Apoptosis

, Volume 6, Issue 6, pp 469–477 | Cite as

Mechanisms of tamoxifen-induced apoptosis

  • S. Mandlekar
  • A.-N. T. Kong
Article

Abstract

Tamoxifen (TAM) has been used in the treatment of breast cancer for over a decade. The observed clinical efficacy of TAM has been attributed to both growth arrest and induction of apoptosis within the breast cancer cells. Although the primary mechanism of action of TAM is believed to be through the inhibition of estrogen receptor (ER), research over the years has indicated that additional, non-ER-mediated mechanisms exist. These include modulation of signaling proteins such as protein kinase C (PKC), calmodulin, transforming growth factor-β (TGFβ), and the protooncogene c-myc. Recent studies, including those from our laboratory, have implicated the role of caspases and mitogen-activated protein kinases (MAPK), including c-Jun N-terminal kinase (JNK) and p38 in TAM-induced apoptotic signaling. Oxidative stress, mitochondrial permeability transition (MPT), ceramide generation as well as changes in cell membrane fluidity may also play important roles in TAM-induced apoptosis. These various signaling pathways underlying TAM-induced apoptosis will be reviewed in this article.

apoptosis breast cancer caspases signal transduction tamoxifen 

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References

  1. 1.
    Furr BJ, Jordan VC. The pharmacology and clinical uses of tamoxifen. Pharmacol Ther 1984; 25: 127-205.Google Scholar
  2. 2.
    Love RR. Tamoxifen therapy in primary breast cancer: Biology, efficacy, and side effects. J Clin Oncol 1989; 7: 803-815.Google Scholar
  3. 3.
    Marshall E. Tamoxifen. 'A big deal,' but a complex hand to play. Science 1998; 280: 196.Google Scholar
  4. 4.
    Katzenellenbogen BS, Katzenellenbogen JA. Estrogen receptor alpha and estrogen receptor beta: Regulation by selective estrogen receptor modulators and importance in breast cancer. Breast Cancer Res 2000; 2: 335-344.Google Scholar
  5. 5.
    Katzenellenbogen BS, Choi I, Delage-Mourroux R, et al. Molecular mechanisms of estrogen action: Selective ligands and receptor pharmacology. J Steroid Biochem Mol Biol 2000; 74: 279-285.Google Scholar
  6. 6.
    Budtz PE. Role of proliferation and apoptosis in net growth rates of human breast cancer cells (MCF-7) treated with oestradiol and/or tamoxifen. Cell Prolif 1999; 32: 289-302.Google Scholar
  7. 7.
    Gelmann EP. Tamoxifen induction of apoptosis in estrogen receptor-negative cancers: New tricks for an old dog? J Natl Cancer Inst 1996; 88: 224-226.Google Scholar
  8. 8.
    Perry RR, Kang Y, Greaves B. Effects of tamoxifen on growth and apoptosis of estrogen-dependent and-independent human breast cancer cells. Ann Surg Oncol 1995; 2: 238-245.Google Scholar
  9. 9.
    Martin G, Melito G, Rivera E, et al. Effect of tamoxifen on intraperitoneal N-nitroso-N-methylurea induced tumors. Cancer Lett 1996; 100: 227-234.Google Scholar
  10. 10.
    Cameron DA, Ritchie AA, Langdon S, Anderson TJ, Miller WR. Tamoxifen induced apoptosis in ZR-75 breast cancer xenografts antedates tumour regression. Breast Cancer Res Treat 1997; 45: 99-107.Google Scholar
  11. 11.
    Johnston SR, Boeddinghaus IM, Riddler S, et al. Idoxifene antagonizes estradiol-dependent MCF-7 breast cancer xenograft growth through sustained induction of apoptosis. Cancer Res 1999; 59: 3646-3651.Google Scholar
  12. 12.
