Tumoricidal activity of endothelium-derived NO and the survival of metastatic cells with high GSH and Bcl-2 levels

Nitric Oxide - Biology and Chemistry

Volumn 19, Issue 2, 2008, Pages 107-114

  Ortega, Angel ^a   Carretero, Julian ^a   Obrador, Elena ^a   Estrela, José M ^a  

^a UNIVERSITY OF VALENCIA   (Spain)

Author keywords

Bcl 2; Chemoradiotherapy; Glutathione; Metastases; Nitric oxide; Oxidative and nitrosative stress; Vascular endothelium

Indexed keywords

CYSTEINE; CYTOKINE; GAMMA GLUTAMYLTRANSFERASE; GLUTATHIONE; HYDROGEN PEROXIDE; HYDROXYL RADICAL; NITRIC OXIDE; PEROXYNITRITE; PROTEIN BCL 2;

ANTINEOPLASTIC ACTIVITY; CELL ADHESION; CELL PROLIFERATION; CELL SURVIVAL; CYTOKINE RELEASE; CYTOTOXICITY; EXTRAVASATION; GLUTATHIONE METABOLISM; GRANULOCYTE; HUMAN; MACROPHAGE; METASTASIS; NITROSATIVE STRESS; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; VASCULAR ENDOTHELIUM;

CELL SURVIVAL; ENDOTHELIUM; GLUTATHIONE; HUMANS; NEOPLASM METASTASIS; NITRIC OXIDE; PROTO-ONCOGENE PROTEINS C-BCL-2;

MAMMALIA; MURINAE;

EID: 47049085675     PISSN: 10898603     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.niox.2008.04.010     Document Type: Review

References (103)

