.Nitric oxide synthases: structure, function and inhibition..Biochem J2001;357:593-615 PMCID:PMC1221991

[12] Lechner M,Rieder J.Inducible nitric oxide synthase (iNOS) in tumor biology: two sides of the same coin..Sem Cancer biol2005;5:277-89

[13] Ridnour LA,Donzelli S,Roberts DD.The biphasic nature of nitric oxide responses in tumor biology..Antiox Redox Signal2006;8:1329-37

[14] Vannini F,Nath N.The dual role of iNOS in cancer..Redox Biol2015;6:334-43 PMCID:PMC4565017

[15] Eyler CE,Yan K,Chandler-Militello D.Glioma stem cell proliferation and tumor growth are promoted by nitric oxide synthase-2..Cell2011;146:53-66 PMCID:PMC3144745

[16] Jahani A.iNOS: a potential therapeutic target for malignant glioma..Curr Mol Med2013;13:1241-9 PMCID:PMC4266467

[17] Tran AN,Walker K.NOS expression and NO function in glioma and implications for patient therapies..Antiox Redox Signal2017;26:986-99 PMCID:PMC5467121

[18] Switzer CH,Ridnour LA,Vitek MP.Nitric oxide and protein phosphatase 2A provide novel therapeutic opportunities in ER-negative breast cancer..Trends Pharmacol Sci2011;32:644-51 PMCID:PMC3380363

[19] Thomas DD.S-nitrosation: current concepts and new developments..Antiox redox signal2012;17:934-6 PMCID:PMC3411337

[20] Broniowska KA.The chemical biology of S-nitrosothiols..Antiox Redox Signal2012;17:969-80 PMCID:PMC3411335

[21] Saleem W,Mobaraki A,Noda S.Reduction of nitric oxide level enhances the radiosensitivity of hypoxic non-small cell lung cancer..Cancer Sci2011;102:2150-6

[22] Matsunaga T,Yomokuni T,Morikawa Y.Nitric oxide confers cisplatin resistance in human lung cancer cells through upregulation of aldo-keto reductase 1B10 and proteasome..Free Radic Biol Med2014;48:1371-85

[23] Dougherty TJ,Fiel R,Boyle DG.Photoirradiation therapy II: cure of animal tumors with hematoporphyrin and light..J Natl cancer Inst1975;55:115-21

[24] Dougherty TJ,Henderson BW,Kessel D.Photodynamic therapy..J Natl Cancer Inst1998;90:889-905 PMCID:PMC4592754

[25] Agostinis P,Cengel KA,Girotti AW.Photodynamic therapy of cancer: an update..CA Cancer J Clin2011;61:250-81 PMCID:PMC3209659

[26] Falk-Mahapatra R.Photodynamic therapy and immunity: an update..Photochem Photobiol2020;96:550-9 PMCID:PMC7293553

[27] Kennedy JC.Endogenous protoporphyrin IX, a clinically useful photosensitizer for photodynamic therapy..J Photochem Photobiol B1992;14:275-92

[28] Peng Q,Moan J,Nesland JM.5-Aminolevulinic acid-based photodynamic therapy: principles and experimental research..Photochem Photobiol1997;65:235-51

[29] Mahmoudi K,Bouras A,Stepp H.5-aminolevulinic acid photodynamic therapy for the treatment of high-grade gliomas..J Neuro-Oncol2019;141:595-607 PMCID:PMC6538286

[30] Yang X,Kraus D.Aminolevulinic acid-based tumor detection and therapy: molecular mechanisms and strategies for enhancement..Int J Mol Sci2015;16:25865-80 PMCID:PMC4632830

[31] Gilissen MJ,Star WM,Sluiter W.Effect of photodynamic therapy on the endothelium-dependent relaxation of isolated rat aortas..Cancer Res1993;53:2548-52

[32] Gupta S,Mukhtar H.Involvement of nitric oxide during phthalocyanine (Pc4) photodynamic therapy-mediated apoptosis..Cancer Res1998;58:1785-8

[33] Henderson BW,Vaughan LA.Potentiation of photodynamic therapy antitumor activity in mice by nitric oxide synthase inhibitors is fluence rate-dependent..Photochem Photobiol1999;70:64-71

[34] Korbelik M,Shibuya H,Stratford MR.Nitric oxide production by tumor tissue: impact on the response to photodynamic therapy..Br J Cancer2000;82:1835-43 PMCID:PMC2363231

[35] Reeves KL,Brown NJ.The role of nitric oxide in the treatment of tumors with aminolaevulinic acid-induced photodynamic therapy..J Photochem Photobiol B2010;101:224-32

[36] Bhowmick R.Signaling events in apoptotic photokilling of 5-aminolevulinic acid-treated tumor cells: inhibitory effects of nitric oxide..Free Radic Biol Med2009;47:731-40 PMCID:PMC2761093

[37] Bhowmick R.Cytoprotective induction of nitric oxide synthase in a cellular model of 5-aminolevulinic-based photodynamic therapy..Free Radic Biol Med2010;48:1296-301 PMCID:PMC2856718