    Mandlekar S, Hebbar V, Christov K, Kong AN. Pharmacodynamics of tamoxifen and its 4-hydroxy and N-desmethyl metabolites: Activation of caspases and induction of apoptosis in rat mammary tumors and in human breast cancer cell lines. Cancer Res 2000; 60: 6601-6606.Google Scholar
  13. 13.
    MacCallum J, Cummings J, Dixon JM, Miller WR. Concentrations of tamoxifen and its major metabolites in hormone responsive and resistant breast tumours. Br J Cancer 2000; 82: 1629-1635.Google Scholar
  14. 14.
    Cameron DA, Keen JC, Dixon JM, et al. Effective tamoxifen therapy of breast cancer involves both antiproliferative and pro-apoptotic changes. Eur J Cancer 2000; 36: 845-851.Google Scholar
  15. 15.
    Keen JC, Dixon JM, Miller EP, et al. The expression of Ki-S1 and BCL-2 and the response to primary tamoxifen therapy in elderly patients with breast cancer. Breast Cancer Res Treat 1997; 44: 123-133.Google Scholar
  16. 16.
    Lim CK, Yuan ZX, Lamb JH, White IN, De Matteis F, Smith LL. A comparative study of tamoxifen metabolism in female rat, mouse and human liver microsomes. Carcinogenesis 1994; 15: 589-593.Google Scholar
  17. 17.
    Lien EA, Solheim E, Ueland PM. Distribution of tamoxifen and its metabolites in rat and human tissues during steadystate treatment. Cancer Res 1991; 51: 4837-4844.Google Scholar
  18. 18.
    Fabian C, Tilzer L, Sternson L. Comparative binding affinities of tamoxifen, 4-hydroxytamoxifen, and desmethyltamoxifen for estrogen receptors isolated from human breast carcinoma: Correlation with blood levels in patients with metastatic breast cancer. Biopharm Drug Dispos 1981; 2: 381-390.Google Scholar
  19. 19.
    Mandlekar S, Yu R, Tan TH, Kong AN. Activation of caspase-3 and c-Jun NH2-terminal kinase-1 signaling pathways in tamoxifen-induced apoptosis of human breast cancer cells. Cancer Res 2000; 60: 5995-6000.Google Scholar
  20. 20.
    Musashi M, Ota S, Shiroshita N. The role of protein kinase C isoforms in cell proliferation and apoptosis. Int J Hematol 2000; 72: 12-19.Google Scholar
  21. 21.
    Cheng AL, Chuang SE, Fine RL, et al. Inhibition of the membrane translocation and activation of protein kinase C, and potentiation of doxorubicin-induced apoptosis of hepatocellular carcinoma cells by tamoxifen. Biochem Pharmacol 1998; 55: 523-531.Google Scholar
  22. 22.
    O'Brian CA, Housey GM, Weinstein IB. Specific and direct binding of protein kinase C to an immobilized tamoxifen analogue. Cancer Res 1988; 48: 3626-3629.Google Scholar
  23. 23.
    Gundimeda U, Chen ZH, Gopalakrishna R. Tamoxifen modulates protein kinase C via oxidative stress in estrogen receptor-negative breast cancer cells. J Biol Chem 1996; 271: 13504-13514.Google Scholar
  24. 24.
    Lavie Y, Zhang ZC, Cao HT, et al. Tamoxifen induces selective membrane association of protein kinase C epsilon in MCF-7 human breast cancer cells. Int J Cancer 1998; 77: 928-932.Google Scholar
  25. 25.
    O'Brian CA, Ward NE, Anderson BW. Role of specific interactions between protein kinase C and triphenylethylenes in inhibition of the enzyme. J Natl Cancer Inst 1988; 80: 1628-1633.Google Scholar
  26. 26.
    Cabot MC, Zhang Z, Cao H, et al. Tamoxifen activates cellular phospholipase C and D and elicits protein kinase C translocation. Int J Cancer 1997; 70: 567-574.Google Scholar
  27. 27.
    Datta R, Kojima H, Yoshida K, Kufe D. Caspase-3-mediated cleavage of protein kinase C theta in induction of apoptosis. J Biol Chem 1997; 272: 20317-20320.Google Scholar
  28. 28.
