Evaluation of hypoxia inducible factor targeting pharmacological drugs as antileishmanial agents
|
摘要
Objective:To evaluate whether hypoxia inducible factor(HIF-1α) targeting pharmacological drugs,echinomycin,resveratrol and CdCl_2 which inhibit HIF-1α stimulation,and mimosine,which enhances the stability of HIF-1α present antileishmanial properties.Methods:The leishmanicidal effect of drugs was evaluated in mouse macrophages and Balb/c mouse model for cutaneous leishmaniosis.Results:Resveratrol and CdCl_2 reduced the parasite load [IC50,(27.3±2.25) μM and(24.8±0.95) μM,respectively].The IC50 value of echinomycin was(22.7±7.36) nM and mimosine did not alter the parasite load in primary macrophages.The macrophage viability IC50 values for resveratrol,echinomycin and CdCl_2 and mimosine were >40 μM,>100 nM,> 200 μM and>2 000 μM,respectively.In vivo no differences between cutaneous lesions from control,resveratrol-and echinomycin-treated Balb/c mice were detected.Conclusions:Resveratrol,echinomycin and CdCl_2 reduce parasite survival in vitro.The HIF-1α targeting pharmacological drugs require further study to more fully determine their anti-Leishmania potential and their role in therapeutic strategies.
Objective:To evaluate whether hypoxia inducible factor(HIF-1α) targeting pharmacological drugs,echinomycin,resveratrol and CdCl_2 which inhibit HIF-1α stimulation,and mimosine,which enhances the stability of HIF-1α present antileishmanial properties.Methods:The leishmanicidal effect of drugs was evaluated in mouse macrophages and Balb/c mouse model for cutaneous leishmaniosis.Results:Resveratrol and CdCl_2 reduced the parasite load [IC50,(27.3±2.25) μM and(24.8±0.95) μM,respectively].The IC50 value of echinomycin was(22.7±7.36) nM and mimosine did not alter the parasite load in primary macrophages.The macrophage viability IC50 values for resveratrol,echinomycin and CdCl_2 and mimosine were >40 μM,>100 nM,> 200 μM and>2 000 μM,respectively.In vivo no differences between cutaneous lesions from control,resveratrol-and echinomycin-treated Balb/c mice were detected.Conclusions:Resveratrol,echinomycin and CdCl_2 reduce parasite survival in vitro.The HIF-1α targeting pharmacological drugs require further study to more fully determine their anti-Leishmania potential and their role in therapeutic strategies.
Objective:To evaluate whether hypoxia inducible factor(HIF-1α) targeting pharmacological drugs,echinomycin,resveratrol and CdCl_2 which inhibit HIF-1α stimulation,and mimosine,which enhances the stability of HIF-1α present antileishmanial properties.Methods:The leishmanicidal effect of drugs was evaluated in mouse macrophages and Balb/c mouse model for cutaneous leishmaniosis.Results:Resveratrol and CdCl_2 reduced the parasite load [IC50,(27.3±2.25) μM and(24.8±0.95) μM,respectively].The IC50 value of echinomycin was(22.7±7.36) nM and mimosine did not alter the parasite load in primary macrophages.The macrophage viability IC50 values for resveratrol,echinomycin and CdCl_2 and mimosine were >40 μM,>100 nM,> 200 μM and>2 000 μM,respectively.In vivo no differences between cutaneous lesions from control,resveratrol-and echinomycin-treated Balb/c mice were detected.Conclusions:Resveratrol,echinomycin and CdCl_2 reduce parasite survival in vitro.The HIF-1α targeting pharmacological drugs require further study to more fully determine their anti-Leishmania potential and their role in therapeutic strategies.
引文
[1]Kaye P,Scott P.Leishmaniasis:complexity at the host-pathogen interface.Nat Rev Microbiol 2011;9(8):604-615.
[2]Okwor I,Uzonna J.Social and economic burden of human Leishmaniasis.Am J Trop Med Hyg 2016;94(3):489-493.
[3]Handler MZ,Patel PA,Kapila R,Al-Qubati Y,Schwartz RA,Handler MZ.Cutaneous and mucocutaneous Leishmaniasis:clinical perspectives.J Am Acad Dermatol 2015;73(6):897-908.