1. Hanahan D., and Weinberg R.A. The hallmarks of cancer. Cell 100 (2000) 57-70
2. Eccles S.A., and Welch D.R. Metastasis: recent discoveries and novel treatment strategies. Lancet 369 (2007) 1742-1757
3. Fidler I.J. Critical determinants of metastasis. Semin Cancer Biol. 12 (2002) 89-96
4. Weigelt B., Peterse J.L., and van 't Veer L.J. Breast cancer metastasis: markers and models. Nat. Rev. Cancer 5 (2005) 591-602
5. Fidler I.J., and Hart I.R. Biological diversity in metastatic neoplasms: origins and implications. Science 217 (1982) 998-1003
6. Tassone P., Tagliaferri P., Fulciniti M.T., Di Martino M.T., and Venuta S. Novel therapeutic approaches based on the targeting of microenvironment-derived survival pathways in human cancer: experimental models and translational issues. Curr. Pharm. Des. 13 (2007) 487-496
7. Langley R.R., and Fidler I.J. Tumor cell-organ microenvironment interactions in the pathogenesis of cancer metastasis. Endocr. Rev. 28 (2007) 297-321
8. Fidler I.J., Naito S., and Pathak S. Orthotopic implantation is essential for the selection, growth and metastasis of human renal cell cancer in nude mice [corrected]. Cancer Metastasis Rev. 9 (1990) 149-165
9. Weiss L. Metastatic inefficiency. Adv. Cancer Res. 54 (1990) 159-211
10. Li L.M., Nicolson G.L., and Fidler I.J. Direct in vitro lysis of metastatic tumor cells by cytokine-activated murine vascular endothelial cells. Cancer Res. 51 (1991) 245-254
11. Bayon L.G., Izquierdo M.A., Sirovich I., van Rooijen N., Beelen R.H., and Meijer S. Role of Kupffer cells in arresting circulating tumor cells and controlling metastatic growth in the liver. Hepatology 23 (1996) 1224-1231
12. Anasagasti M.J., Alvarez A., Martin J.J., Mendoza L., and Vidal-Vanaclocha F. Sinusoidal endothelium release of hydrogen peroxide enhances very late antigen-4-mediated melanoma cell adherence and tumor cytotoxicity during interleukin-1 promotion of hepatic melanoma metastasis in mice. Hepatology 25 (1997) 840-846
13. Wang H.H., McIntosh A.R., Hasinoff B.B., Rector E.S., Ahmed N., Nance D.M., and Orr F.W. B16 melanoma cell arrest in the mouse liver induces nitric oxide release and sinusoidal cytotoxicity: a natural hepatic defense against metastasis. Cancer Res. 60 (2000) 5862-5869
14. Carretero J., Obrador E., Esteve J.M., Ortega A., Pellicer J.A., Sempere F.V., and Estrela J.M. Tumoricidal activity of endothelial cells. Inhibition of endothelial nitric oxide production abrogates tumor cytotoxicity induced by hepatic sinusoidal endothelium in response to B16 melanoma adhesion in vitro. J. Biol. Chem. 276 (2001) 25775-25782
15. Obrador E., Navarro J., Mompo J., Asensi M., Pellicer J.A., and Estrela J.M. Glutathione and the rate of cellular proliferation determine tumour cell sensitivity to tumour necrosis factor in vivo. Biochem. J. 325 Pt 1 (1997) 183-189
16. Fidler I.J., and Nicolson G.L. Organ selectivity for implantation survival and growth of B16 melanoma variant tumor lines. J. Natl. Cancer Inst. 57 (1976) 1199-1202
17. Fidler I.J. Metastasis: quantitative analysis of distribution and fate of tumor embolilabeled with 125 I-5-iodo-2'-deoxyuridine. J. Natl. Cancer Inst. 45 (1970) 773-782
18. Barbera-Guillem E., Smith I., and Weiss L. Cancer-cell traffic in the liver. II. Arrest, transit and death of B16F10 and M5076 cells in the sinusoids. Int. J. Cancer 53 (1993) 298-301
19. Weiss L., Nannmark U., Johansson B.R., and Bagge U. Lethal deformation of cancer cells in the microcirculation: a potential rate regulator of hematogenous metastasis. Int. J. Cancer 50 (1992) 103-107
20. Weiss L. Biomechanical Interactions of Cancer Cells With The Microvasculature During Hematogenous Metastasis (1992), Springer, Netherlands
21. Glaves D. Intravascular death of disseminated cancer cells mediated by superoxide anion. Invasion Metastasis 6 (1986) 101-111
22. Bouwens L., Jacobs R., Remels L., and Wisse E. Natural cytotoxicity of rat hepatic natural killer cells and macrophages against a syngeneic colon adenocarcinoma. Cancer Immunol. Immunother. 27 (1988) 137-141
23. Bockhorn M., Jain R.K., and Munn L.L. Active versus passive mechanisms in metastasis: do cancer cells crawl into vessels, or are they pushed?. Lancet Oncol. 8 (2007) 444-448