    Ghayur T, Hugunin M, Talanian RV, et al. Proteolytic activation of protein kinase C delta by an ICE/CED 3-like protease induces characteristics of apoptosis. J Exp Med 1996; 184: 2399-2404.Google Scholar
  29. 29.
    Majumder PK, Pandey P, Sun X, et al. Mitochondrial translocation of protein kinase C delta in phorbol ester-induced cytochrome c release and apoptosis. J Biol Chem 2000; 275: 21793-21796.Google Scholar
  30. 30.
    Horgan K, Cooke E, Hallett MB, Mansel RE. Inhibition of protein kinase C mediated signal transduction by tamoxifen. Importance for antitumour activity. Biochem Pharmacol 1986; 35: 4463-4465.Google Scholar
  31. 31.
    O'Brian CA, Ioannides CG, Ward NE, Liskamp RM. Inhibition of protein kinase C and calmodulin by the geometric isomers cis-and trans-tamoxifen. Biopolymers 1990; 29: 97-104.Google Scholar
  32. 32.
    Gulino A, Barrera G, Vacca A, et al. Calmodulin antagonism and growth-inhibiting activity of triphenylethylene antiestrogens in MCF-7 human breast cancer cells. Cancer Res 1986; 46: 6274-6278.Google Scholar
  33. 33.
    Improta-Brears T, Whorton AR, Codazzi F, York JD, Meyer T, McDonnell DP. Estrogen-induced activation of mitogenactivated protein kinase requires mobilization of intracellular calcium. Proc Natl Acad Sci USA 1999; 96: 4686-4691.Google Scholar
  34. 34.
    Zhang W, Couldwell WT, Song H, Takano T, Lin JH, Nedergaard M. Tamoxifen-induced enhancement of calcium signaling in glioma and MCF-7 breast cancer cells. Cancer Res 2000; 60: 5395-5400.Google Scholar
  35. 35.
    Maurer BJ, Metelitsa LS, Seeger RC, Cabot MC, Reynolds CP. Increase of ceramide and induction of mixed apoptosis/necrosis by N-(4-hydroxyphenyl)-retinamide in neuroblastoma cell lines. J Natl Cancer Inst 1999; 91: 1138-1146.Google Scholar
  36. 36.
    Haimovitz-Friedman A, Kolesnick RN, Fuks Z. Ceramide signaling in apoptosis. Br Med Bull 1997; 53: 539-553.Google Scholar
  37. 37.
    Perry DK. The role of de novo ceramide synthesis in chemotherapy-induced apoptosis. Ann NY Acad Sci 2000; 905: 91-96.Google Scholar
  38. 38.
    Sawada M, Nakashima S, Banno Y, et al. Ordering of ceramide formation, caspase activation, and Bax/Bcl-2 expression during etoposide-induced apoptosis in C6 glioma cells. Cell Death Differ 2000; 7: 761-772.Google Scholar
  39. 39.
    Yao B, Zhang Y, Delikat S, Mathias S, Basu S, Kolesnick R. Phosphorylation of Raf by ceramide-activated protein kinase. Nature 1995; 378: 307-310.Google Scholar
  40. 40.
    Basu S, Kolesnick R. Stress signals for apoptosis: Ceramide and c-Jun kinase. Oncogene 1998; 17: 3277-3285.Google Scholar
  41. 41.
    Zhou H, Summers SA, Birnbaum MJ, Pittman RN. Inhibition of Akt kinase by cell-permeable ceramide and its implications for ceramide-induced apoptosis. J Biol Chem 1998; 273: 16568-16575.Google Scholar
  42. 42.
    Salinas M, Lopez-Valdaliso R, Martin D, Alvarez A, Cuadrado A. Inhibition of PKB/Akt1 by C2-ceramide involves activation of ceramide-activated protein phosphatase in PC12 cells. Mol Cell Neurosci 2000; 15: 156-169.Google Scholar
  43. 43.
    Ruvolo PP, Deng X, Ito T, Carr BK, May WS. Ceramide induces Bcl2 dephosphorylation via a mechanism involving mitochondrial PP2A. J Biol Chem 1999; 274: 20296-20300.Google Scholar
  44. 44.
    Lavie Y, Cao H, Volner A, et al. Agents that reverse multidrug resistance, tamoxifen, verapamil, and cyclosporin A, block glycosphingolipid metabolism by inhibiting ceramide glycosylation in human cancer cells. J Biol Chem 1997; 272: 1682-1687.Google Scholar
