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. 1996 May 15;97(10):2268–2276. doi: 10.1172/JCI118668

Redox control of resistance to cis-diamminedichloroplatinum (II) (CDDP): protective effect of human thioredoxin against CDDP-induced cytotoxicity.

T Sasada 1, S Iwata 1, N Sato 1, Y Kitaoka 1, K Hirota 1, K Nakamura 1, A Nishiyama 1, Y Taniguchi 1, A Takabayashi 1, J Yodoi 1
PMCID: PMC507306  PMID: 8636406

Abstract

Thioredoxin is a small ubiquitous protein with multiple biological functions, including cellular defense mechanisms against oxidative stress. In the present study, we investigated the role of human thioredoxin (hTRX) in the acquisition of cellular resistance to cis-diamminedichloroplatinum (II) (CDDP). The expression and activity of hTRX in Jurkat T cells was dose-dependently enhanced by exposure to CDDP, as determined by immunoblot analysis and insulin reducing assay. Furthermore, chloramphenicol acetyltransferase analysis using the hTRX promoter-reporter gene construct revealed that treatment of Jurkat cells with CDDP caused transcriptional activation of the hTRX gene, which might be mediated through increased generation of intracellular reactive oxygen intermediates. To examine the biological significance of hTRX induction, we established hTRX-overexpressing derivatives of L929 fibrosarcoma cells by stable transfection with the hTRX cDNA. The clones, which constitutively expressed the exogenous hTRX, displayed increased resistance to CDDP-induced cytotoxicity, compared with the control clones. After exposure to CDDP, the control cells showed a significant increase in the intracellular accumulation of peroxides, whereas the hTRX-transfected cells did not. Taken together, these results suggest that overexpressed hTRX is responsible for the development of cellular resistance to CDDP, possibly by scavenging intracellular toxic oxidants generated by this anticancer agent.