24. Fidler I.J. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat. Rev. Cancer 3 (2003) 453-458
25. Sahai E. Illuminating the metastatic process. Nat. Rev. Cancer 7 (2007) 737-749
26. Mehlen P., and Puisieux A. Metastasis: a question of life or death. Nat. Rev. Cancer 6 (2006) 449-458
27. Koukoulis G.K., Patriarca C., and Gould V.E. Adhesion molecules and tumor metastasis. Hum. Pathol. 29 (1998) 889-892
28. Borsig L., Wong R., Hynes R.O., Varki N.M., and Varki A. Synergistic effects of L- and P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis. Proc. Natl. Acad. Sci. USA 99 (2002) 2193-2198
29. Wilson J., and Balkwill F. The role of cytokines in the epithelial cancer microenvironment. Semin. Cancer Biol. 12 (2002) 113-120
30. Kobayashi H., Boelte K.C., and Lin P.C. Endothelial cell adhesion molecules and cancer progression. Curr. Med. Chem. 14 (2007) 377-386
31. Guo W., and Giancotti F.G. Integrin signalling during tumour progression. Nat. Rev. Mol. Cell Biol. 5 (2004) 816-826
32. Khatib A.M., Kontogiannea M., Fallavollita L., Jamison B., Meterissian S., and Brodt P. Rapid induction of cytokine and E-selectin expression in the liver in response to metastatic tumor cells. Cancer Res. 59 (1999) 1356-1361
33. Auguste P., Fallavollita L., Wang N., Burnier J., Bikfalvi A., and Brodt P. The host inflammatory response promotes liver metastasis by increasing tumor cell arrest and extravasation. Am. J. Pathol. 170 (2007) 1781-1792
34. Orr F.W., Wang H.H., Lafrenie R.M., Scherbarth S., and Nance D.M. Interactions between cancer cells and the endothelium in metastasis. J. Pathol. 190 (2000) 310-329
35. Garofalo A., Chirivi R.G., Foglieni C., Pigott R., Mortarini R., Martin-Padura I., Anichini A., Gearing A.J., Sanchez-Madrid F., Dejana E., et al. Involvement of the very late antigen 4 integrin on melanoma in interleukin-1-augmented experimental metastases. Cancer Res. 55 (1995) 414-419
36. Klemke M., Weschenfelder T., Konstandin M.H., and Samstag Y. High affinity interaction of integrin alpha4beta1 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1) enhances migration of human melanoma cells across activated endothelial cell layers. J. Cell Physiol. 212 (2007) 368-374
37. Anasagasti M.J., Alvarez A., Avivi C., and Vidal-Vanaclocha F. Interleukin-1-mediated H2O2 production by hepatic sinusoidal endothelium in response to B16 melanoma cell adhesion. J. Cell Physiol. 167 (1996) 314-323
38. Marui N., Offermann M.K., Swerlick R., Kunsch C., Rosen C.A., Ahmad M., Alexander R.W., and Medford R.M. Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells. J. Clin. Invest. 92 (1993) 1866-1874
39. Anasagasti M.J., Olaso E., Calvo F., Mendoza L., Martin J.J., Bidaurrazaga J., and Vidal-Vanaclocha F. Interleukin 1-dependent and -independent mouse melanoma metastases. J. Natl. Cancer Inst. 89 (1997) 645-651
40. Mendoza L., Olaso E., Anasagasti M.J., Fuentes A.M., and Vidal-Vanaclocha F. Mannose receptor-mediated endothelial cell activation contributes to B16 melanoma cell adhesion and metastasis in liver. J. Cell Physiol. 174 (1998) 322-330
41. Burdon R.H. Superoxide and hydrogen peroxide in relation to mammalian cell proliferation. Free Radic. Biol. Med. 18 (1995) 775-794
42. Jadeski L.C., Chakraborty C., and Lala P.K. Nitric oxide-mediated promotion of mammary tumour cell migration requires sequential activation of nitric oxide synthase, guanylate cyclase and mitogen-activated protein kinase. Int. J. Cancer 106 (2003) 496-504
43. Wang L., Shi G.G., Yao J.C., Gong W., Wei D., Wu T.T., Ajani J.A., Huang S., and Xie K. Expression of endothelial nitric oxide synthase correlates with the angiogenic phenotype of and predicts poor prognosis in human gastric cancer. Gastric Cancer 8 (2005) 18-28
44. Tu Y.T., Tao J., Liu Y.Q., Li Y., Huang C.Z., Zhang X.B., and Lin Y. Expression of endothelial nitric oxide synthase and vascular endothelial growth factor in human malignant melanoma and their relation to angiogenesis. Clin. Exp. Dermatol. 31 (2006) 413-418