  45. 45.
    Kang Y, Cortina R, Perry RR. Role of c-myc in tamoxifeninduced apoptosis estrogen-independent breast cancer cells. J Natl Cancer Inst 1996; 88: 279-284.Google Scholar
  46. 46.
    Leng Y, Gu ZP, Cao L. Apoptosis induced by droloxifene and c-myc, bax and bcl-2 mRNA expression in cultured luteal cells of rats. Eur J Pharmacol 2000; 409: 123-131.Google Scholar
  47. 47.
    Hotti A, Jarvinen K, Siivola P, Holtta E. Caspases and mitochondria in c-Myc-induced apoptosis: Identification of ATM as a new target of caspases. Oncogene 2000; 19: 2354-2362.Google Scholar
  48. 48.
    Kangas A, Nicholson DW, Hottla E. Involvement of CPP32/Caspase-3 in c-Myc-induced apoptosis. Oncogene 1998; 16: 387-398.Google Scholar
  49. 49.
    Dong J, Naito M, Tsuruo T. c-Myc plays a role in cellular susceptibility to death receptor-mediated and chemotherapyinduced apoptosis in human monocytic leukemia U937 cells. Oncogene 1997; 15: 639-647.Google Scholar
  50. 50.
    Xu Y, Nguyen Q, Lo DC, Czaja MJ. c-myc-dependent hepatoma cell apoptosis results from oxidative stress and not a deficiency of growth factors. J Cell Physiol 1997; 170: 192-199.Google Scholar
  51. 51.
    Klefstrom J, Arighi E, Littlewood T, et al. Induction of TNF-sensitive cellular phenotype by c-Myc involves p53 and impaired NF-kappaB activation. Embo J 1997; 16: 7382-7392.Google Scholar
  52. 52.
    Prendergast GC. Mechanisms of apoptosis by c-Myc. Oncogene 1999; 18: 2967-2987.Google Scholar
  53. 53.
    Dang CV. c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol 1999; 19: 1-11.Google Scholar
  54. 54.
    Packham G, Cleveland JL. Ornithine decarboxylase is a mediator of c-Myc-induced apoptosis. Mol Cell Biol 1994; 14: 5741-5747.Google Scholar
  55. 55.
    Shim H, Dolde C, Lewis et al. c-Myc transactivation of LDHA: Implications for tumor metabolism and growth. Proc Natl Acad Sci USA 1997; 94: 6658-6663.Google Scholar
  56. 56.
    Hoang AT, Cohen KJ, Barrett JF, Bergstrom DA, Dang CV. Participation of cyclin A in Myc-induced apoptosis. Proc Natl Acad Sci USA 1994; 91: 6875-6879.Google Scholar
  57. 57.
    Hueber AO, Zornig M, Lyon D, Suda T, Nagata S, Evan GI. Requirement for the CD95 receptor-ligand pathway in c-Myc-induced apoptosis. Science 1997; 278: 1305-1309.Google Scholar
  58. 58.
    Hu MC, Wang YP, Mikhail A, Qiu WR, Tan TH. Murine p38-delta mitogen-activated protein kinase, a developmentally regulated protein kinase that is activated by stress and proinflammatory cytokines. J Biol Chem 1999; 274: 7095-7102.Google Scholar
  59. 59.
    Bagrodia S, Derijard B, Davis RJ, Cerione RA. Cdc42 and PAK-mediated signaling leads to Jun kinase and p38 mitogen-activated protein kinase activation. J Biol Chem 1995; 270: 27995-27998.Google Scholar
  60. 60.
    Zhang S, Han J, Sells MA, et al. Rho family GTPases regulate p38 mitogen-activated protein kinase through the downstream mediator Pak1. J Biol Chem 1995; 270: 23934-23936.Google Scholar
  61. 61.
    Fanger GR, Gerwins P, Widmann C, Jarpe MB, Johnson GL. MEKKs, GCKs, MLKs, PAKs, TAKs, and tpls: Upstream regulators of the c-Jun amino-terminal kinases? Curr Opin Genet Dev 1997; 7: 67-74.Google Scholar
  62. 62.
    Ono K, Han J. The p38 signal transduction pathway: Activation and function. Cell Signal 2000; 12: 1-13.Google Scholar
  63. 63.
    Han J, Lee JD, Bibbs L, Ulevitch RJ. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 1994; 265: 808-811.Google Scholar