[4]No JH.Visceral Leishmaniasis:Revisiting current treatments and approaches for future discoveries.Acta Trop 2016;155(2016):113-123.
[5]Araújo AP,Arrais-Silva WW,Giorgio S.Infection by Leishmania amazonensis in mice:a potential model for chronic hypoxia.Acta Histochem 2012;114(8):797-804.
[6]Mahnke A,Meier RJ,Schatz V,Hofmann J,Castiglione K,Schleicher U,et al.Hypoxia in Leishmania major skin lesions impairs the NO-dependent leishmanicidal activity of macrophages.J Invest Dermatol 2014;134(9):2339-2346.
[7]Araujo AP,Giorgio S.Immunohistochemical evidence of stress and inflammatory markers in mouse models of cutaneous leishmaniosis.Arch Dermatol Res 2015;307(8):671-682.
[8]Arrais-Silva WW,Paffaro VA Jr,Yamada AT,Giorgio S.Expression of hypoxia-inducible factor-1alpha in the cutaneous lesions of BALB/c mice infected with Leishmania amazonensis.Exp Mol Pathol 2005;78(1):49-54.
[9]Degrossoli A,Bosetto MC,Lima CB,Giorgio S.Expression of hypoxiainducible factor 1alpha in mononuclear phagocytes infected with Leishmania amazonensis.Immunol Lett 2007;114(2):119-125.
[10]Werth N,Beerlage C,Rosenberger C,Yazdi AS,Edelmann M,Amr A,et al.Activation of hypoxia inducible factor 1 is a general phenomenon in infections with human pathogens.PLoS One 2010;5(7):e11576.
[11]Singh AK,Mukhopadhyay C,Biswas S,Singh VK,Mukhopadhyay CK.Intracellular pathogen Leishmania donovani activates hypoxia inducible factor-1 by dual mechanism for survival advantage within macrophage.PLoS One 2012;7(6):e38489.
[12]Semenza GL.Targeting hypoxia-inducible factor 1 to stimulate tissue vascularization.J Investig Med 2016;64(2):361-363.
[13]Hubbi ME,Semenza GL.Regulation of cell proliferation by hypoxiainducible factors.Am J Physiol Cell Physiol 2015;309(12):C775-782.
[14]Yang C,Jiang L,Zhang H,Shimoda LA,De Berardinis RJ,Semenza GL.Analysis of hypoxia-induced metabolic reprogramming.Methods Enzymol 2014;542(2014):425-455
[15]Tang CM,Yu J.Hypoxia-inducible factor-1 as a therapeutic target in cancer.J Gastroenterol Hepatol 2013;28(3):401-405.
[16]Miranda E,Nordgren IK,Male AL,Lawrence CE,Hoakwie F,Cuda F,et al.A cyclic peptide inhibitor of HIF-1 heterodimerization that inhibits hypoxia signaling in cancer cells.J Am Chem Soc 2013;135(28):10418-10425.
[17]Sharma M,Machuy N,B?hme L,Karunakaran K,M?urer AP,Meyer TF,et al.HIF-1αis involved in mediating apoptosis resistance to Chlamydia trachomatis-infected cells.Cell Microbiol 2011;13(10):1573-1585.
[18]Darekar S,Georgiou K,Yurchenko M,Yenamandra SP,Chachami G,Simos G,et al.Epstein-Barr virus immortalization of human B-cells leads to stabilization of hypoxia-induced factor 1 alpha,congruent with the Warburg effect.PLoS One 2012;7(7):e42072.
[19]Metheni M,Lombès A,Bouillaud F,Batteux F,Langsley G.HIF-1αinduction,proliferation and glycolysis of Theileria-infected leukocytes.Cell Microbiol 2015;17(4):467-472.
[20]Bhandari T,Nizet V.Hypoxia-inducible factor(HIF)as a pharmacological target for prevention and treatment of infectious diseases.Infect Dis Ther2014;3(2):159-174.
[21]Jones DT,Harris AL.Identification of novel small-molecule inhibitors of hypoxia-inducible factor-1 transactivation and DNA binding.Mol Cancer Ther 2006;5(9):2193-2202.