45. Fukumura D., Kashiwagi S., and Jain R.K. The role of nitric oxide in tumour progression. Nat. Rev. Cancer 6 (2006) 521-534
46. Qiu H., Orr F.W., Jensen D., Wang H.H., McIntosh A.R., Hasinoff B.B., Nance D.M., Pylypas S., Qi K., Song C., Muschel R.J., and Al-Mehdi A.B. Arrest of B16 melanoma cells in the mouse pulmonary microcirculation induces endothelial nitric oxide synthase-dependent nitric oxide release that is cytotoxic to the tumor cells. Am. J. Pathol. 162 (2003) 403-412
47. Jessup J.M., Battle P., Waller H., Edmiston K.H., Stolz D.B., Watkins S.C., Locker J., and Skena K. Reactive nitrogen and oxygen radicals formed during hepatic ischemia-reperfusion kill weakly metastatic colorectal cancer cells. Cancer Res. 59 (1999) 1825-1829
48. Albertsson P.A., Nannmark U., and Johansson B.R. Melanoma cell destruction in the microvasculature of perfused hearts is reduced by pretreatment with vitamin E. Clin. Exp. Metastasis 13 (1995) 269-276
49. Eskenazi A.E., Pinkas J., Whitin J.C., Arguello F., Cohen H.J., and Frantz C.N. Role of antioxidant enzymes in the induction of increased experimental metastasis by hydroxyurea. J. Natl. Cancer Inst. 85 (1993) 711-721
50. Anasagasti M.J., Martin J.J., Mendoza L., Obrador E., Estrela J.M., McCuskey R.S., and Vidal-Vanaclocha F. Glutathione protects metastatic melanoma cells against oxidative stress in the murine hepatic microvasculature. Hepatology 27 (1998) 1249-1256
51. Carretero J., Obrador E., Anasagasti M.J., Martin J.J., Vidal-Vanaclocha F., and Estrela J.M. Growth-associated changes in glutathione content correlate with liver metastatic activity of B16 melanoma cells. Clin. Exp. Metastasis 17 (1999) 567-574
52. Obrador E., Carretero J., Ortega A., Medina I., Rodilla V., Pellicer J.A., and Estrela J.M. gamma-Glutamyl transpeptidase overexpression increases metastatic growth of B16 melanoma cells in the mouse liver. Hepatology 35 (2002) 74-81
53. Ortega A.L., Carretero J., Obrador E., Gambini J., Asensi M., Rodilla V., and Estrela J.M. Tumor cytotoxicity by endothelial cells. Impairment of the mitochondrial system for glutathione uptake in mouse B16 melanoma cells that survive after in vitro interaction with the hepatic sinusoidal endothelium. J. Biol. Chem. 278 (2003) 13888-13897
54. Obrador E., Carretero J., Pellicer J.A., and Estrela J.M. Possible mechanisms for tumour cell sensitivity to TNF-alpha and potential therapeutic applications. Curr. Pharm. Biotechnol. 2 (2001) 119-130
55. Lowe S.W., and Lin A.W. Apoptosis in cancer. Carcinogenesis 21 (2000) 485-495
56. Ortega A., Ferrer P., Carretero J., Obrador E., Asensi M., Pellicer J.A., and Estrela J.M. Down-regulation of glutathione and Bcl-2 synthesis in mouse B16 melanoma cells avoids their survival during interaction with the vascular endothelium. J. Biol. Chem. 278 (2003) 39591-39599
57. Hirst D.G., and Robson T. Nitrosative stress in cancer therapy. Front Biosci. 12 (2007) 3406-3418
58. Xie K., and Huang S. Regulation of cancer metastasis by stress pathways. Clin. Exp. Metastasis 20 (2003) 31-43
59. Fratelli M., Goodwin L.O., Orom U.A., Lombardi S., Tonelli R., Mengozzi M., and Ghezzi P. Gene expression profiling reveals a signaling role of glutathione in redox regulation. Proc. Natl. Acad. Sci. USA 102 (2005) 13998-14003
60. Kroncke K.D. Mechanisms and biological consequences of nitrosative stress. Biol. Chem. 384 (2003) 1341
61. Benlloch M., Ortega A., Ferrer P., Segarra R., Obrador E., Asensi M., Carretero J., and Estrela J.M. Acceleration of glutathione efflux and inhibition of gamma-glutamyltranspeptidase sensitize metastatic B16 melanoma cells to endothelium-induced cytotoxicity. J. Biol. Chem. 280 (2005) 6950-6959
62. Mena S., Benlloch M., Ortega A., Carretero J., Obrador E., Asensi M., Petschen I., Brown B.D., and Estrela J.M. Bcl-2 and glutathione depletion sensitizes B16 melanoma to combination therapy and eliminates metastatic disease. Clin. Cancer Res. 13 (2007) 2658-2666
63. Ferrer P., Asensi M., Priego S., Benlloch M., Mena S., Ortega A., Obrador E., Esteve J.M., and Estrela J.M. Nitric oxide mediates natural polyphenol-induced Bcl-2 down-regulation and activation of cell death in metastatic B16 melanoma. J. Biol. Chem. 282 (2007) 2880-2890