  64. 64.
    Shtil AA, Mandlekar S, Yu R, et al. Differential regulation of mitogen-activated protein kinases by microtubule-binding agents in human breast cancer cells. Oncogene 1999; 18: 377-384.Google Scholar
  65. 65.
    Moriguchi T, Kuroyanagi N, Yamaguchi K, et al. A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3. J Biol Chem 1996; 271: 13675-13679.Google Scholar
  66. 66.
    Chen YR, Wang X, Templeton D, Davis RJ, Tan TH. The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and gamma radiation. Duration of JNK activation may determine cell death and proliferation. J Biol Chem 1996; 271: 31929-31936.Google Scholar
  67. 67.
    Yu R, Jiao JJ, Duh JL, Tan TH, Kong AN. Phenethyl isothiocyanate, a natural chemopreventive agent, activates c-Jun N-terminal kinase 1. Cancer Res 1996; 56: 2954-2959.Google Scholar
  68. 68.
    Chen YR, Wang W, Kong AN, Tan TH. Molecular mechanisms of c-Jun N-terminal kinase-mediated apoptosis induced by anticarcinogenic isothiocyanates. J Biol Chem 1998; 273: 1769-1775.Google Scholar
  69. 69.
    Yu R, Shtil AA, Tan TH, Roninson IB, Kong AN. Adriamycin activates c-jun N-terminal kinase in human leukemia cells: A relevance to apoptosis. Cancer Lett 1996; 107: 73-81.Google Scholar
  70. 70.
    Zanke BW, Boudreau K, Rubie E, et al. The stress-activated protein kinase pathway mediates cell death following injury induced by cis-platinum, UV irradiation or heat. Curr Biol 1996; 6: 606-613.Google Scholar
  71. 71.
    Yuasa T, Ohno S, Kehrl JH, Kyriakis JM. Tumor necrosis factor signaling to stress-activated protein kinase (SAPK)/Jun NH2-terminal kinase (JNK) and p38. Germinal center kinase couples TRAF2 to mitogen-activated protein kinase/ERK kinase kinase 1 and SAPK while receptor interacting protein associates with a mitogen-activated protein kinase upstream of MKK6 and p38. J Biol Chem 1998; 273: 22681-22692.Google Scholar
  72. 72.
    Hibi M, Lin A, Smeal T, Minden A, Karin M. Identification of an oncoprotein-and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev 1993; 7: 2135-2148.Google Scholar
  73. 73.
    Ichijo H, Nishida E, Irie K, et al. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 1997; 275: 90-94.Google Scholar
  74. 74.
    Wang XZ, Ron D. Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP kinase. Science 1996; 272: 1347-1349.Google Scholar
  75. 75.
    Deak M, Clifton AD, Lucocq LM, Alessi DR. Mitogen-and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. Embo J 1998; 17: 4426-4441.Google Scholar
  76. 76.
    Zhang CC, Shapiro DJ. Activation of the p38 mitogenactivated protein kinase pathway by estrogen or by 4-hydroxytamoxifen is coupled to estrogen receptor-induced apoptosis. J Biol Chem 2000; 275: 479-486.Google Scholar
  77. 77.
    Earnshaw WC, Martins LM, Kaufmann SH. Mammalian caspases: Structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem 1999; 68: 383-424.Google Scholar
  78. 78.
    Thornberry NA. Caspases: Key mediators of apoptosis. Chem Biol 1998; 5: R97-103. (Review).Google Scholar
  79. 79.
    Cohen GM. Caspases: The executioners of apoptosis. Biochem J 1997; 326: 1-16.Google Scholar
  80. 80.
    Ashkenazi A, Dixit VM. Apoptosis control by death and decoy receptors. Curr Opin Cell Biol 1999; 11: 255-260.Google Scholar
  81. 81.
    Boesen-de Cock JG, Tepper AD, de Vries E, van Blitterswijk WJ, Borst J. Common regulation of apoptosis signaling induced by CD95 and the DNA-damaging stimuli etoposide and gamma-radiation downstream from caspase-8 activation. J Biol Chem 1999; 274: 14255-14261.Google Scholar