[22]Zhang Q,Tang X,Lu QY,Zhang ZF,Brown J,Le AD.Resveratrol inhibits hypoxia-induced accumulation of hypoxia-inducible factor-1alpha and VEGF expression in human tongue squamous cell carcinoma and hepatoma cells.Mol Cancer Ther 2005;4(10):1465-1474.
[23]Yonekura S,Itoh M,Okuhashi Y,Takahashi Y,Ono A,Nara N,et al.Effects of the HIF1 inhibitor,echinomycin,on growth and NOTCHsignalling in leukaemia cells.Anticancer Res 2013;33(8):3099-3103.
[24]Eltzschig HK,Bratton DL,Colgan SP.Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases.Nat Rev Drug Discov 2014;13(11):852-869.
[25]Mitani T,Ito Y,Harada N,Nakano Y,Inui H,Ashida H,et al.Resveratrol reduces the hypoxia-induced resistance to doxorubicin in breast cancer cells.J Nutr Sci Vitaminol(Tokyo)2014;60(2):122-128.
[26]Borsi E,Terragna C,Brioli A,Tacchetti P,Martello M,Cavo M.Therapeutic targeting of hypoxia and hypoxia-inducible factor 1 alpha in multiple myeloma.Transl Res 2015;165(6):641-650.
[27]Nickols NG,Jacobs CS,Farkas ME,Dervan PB.Modulating hypoxiainducible transcription by disrupting the HIF-1-DNA interface.ACSChem Biol 2007;2(8):561-571.
[28]Cao X,Luo T,Luo X,Tang Z.Resveratrol prevents AngⅡ-induced hypertension via AMPK activation and Rho A/ROCK suppression in mice.Hypertens Res 2014;37(9):803-810.
[29]Chun YS,Choi E,Kim GT,Choi H,Kim CH,Lee MJ,et al.Cadmium blocks hypoxia-inducible factor(HIF)-1-mediated response to hypoxia by stimulating the proteasome-dependent degradation of HIF-1alpha.Eur J Biochem 2000;267(13):4198-4204.
[30]Zinkernagel AS,Peyssonnaux C,Johnson RS,Nizet V.Pharmacologic augmentation of hypoxia-inducible factor-1alpha with mimosine boosts the bactericidal capacity of phagocytes.J Infect Dis 2008;197(2):214-217.
[31]Degrossoli A,Colhone MC,Arrais-Silva WW,Giorgio S.Hypoxia modulates expression of the 70-k D heat shock protein and reduces Leishmania infection in macrophages.J Biomed Sci 2004;1(6):847-854.
[32]Giorgio S,Linares E,Ischiropoulos H,Von Zuben FJ,Yamada A,Augusto O.In vivo formation of electron paramagnetic resonancedetectable nitric oxide and of nitrotyrosine is not impaired during murine Leishmaniasis.Infect Immun 1998;66(2):807-814.
[33]de Mesquita Barbosa A,Dos Santos Costa S,da Rocha JR,Montanari CA,Giorgio S.Evaluation of the leishmanicidal and cytotoxic effects of inhibitors for microorganism metabolic pathway enzymes.Biomed Pharmacother 2015;74(2015):95-100.
[34]Foster BJ,Clagett-Carr K,Shoemaker DD,Suffness M,Plowman J,Trissel LA,et al.Echinomycin:the first bifunctional intercalating agent in clinical trials.Invest New Drugs 1985;3(4):403-410.
[35]Yu L,Sun ZJ,Wu SL,Pan CE.Effect of resveratrol on cell cycle proteins in murine transplantable liver cancer.World J Gastroenterol 2003;9(10):2341-2343.
[36]Park YS,Shin WS,Kim SK.In vitro and in vivo activities of echinomycin against clinical isolates of Staphylococcus aureus.J Antimicrob Chemother2008;61(1):163-168.
[37]Kong D,Park EJ,Stephen AG,Calvani M,Cardellina JH,Monks A,et al.Echinomycin,a small-molecule inhibitor of hypoxia-inducible factor-1DNA-binding activity.Cancer Res 2005;65:9047-9055.