[38] Bhowmick R.Rapid upregulation of cytoprotective nitric oxide in breast tumor cels subjected to a photodynamic therapy-like oxidative challenge..Photochem Photobiol2011;87:378-86 PMCID:PMC3048913

[39] Bhowmick R.Pro-survival and pro-growth effects of stress-induced nitric oxide in a prostate cancer photodynamic therapy model..Cancer Lett2014;343:115-22 PMCID:PMC3874260

[40] Fahey JM.Accelerated migration and invasion of prostate cancer cells after a photodynamic therapy-like challenge: role of nitric oxide..Nitric Oxide2015;49:47-55 PMCID:PMC4545398

[41] Fahey JM.Nitric oxide-mediated resistance to photodynamic therapy in a human breast tumor xenograft model: improved outcome with NOS2 inhibitors..Nitric Oxide2017;62:52-61 PMCID:PMC5215003

[42] Fahey JM,Korytowski W,Girotti AW.Antagonistic effects of endogenous nitric oxide in a glioblastoma photodynamic therapy model..Photochem Photobiol2016;92:842-53 PMCID:PMC5161550

[43] Kumar B,Khandrika L,Koul HK.Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype..Cancer Res2008;68:1777-85

[44] Stamenkovic I.Matrix metalloproteinases in tumor invasion and metastasis..Semin Cancer Biol2000;10:415-33

[45] Kachra Z,Delbecchi L,Berthelet F.Expression of matrix metalloproteinases and their inhibitors in human brain tumors..Clin Exp Metastasis1999;17:555-66

[46] Veeravalli KK.MMP-9 and UPAR regulated glioma cell migration..Cell Adh Migr2012;6:509-12 PMCID:PMC3547895

[47] O’Sullivan S,Ledwidge M,Gilmer JF.Nitric oxide-matrix metalloproteinase-9 interactions: biology and pharmacological significance..Biochim Biophys Acta2014;1843:603-17

[48] Fahey JM.Upstream signaling events leading ot elevated production of pro-survival nitric oxide in photodynamically-challenged glioblastoma cells..Free Radic Biol Med2019;137:37-45 PMCID:PMC6526063

[49] Huang B,Zhow MM,Chen LF.Brd4 coactivates transcriptional activation of NF-κB via specific binding of acetylated RelA..Mol Cell Biol2009;29:1375-87 PMCID:PMC2643823

[50] Filippakopoulos P.Targeting bromodomains: epigenetic readers of lysine acetylation..Nat Rev Drug Discov2014;13:337-56

[51] Shu S.BET bromodomain proteins as cancer therapeutic targets..Cold Spring Harb Symp Quant Biol2016;81:123-9

[52] Wienerroither S,Rosebrock F,Bradner J.Regulation of NO synthesis, local inflammation and innate immunity to pathogens by BET family proteins..Mol Cell Biol2014;34:415-27 PMCID:PMC3911514

[53] Kleszcz R,Baer-Dubowska W.Targeting aberrant cancer metabolism: the role of sirtuins..Pharmacol Rep2015;67:1068-80

[54] Lin Z.The roles of SIRT1 in cancer..Genes Cancer2013;4:97-104 PMCID:PMC3764469

[55] Fionda C,Santoni A.Immunoregulatory and effector activities of nitric oxide and reactive nitrogen species in cancer..Curr Med Chem2016;23:2618-36

[56] Matsumoto H,Hatashita M,Shioura H.Induction of radioresistance by a nitric oxide-mediated bystander effect..Radiat Res2001;155:387-96

[57] Matsumoto H,Ohnishi T.Nitric oxide radicals choreograph a radioadaptive response..Cancer Res2007;67:8574-9

[58] Bazak J,Wawak K,Girotti AW.Enhanced aggressiveness of bystander cells in an anti-tumor photodynamic therapy model: role of nitric oxide produced by targeted cells..Free Radic Biol Med2017;102:111-21

[59] Bazak J,Girotti AW.Bystander effects of nitric oxide in cellular models of anti-tumor photodynamic therapy..Cancers (Basel)2019;11:1674 PMCID:PMC6895962

[60] Hansel TT,Donnelly LE,Currie MG.A selective inhibitor of inducible nitric oxide synthase inhibits exhaled breath nitric oxide in healthy volunteers and asthmatics..FASEB J2003;17:1298-317

[61] Singh D,Knowles RG,Woodcock A.Selective inducible nitric oxide synthase inhibition has no effect on allergen challenge in asthma..Am J Respir Crit Care Med2007;176:988-93

[62] Filippakopoulos P,Picaud S,Smith WB.Selective inhibition of BET bromodomains..Nature2010;468:1067-73 PMCID:PMC3010259

[63] Fahey JM,Smith BC.Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1..J Biol Chem2018;293:5345-459 PMCID:PMC5892570

[64] Lam FC,Wyckoff J,Hwang MK.Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles..Nat Commun2018;9:1991 PMCID:PMC5959860