  82. 82.
    Fulda S, Sieverts H, Friesen C, Herr I, Debatin KM. The CD95 (APO-1/Fas) system mediates drug-induced apoptosis in neuroblastoma cells. Cancer Res 1997; 57: 3823-3829.Google Scholar
  83. 83.
    Fulda S, Scaffidi C, Susin SA, et al. Activation of mitochondria and release of mitochondrial apoptogenic factors by betulinic acid. J Biol Chem 1998; 273: 33942-33948.Google Scholar
  84. 84.
    Micheau O, Solary E, Hammann A, Dimanche-Boitrel MT. Fas ligand-independent, FADD-mediated activation of the Fas death pathway by anticancer drugs. J Biol Chem 1999; 274: 7987-7992.Google Scholar
  85. 85.
    Wesselborg S, Engels IH, Rossmann E, Los M, Schulze-Osthoff K. Anticancer drugs induce caspase-8/FLICE activation and apoptosis in the absence of CD95 receptor/ligand interaction. Blood 1999; 93: 3053-3063.Google Scholar
  86. 86.
    Shen HM, Yang CF, Ding WX, Liu J, Ong CN. Superoxide radical-initiated apoptotic signalling pathway in selenitetreated HepG(2) cells: Mitochondria serve as the main target. Free Radic Biol Med 2001; 30: 9-21.Google Scholar
  87. 87.
    Larochette N, Decaudin D, Jacotot E, et al. Arsenite induces apoptosis via a direct effect on the mitochondrial permeability transition pore. Exp Cell Res 1999; 249: 413-421.Google Scholar
  88. 88.
    Chauhan D, Pandey P, Ogata A, et al. Cytochrome cdependent and-independent induction of apoptosis in multiple myeloma cells. J Biol Chem 1997; 272: 29995-29997.Google Scholar
  89. 89.
    Degen WG, Pruijn GJ, Raats JM, van Venrooij WJ. Caspasedependent cleavage of nucleic acids. Cell Death Differ 2000; 7: 616-627.Google Scholar
  90. 90.
    Stroh C, Schulze-Osthoff K. Death by a thousand cuts: An ever increasing list of caspase substrates. Cell Death Differ 1998; 5: 997-1000.Google Scholar
  91. 91.
    Casciola-Rosen LA, Miller DK, Anhalt GJ, Rosen A. Specific cleavage of the 70-kDa protein component of the U1 small nuclear ribonucleoprotein is a characteristic biochemical feature of apoptotic cell death. J Biol Chem 1994; 269: 30757-30760.Google Scholar
  92. 92.
    Casciola-Rosen LA, Anhalt GJ, Rosen A. DNA-dependent protein kinase is one of a subset of autoantigens specifically cleaved early during apoptosis. J Exp Med 1995; 182: 1625-1634.Google Scholar
  93. 93.
    Faleiro L, Lazebnik Y. Caspases disrupt the nuclearcytoplasmic barrier. J Cell Biol 2000; 151: 951-959.Google Scholar
  94. 94.
    Fattman CL, An B, Sussman L, Dou QP. p53-independent dephosphorylation and cleavage of retinoblastoma protein during tamoxifen-induced apoptosis in human breast carcinoma cells. Cancer Lett 1998; 130: 103-113.Google Scholar
  95. 95.
    Hirsch T, Susin SA, Marzo I, Marchetti P, Zamzami N, Kroemer G. Mitochondrial permeability transition in apoptosis and necrosis. Cell Biol Toxicol 1998; 14: 141-145.Google Scholar
  96. 96.
    Li P, Nijhawan D, Budihardjo I, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997; 91: 479-489.Google Scholar
  97. 97.
    Zou H, Li Y, Liu X, Wang X. An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem 1999; 274: 11549-11556.Google Scholar
  98. 98.
    Tuquet C, Dupont J, Mesneau A, Roussaux J. Effects of tamoxifen on the electron transport chain of isolated rat liver mitochondria. Cell Biol Toxicol 2000; 16: 207-219.Google Scholar
  99. 99.