[38]Radkar V,Hardej D,Lau-Cam C,Billack B.Evaluation of resveratrol and piceatannol cytotoxicity in macrophages,T cells,and skin cells.Arh Hig Rada Toksikol 2007;58(19):293-304.
[39]Tsuzuki T,Okada H,Cho H,Tsuji S,Nishigaki A,Yasuda K,et al.Hypoxic stress simultaneously stimulates vascular endothelial growth factor via hypoxia-inducible factor-1αand inhibits stromal cell-derived factor-1 in human endometrial stromal cells.Hum Reprod 2012;27(2):523-530.
[40]IARC.Cadmium and cadmium compounds.IARC Monogr Eval Carcinog Risks Hum 1993;58(1993):119-237.
[41]Kedzierski L,Curtis JM,Kaminska M,Jodynis-Liebert J,Murias M.In vitro anti Leishmanial activity of resveratrol and its hydroxylated analogues against Leishmania major promastigotes and amastigotes.Parasitol Res 2007;102(1):91-97.
[42]Juan ME,Vinardell MP,Planas JM.The daily oral administration of high doses of trans-resveratrol to rats for 28 days is not harmful.J Nutr 2002;132(2):257-260.
[43]Pereira BA,Alves CR.Immunological characteristics of experimental murine infection with Leishmania(Leishmania)amazonensis.Vet Parasitol 2008;158(4):239-255.
[44]Otoguro K,Ishiyama A,Namatame M,Nishihara A,Furusawa T,Masuma R,et al.Selective and potent in vitro antitrypanosomal activities of ten microbial metabolites.J Antibiot(Tokyo)2008;61(10):372-378.
[45]Chawla B,Kumar RR,Tyagi N,Subramanian G,Srinivasan N,Park MH,et al.A unique modification of the eukaryotic initiation factor 5A shows the presence of the complete hypusine pathway in Leishmania donovani.PLoS One 2012;7(3):e33138.
[2]Okwor I,Uzonna J.Social and economic burden of human Leishmaniasis.Am J Trop Med Hyg 2016;94(3):489-493.
[3]Handler MZ,Patel PA,Kapila R,Al-Qubati Y,Schwartz RA,Handler MZ.Cutaneous and mucocutaneous Leishmaniasis:clinical perspectives.J Am Acad Dermatol 2015;73(6):897-908.
[4]No JH.Visceral Leishmaniasis:Revisiting current treatments and approaches for future discoveries.Acta Trop 2016;155(2016):113-123.
[5]Araújo AP,Arrais-Silva WW,Giorgio S.Infection by Leishmania amazonensis in mice:a potential model for chronic hypoxia.Acta Histochem 2012;114(8):797-804.
[6]Mahnke A,Meier RJ,Schatz V,Hofmann J,Castiglione K,Schleicher U,et al.Hypoxia in Leishmania major skin lesions impairs the NO-dependent leishmanicidal activity of macrophages.J Invest Dermatol 2014;134(9):2339-2346.
[7]Araujo AP,Giorgio S.Immunohistochemical evidence of stress and inflammatory markers in mouse models of cutaneous leishmaniosis.Arch Dermatol Res 2015;307(8):671-682.
[8]Arrais-Silva WW,Paffaro VA Jr,Yamada AT,Giorgio S.Expression of hypoxia-inducible factor-1alpha in the cutaneous lesions of BALB/c mice infected with Leishmania amazonensis.Exp Mol Pathol 2005;78(1):49-54.
[9]Degrossoli A,Bosetto MC,Lima CB,Giorgio S.Expression of hypoxiainducible factor 1alpha in mononuclear phagocytes infected with Leishmania amazonensis.Immunol Lett 2007;114(2):119-125.
[10]Werth N,Beerlage C,Rosenberger C,Yazdi AS,Edelmann M,Amr A,et al.Activation of hypoxia inducible factor 1 is a general phenomenon in infections with human pathogens.PLoS One 2010;5(7):e11576.
[11]Singh AK,Mukhopadhyay C,Biswas S,Singh VK,Mukhopadhyay CK.Intracellular pathogen Leishmania donovani activates hypoxia inducible factor-1 by dual mechanism for survival advantage within macrophage.PLoS One 2012;7(6):e38489.