64. Chanvorachote P., Nimmannit U., Stehlik C., Wang L., Jiang B.H., Ongpipatanakul B., and Rojanasakul Y. Nitric oxide regulates cell sensitivity to cisplatin-induced apoptosis through S-nitrosylation and inhibition of Bcl-2 ubiquitination. Cancer Res. 66 (2006) 6353-6560
65. Azad N., Vallyathan V., Wang L., Tantishaiyakul V., Stehlik C., Leonard S.S., and Rojanasakul Y. S-nitrosylation of Bcl-2 inhibits its ubiquitin-proteasomal degradation. A novel antiapoptotic mechanism that suppresses apoptosis. J. Biol. Chem. 281 (2006) 34124-34134
66. Dhakshinamoorthy S., Sridharan S.R., Li L., Ng P.Y., Boxer L.M., and Porter A.G. Protein/DNA arrays identify nitric oxide-regulated cis-element and trans-factor activities some of which govern neuroblastoma cell viability. Nucleic Acids Res. 35 (2007) 5439-5451
67. Martinez-Lacaci I., Garcia Morales P., Soto J.L., and Saceda M. Tumour cells resistance in cancer therapy. Clin. Transl. Oncol. 9 (2007) 13-20
68. Danial N.N. Bcl-2 Family proteins: critical checkpoints of apoptotic cell death. Clin. Cancer Res. 13 (2007) 7254-7263
69. Baliga B.C., and Kumar S. Role of Bcl-2 family of proteins in malignancy. Hematol. Oncol. 20 (2002) 63-74
70. Reed J.C. Bcl-2 family proteins: strategies for overcoming chemoresistance in cancer. Adv. Pharmacol. 41 (1997) 501-532
71. Takaoka A., Adachi M., Okuda H., Sato S., Yawata A., Hinoda Y., Takayama S., Reed J.C., and Imai K. Anti-cell death activity promotes pulmonary metastasis of melanoma cells. Oncogene 14 (1997) 2971-2977
72. Owen-Schaub L.B., van Golen K.L., Hill L.L., and Price J.E. Fas and Fas ligand interactions suppress melanoma lung metastasis. J. Exp. Med. 188 (1998) 1717-1723
73. Wong C.W., Lee A., Shientag L., Yu J., Dong Y., Kao G., Al-Mehdi A.B., Bernhard E.J., and Muschel R.J. Apoptosis: an early event in metastatic inefficiency. Cancer Res. 61 (2001) 333-338
74. Sartorius U.A., and Krammer P.H. Upregulation of Bcl-2 is involved in the mediation of chemotherapy resistance in human small cell lung cancer cell lines. Int. J. Cancer 97 (2002) 584-592
75. Um J.H., Kwon J.K., Kang C.D., Kim M.J., Ju D.S., Bae J.H., Kim D.W., Chung B.S., and Kim S.H. Relationship between antiapoptotic molecules and metastatic potency and the involvement of DNA-dependent protein kinase in the chemosensitization of metastatic human cancer cells by epidermal growth factor receptor blockade. J. Pharmacol. Exp. Ther. 311 (2004) 1062-1070
76. Hickman J.A. Apoptosis and tumourigenesis. Curr. Opin. Genet. Dev. 12 (2002) 67-72
77. Kroemer G., and Reed J.C. Mitochondrial control of cell death. Nat. Med. 6 (2000) 513-519
78. Estrela J.M., Ortega A., and Obrador E. Glutathione in cancer biology and therapy. Crit. Rev. Clin. Lab. Sci. 43 (2006) 143-181
79. Arai M., Imai H., Koumura T., Yoshida M., Emoto K., Umeda M., Chiba N., and Nakagawa Y. Mitochondrial phospholipid hydroperoxide glutathione peroxidase plays a major role in preventing oxidative injury to cells. J. Biol. Chem. 274 (1999) 4924-4933
80. Vahrmeijer A.L., Hoetelmans R.W., Mulder G.J., Schutrups J., van Vlierberghe R.L., van de Velde C.J., and van Dierendonck J.H. Development of resistance to glutathione depletion-induced cell death in CC531 colon carcinoma cells: association with increased expression of bcl-2. Biochem. Pharmacol. 59 (2000) 1557-1562
81. Mirkovic N., Voehringer D.W., Story M.D., McConkey D.J., McDonnell T.J., and Meyn R.E. Resistance to radiation-induced apoptosis in Bcl-2-expressing cells is reversed by depleting cellular thiols. Oncogene 15 (1997) 1461-1470
82. Armstrong J.S., and Jones D.P. Glutathione depletion enforces the mitochondrial permeability transition and causes cell death in Bcl-2 overexpressing HL60 cells. Faseb. J. 16 (2002) 1263-1265
83. Rudin C.M., Yang Z., Schumaker L.M., VanderWeele D.J., Newkirk K., Egorin M.J., Zuhowski E.G., and Cullen K.J. Inhibition of glutathione synthesis reverses Bcl-2-mediated cisplatin resistance. Cancer Res. 63 (2003) 312-318
84. Wright S.C., Wang H., Wei Q.S., Kinder D.H., and Larrick J.W. Bcl-2-mediated resistance to apoptosis is associated with glutathione-induced inhibition of AP24 activation of nuclear DNA fragmentation. Cancer Res. 58 (1998) 5570-5576