    Dietze EC, Caldwell LE, Grupin SL, Mancini M, Seewaldt VL. Tamoxifen but not 4-hydroxytamoxifen initiates apoptosis in p53(-) normal human mammary epithelial cells by inducing mitochondrial depolarization. J Biol Chem 2000; 63: 3.Google Scholar
  100. 100.
    Zhou G, Lee SC, Yao Z, Tan TH. Hematopoietic progenitor kinase 1 is a component of transforming growth factor betainduced c-Jun N-terminal kinase signaling cascade. J Biol Chem 1999; 274: 13133-13138.Google Scholar
  101. 101.
    Butta A, MacLennan K, Flanders KC, et al. Induction of transforming growth factor beta 1 in human breast cancer in vivo following tamoxifen treatment. Cancer Res 1992; 52: 4261-4264.Google Scholar
  102. 102.
    van Roozendaal CE, Klijn JG, van Ooijen B, et al. Transforming growth factor beta secretion from primary breast cancer fibroblasts. Mol Cell Endocrinol 1995; 111: 1-6.Google Scholar
  103. 103.
    Koli KM, Ramsey TT, Ko Y, Dugger TC, Brattain MG, Arteaga CL. Blockade of transforming growth factor-beta signaling does not abrogate antiestrogen-induced growth inhibition of human breast carcinoma cells. J Biol Chem 1997; 272: 8296-8302.Google Scholar
  104. 104.
    Perry RR, Kang Y, Greaves BR. Relationship between tamoxifen-induced transforming growth factor beta 1 expression, cytostasis and apoptosis in human breast cancer cells. Br J Cancer 1995; 72: 1441-1446.Google Scholar
  105. 105.
    Colletta AA, Wakefield LM, Howell FV, et al. Anti-oestrogens induce the secretion of active transforming growth factor beta from human fetal fibroblasts. Br J Cancer 1990; 62: 405-409.Google Scholar
  106. 106.
    Chen H, Tritton TR, Kenny N, Absher M, Chiu JF. Tamoxifen induces TGF-beta 1 activity and apoptosis of human MCF-7 breast cancer cells in vitro. J Cell Biochem 1996; 61: 9-17.Google Scholar
  107. 107.
    Custodio JB, Dinis TC, Almeida LM, MadeiraVM. Tamoxifen and hydroxytamoxifen as intramembraneous inhibitors of lipid peroxidation. Evidence for peroxyl radical scavenging activity. Biochem Pharmacol 1994; 47: 1989-1998.Google Scholar
  108. 108.
    Custodio JB, Moreno AJ, Wallace KB. Tamoxifen inhibits induction of the mitochondrial permeability transition by Ca2+ and inorganic phosphate. Toxicol Appl Pharmacol 1998; 152: 10-17.Google Scholar
  109. 109.
    Shao ZM, Radziszewski WJ, Barsky SH. Tamoxifen enhances myoepithelial cell suppression of human breast carcinoma progression in vitro by two different effector mechanisms. Cancer Lett 2000; 157: 133-144.Google Scholar
  110. 110.
    Mor G, Kohen F, Garcia-Velasco J, et al. Regulation of fas ligand expression in breast cancer cells by estrogen: Functional differences between estradiol and tamoxifen. J Steroid Biochem Mol Biol 2000; 73: 185-194.Google Scholar
  111. 111.
    Guvakova MA, Surmacz E. Tamoxifen interferes with the insulin-like growth factor I receptor (IGF-IR) signaling pathway in breast cancer cells. Cancer Res 1997; 57: 2606-2610.Google Scholar
  112. 112.
    Colletta AA, Benson JR, Baum M. Alternative mechanisms of action of anti-oestrogens. Breast Cancer Res Treat 1994; 31: 5-9.Google Scholar

Copyright information

© Kluwer Academic Publishers 2001

Authors and Affiliations

  • S. Mandlekar
    • 1
  • A.-N. T. Kong
    • 2
  1. 1.Department of Drug Metabolism and PharmacokineticsDuPont Pharmaceuticals CompanyNewarkUSA
  2. 2.Department of Pharmaceutics, College of Pharmacy and the Environmental and Occupational Health Sciences InstituteRutgers UniversityPiscatawayUSA

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