[12]Semenza GL.Targeting hypoxia-inducible factor 1 to stimulate tissue vascularization.J Investig Med 2016;64(2):361-363.
[13]Hubbi ME,Semenza GL.Regulation of cell proliferation by hypoxiainducible factors.Am J Physiol Cell Physiol 2015;309(12):C775-782.
[14]Yang C,Jiang L,Zhang H,Shimoda LA,De Berardinis RJ,Semenza GL.Analysis of hypoxia-induced metabolic reprogramming.Methods Enzymol 2014;542(2014):425-455
[15]Tang CM,Yu J.Hypoxia-inducible factor-1 as a therapeutic target in cancer.J Gastroenterol Hepatol 2013;28(3):401-405.
[16]Miranda E,Nordgren IK,Male AL,Lawrence CE,Hoakwie F,Cuda F,et al.A cyclic peptide inhibitor of HIF-1 heterodimerization that inhibits hypoxia signaling in cancer cells.J Am Chem Soc 2013;135(28):10418-10425.
[17]Sharma M,Machuy N,B?hme L,Karunakaran K,M?urer AP,Meyer TF,et al.HIF-1αis involved in mediating apoptosis resistance to Chlamydia trachomatis-infected cells.Cell Microbiol 2011;13(10):1573-1585.
[18]Darekar S,Georgiou K,Yurchenko M,Yenamandra SP,Chachami G,Simos G,et al.Epstein-Barr virus immortalization of human B-cells leads to stabilization of hypoxia-induced factor 1 alpha,congruent with the Warburg effect.PLoS One 2012;7(7):e42072.
[19]Metheni M,Lombès A,Bouillaud F,Batteux F,Langsley G.HIF-1αinduction,proliferation and glycolysis of Theileria-infected leukocytes.Cell Microbiol 2015;17(4):467-472.
[20]Bhandari T,Nizet V.Hypoxia-inducible factor(HIF)as a pharmacological target for prevention and treatment of infectious diseases.Infect Dis Ther2014;3(2):159-174.
[21]Jones DT,Harris AL.Identification of novel small-molecule inhibitors of hypoxia-inducible factor-1 transactivation and DNA binding.Mol Cancer Ther 2006;5(9):2193-2202.
[22]Zhang Q,Tang X,Lu QY,Zhang ZF,Brown J,Le AD.Resveratrol inhibits hypoxia-induced accumulation of hypoxia-inducible factor-1alpha and VEGF expression in human tongue squamous cell carcinoma and hepatoma cells.Mol Cancer Ther 2005;4(10):1465-1474.
[23]Yonekura S,Itoh M,Okuhashi Y,Takahashi Y,Ono A,Nara N,et al.Effects of the HIF1 inhibitor,echinomycin,on growth and NOTCHsignalling in leukaemia cells.Anticancer Res 2013;33(8):3099-3103.
[24]Eltzschig HK,Bratton DL,Colgan SP.Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases.Nat Rev Drug Discov 2014;13(11):852-869.
[25]Mitani T,Ito Y,Harada N,Nakano Y,Inui H,Ashida H,et al.Resveratrol reduces the hypoxia-induced resistance to doxorubicin in breast cancer cells.J Nutr Sci Vitaminol(Tokyo)2014;60(2):122-128.
[26]Borsi E,Terragna C,Brioli A,Tacchetti P,Martello M,Cavo M.Therapeutic targeting of hypoxia and hypoxia-inducible factor 1 alpha in multiple myeloma.Transl Res 2015;165(6):641-650.
[27]Nickols NG,Jacobs CS,Farkas ME,Dervan PB.Modulating hypoxiainducible transcription by disrupting the HIF-1-DNA interface.ACSChem Biol 2007;2(8):561-571.
[28]Cao X,Luo T,Luo X,Tang Z.Resveratrol prevents AngⅡ-induced hypertension via AMPK activation and Rho A/ROCK suppression in mice.Hypertens Res 2014;37(9):803-810.