85. Chang W.K., Yang K.D., Chuang H., Jan J.T., and Shaio M.F. Glutamine protects activated human T cells from apoptosis by up-regulating glutathione and Bcl-2 levels. Clin. Immunol. 104 (2002) 151-160
86. Jang J.H., and Surh Y.J. Potentiation of cellular antioxidant capacity by Bcl-2: implications for its antiapoptotic function. Biochem. Pharmacol. 66 (2003) 1371-1379
87. D'Alessio M., Cerella C., Amici C., Pesce C., Coppola S., Fanelli C., De Nicola M., Cristofanon S., Clavarino G., Bergamaschi A., Magrini A., Gualandi G., and Ghibelli L. Glutathione depletion up-regulates Bcl-2 in BSO-resistant cells. Faseb. J. 18 (2004) 1609-1611
88. Grover R., and Wilson G.D. Bcl-2 expression in malignant melanoma and its prognostic significance. Eur. J. Surg. Oncol. 22 (1996) 347-349
89. Selzer E., Schlagbauer-Wadl H., Okamoto I., Pehamberger H., Potter R., and Jansen B. Expression of Bcl-2 family members in human melanocytes, in melanoma metastases and in melanoma cell lines. Melanoma Res. 8 (1998) 197-203
90. Vlaykova T., Talve L., Hahka-Kemppinen M., Hernberg M., Muhonen T., Collan Y., and Pyrhonen S. Immunohistochemically detectable bcl-2 expression in metastatic melanoma: association with survival and treatment response. Oncology 62 (2002) 259-268
91. Kim R., Emi M., Tanabe K., and Toge T. Therapeutic potential of antisense Bcl-2 as a chemosensitizer for cancer therapy. Cancer 101 (2004) 2491-2502
92. Jansen B., Wacheck V., Heere-Ress E., Schlagbauer-Wadl H., Hoeller C., Lucas T., Hoermann M., Hollenstein U., Wolff K., and Pehamberger H. Chemosensitisation of malignant melanoma by BCL2 antisense therapy. Lancet 356 (2000) 1728-1733
93. Klasa R.J., Bally M.B., Ng R., Goldie J.H., Gascoyne R.D., and Wong F.M. Eradication of human non-Hodgkin's lymphoma in SCID mice by BCL-2 antisense oligonucleotides combined with low-dose cyclophosphamide. Clin. Cancer Res. 6 (2000) 2492-2500
94. Benlloch M., Mena S., Ferrer P., Obrador E., Asensi M., Pellicer J.A., Carretero J., Ortega A., and Estrela J.M. Bcl-2 and Mn-SOD antisense oligodeoxynucleotides and a glutamine-enriched diet facilitate elimination of highly resistant B16 melanoma cells by tumor necrosis factor-alpha and chemotherapy. J. Biol. Chem. 281 (2006) 69-79
95. Gleave M.E., Miayake H., Goldie J., Nelson C., and Tolcher A. Targeting bcl-2 gene to delay androgen-independent progression and enhance chemosensitivity in prostate cancer using antisense bcl-2 oligodeoxynucleotides. Urology 54 (1999) 36-46
96. Dias N., and Stein C.A. Potential roles of antisense oligonucleotides in cancer therapy. The example of Bcl-2 antisense oligonucleotides. Eur. J. Pharm. Biopharm. 54 (2002) 263-269
97. Zangemeister-Wittke U., and Ziegler A. Bcl-2 antisense therapy for cancer: the art of persuading tumour cells to commit suicide. Apoptosis 3 (1998) 67-74
98. Jansen B., Schlagbauer-Wadl H., Brown B.D., Bryan R.N., van Elsas A., Muller M., Wolff K., Eichler H.G., and Pehamberger H. bcl-2 antisense therapy chemosensitizes human melanoma in SCID mice. Nat. Med. 4 (1998) 232-234
99. Garber K. Targeting mitochondria emerges as therapeutic strategy. J. Natl. Cancer Inst. 97 (2005) 1800-1801
100. Hochwald S.N., Harrison L.E., Rose D.M., Anderson M., and Burt M.E. gamma-Glutamyl transpeptidase mediation of tumor glutathione utilization in vivo. J. Natl. Cancer Inst. 88 (1996) 193-197
101. Carretero J., Obrador E., Pellicer J.A., Pascual A., and Estrela J.M. Mitochondrial glutathione depletion by glutamine in growing tumor cells. Free Radic. Biol. Med. 29 (2000) 913-923
102. S. Mena, M. Benlloch, A. Ortega, J. Carretero, E. Obrador, J.A. Pellicer, B.D. Brown, J.M. Estrela, Bcl-2 antisense oligodeoxynucleotides- and GSH depletion-induced sensitization to chemoradiotherapy lead to complete regression of A375 melanoma xenografts, AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications San Francisco (USA), 2007.
103. Choi B.M., Pae H.O., Jang S.I., Kim Y.M., and Chung H.T. Nitric oxide as a pro-apoptotic as well as anti-apoptotic modulator. J. Biochem. Mol. Biol. 35 (2002) 116-126