[29]Chun YS,Choi E,Kim GT,Choi H,Kim CH,Lee MJ,et al.Cadmium blocks hypoxia-inducible factor(HIF)-1-mediated response to hypoxia by stimulating the proteasome-dependent degradation of HIF-1alpha.Eur J Biochem 2000;267(13):4198-4204.
[30]Zinkernagel AS,Peyssonnaux C,Johnson RS,Nizet V.Pharmacologic augmentation of hypoxia-inducible factor-1alpha with mimosine boosts the bactericidal capacity of phagocytes.J Infect Dis 2008;197(2):214-217.
[31]Degrossoli A,Colhone MC,Arrais-Silva WW,Giorgio S.Hypoxia modulates expression of the 70-k D heat shock protein and reduces Leishmania infection in macrophages.J Biomed Sci 2004;1(6):847-854.
[32]Giorgio S,Linares E,Ischiropoulos H,Von Zuben FJ,Yamada A,Augusto O.In vivo formation of electron paramagnetic resonancedetectable nitric oxide and of nitrotyrosine is not impaired during murine Leishmaniasis.Infect Immun 1998;66(2):807-814.
[33]de Mesquita Barbosa A,Dos Santos Costa S,da Rocha JR,Montanari CA,Giorgio S.Evaluation of the leishmanicidal and cytotoxic effects of inhibitors for microorganism metabolic pathway enzymes.Biomed Pharmacother 2015;74(2015):95-100.
[34]Foster BJ,Clagett-Carr K,Shoemaker DD,Suffness M,Plowman J,Trissel LA,et al.Echinomycin:the first bifunctional intercalating agent in clinical trials.Invest New Drugs 1985;3(4):403-410.
[35]Yu L,Sun ZJ,Wu SL,Pan CE.Effect of resveratrol on cell cycle proteins in murine transplantable liver cancer.World J Gastroenterol 2003;9(10):2341-2343.
[36]Park YS,Shin WS,Kim SK.In vitro and in vivo activities of echinomycin against clinical isolates of Staphylococcus aureus.J Antimicrob Chemother2008;61(1):163-168.
[37]Kong D,Park EJ,Stephen AG,Calvani M,Cardellina JH,Monks A,et al.Echinomycin,a small-molecule inhibitor of hypoxia-inducible factor-1DNA-binding activity.Cancer Res 2005;65:9047-9055.
[38]Radkar V,Hardej D,Lau-Cam C,Billack B.Evaluation of resveratrol and piceatannol cytotoxicity in macrophages,T cells,and skin cells.Arh Hig Rada Toksikol 2007;58(19):293-304.
[39]Tsuzuki T,Okada H,Cho H,Tsuji S,Nishigaki A,Yasuda K,et al.Hypoxic stress simultaneously stimulates vascular endothelial growth factor via hypoxia-inducible factor-1αand inhibits stromal cell-derived factor-1 in human endometrial stromal cells.Hum Reprod 2012;27(2):523-530.
[40]IARC.Cadmium and cadmium compounds.IARC Monogr Eval Carcinog Risks Hum 1993;58(1993):119-237.
[41]Kedzierski L,Curtis JM,Kaminska M,Jodynis-Liebert J,Murias M.In vitro anti Leishmanial activity of resveratrol and its hydroxylated analogues against Leishmania major promastigotes and amastigotes.Parasitol Res 2007;102(1):91-97.
[42]Juan ME,Vinardell MP,Planas JM.The daily oral administration of high doses of trans-resveratrol to rats for 28 days is not harmful.J Nutr 2002;132(2):257-260.
[43]Pereira BA,Alves CR.Immunological characteristics of experimental murine infection with Leishmania(Leishmania)amazonensis.Vet Parasitol 2008;158(4):239-255.
[44]Otoguro K,Ishiyama A,Namatame M,Nishihara A,Furusawa T,Masuma R,et al.Selective and potent in vitro antitrypanosomal activities of ten microbial metabolites.J Antibiot(Tokyo)2008;61(10):372-378.
[45]Chawla B,Kumar RR,Tyagi N,Subramanian G,Srinivasan N,Park MH,et al.A unique modification of the eukaryotic initiation factor 5A shows the presence of the complete hypusine pathway in Leishmania donovani.PLoS One 2012;7(3):e33138.