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Selected References

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  1. Abate C., Patel L., Rauscher F. J., 3rd, Curran T. Redox regulation of fos and jun DNA-binding activity in vitro. Science. 1990 Sep 7;249(4973):1157–1161. doi: 10.1126/science.2118682. [DOI] [PubMed] [Google Scholar]
  2. Andrews P. A., Murphy M. P., Howell S. B. Metallothionein-mediated cisplatin resistance in human ovarian carcinoma cells. Cancer Chemother Pharmacol. 1987;19(2):149–154. doi: 10.1007/BF00254568. [DOI] [PubMed] [Google Scholar]
  3. Arnér E. S., Björnstedt M., Holmgren A. 1-Chloro-2,4-dinitrobenzene is an irreversible inhibitor of human thioredoxin reductase. Loss of thioredoxin disulfide reductase activity is accompanied by a large increase in NADPH oxidase activity. J Biol Chem. 1995 Feb 24;270(8):3479–3482. doi: 10.1074/jbc.270.8.3479. [DOI] [PubMed] [Google Scholar]
  4. Bass D. A., Parce J. W., Dechatelet L. R., Szejda P., Seeds M. C., Thomas M. Flow cytometric studies of oxidative product formation by neutrophils: a graded response to membrane stimulation. J Immunol. 1983 Apr;130(4):1910–1917. [PubMed] [Google Scholar]
  5. Björnstedt M., Hamberg M., Kumar S., Xue J., Holmgren A. Human thioredoxin reductase directly reduces lipid hydroperoxides by NADPH and selenocystine strongly stimulates the reaction via catalytically generated selenols. J Biol Chem. 1995 May 19;270(20):11761–11764. doi: 10.1074/jbc.270.20.11761. [DOI] [PubMed] [Google Scholar]
  6. Björnstedt M., Xue J., Huang W., Akesson B., Holmgren A. The thioredoxin and glutaredoxin systems are efficient electron donors to human plasma glutathione peroxidase. J Biol Chem. 1994 Nov 25;269(47):29382–29384. [PubMed] [Google Scholar]
  7. Buttke T. M., Sandstrom P. A. Oxidative stress as a mediator of apoptosis. Immunol Today. 1994 Jan;15(1):7–10. doi: 10.1016/0167-5699(94)90018-3. [DOI] [PubMed] [Google Scholar]
  8. Chae H. Z., Chung S. J., Rhee S. G. Thioredoxin-dependent peroxide reductase from yeast. J Biol Chem. 1994 Nov 4;269(44):27670–27678. [PubMed] [Google Scholar]
  9. Chiu C. S., Chan A. K., Wright J. A. Inhibition of mammalian ribonucleotide reductase by cis-diamminedichloroplatinum(II). Biochem Cell Biol. 1992 Dec;70(12):1332–1338. doi: 10.1139/o92-181. [DOI] [PubMed] [Google Scholar]
  10. Chu G. Cellular responses to cisplatin. The roles of DNA-binding proteins and DNA repair. J Biol Chem. 1994 Jan 14;269(2):787–790. [PubMed] [Google Scholar]
  11. Cohen M. H., Chretien P. B., Ihde D. C., Fossieck B. E., Jr, Makuch R., Bunn P. A., Jr, Johnston A. V., Shackney S. E., Matthews M. J., Lipson S. D. Thymosin fraction V and intensive combination chemotherapy. Prolonging the survival of patients with small-cell lung cancer. JAMA. 1979 Apr 27;241(17):1813–1815. doi: 10.1001/jama.241.17.1813. [DOI] [PubMed] [Google Scholar]
  12. Dedon P. C., Borch R. F. Characterization of the reactions of platinum antitumor agents with biologic and nonbiologic sulfur-containing nucleophiles. Biochem Pharmacol. 1987 Jun 15;36(12):1955–1964. doi: 10.1016/0006-2952(87)90494-1. [DOI] [PubMed] [Google Scholar]
  13. Devary Y., Gottlieb R. A., Lau L. F., Karin M. Rapid and preferential activation of the c-jun gene during the mammalian UV response. Mol Cell Biol. 1991 May;11(5):2804–2811. doi: 10.1128/mcb.11.5.2804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Dole M., Nuñez G., Merchant A. K., Maybaum J., Rode C. K., Bloch C. A., Castle V. P. Bcl-2 inhibits chemotherapy-induced apoptosis in neuroblastoma. Cancer Res. 1994 Jun 15;54(12):3253–3259. [PubMed] [Google Scholar]
  15. Fujii S., Nanbu Y., Nonogaki H., Konishi I., Mori T., Masutani H., Yodoi J. Coexpression of adult T-cell leukemia-derived factor, a human thioredoxin homologue, and human papillomavirus DNA in neoplastic cervical squamous epithelium. Cancer. 1991 Oct 1;68(7):1583–1591. doi: 10.1002/1097-0142(19911001)68:7<1583::aid-cncr2820680720>3.0.co;2-n. [DOI] [PubMed] [Google Scholar]
  16. Gasdaska P. Y., Oblong J. E., Cotgreave I. A., Powis G. The predicted amino acid sequence of human thioredoxin is identical to that of the autocrine growth factor human adult T-cell derived factor (ADF): thioredoxin mRNA is elevated in some human tumors. Biochim Biophys Acta. 1994 Aug 2;1218(3):292–296. doi: 10.1016/0167-4781(94)90180-5. [DOI] [PubMed] [Google Scholar]
  17. Godwin A. K., Meister A., O'Dwyer P. J., Huang C. S., Hamilton T. C., Anderson M. E. High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3070–3074. doi: 10.1073/pnas.89.7.3070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hannemann J., Baumann K. Cisplatin-induced lipid peroxidation and decrease of gluconeogenesis in rat kidney cortex: different effects of antioxidants and radical scavengers. Toxicology. 1988 Oct;51(2-3):119–132. doi: 10.1016/0300-483x(88)90143-6. [DOI] [PubMed] [Google Scholar]
  19. Hockenbery D. M., Oltvai Z. N., Yin X. M., Milliman C. L., Korsmeyer S. J. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell. 1993 Oct 22;75(2):241–251. doi: 10.1016/0092-8674(93)80066-n. [DOI] [PubMed] [Google Scholar]
  20. Hollander M. C., Fornace A. J., Jr Induction of fos RNA by DNA-damaging agents. Cancer Res. 1989 Apr 1;49(7):1687–1692. [PubMed] [Google Scholar]
  21. Holmgren A., Björnstedt M. Thioredoxin and thioredoxin reductase. Methods Enzymol. 1995;252:199–208. doi: 10.1016/0076-6879(95)52023-6. [DOI] [PubMed] [Google Scholar]
  22. Holmgren A. Thioredoxin and glutaredoxin systems. J Biol Chem. 1989 Aug 25;264(24):13963–13966. [PubMed] [Google Scholar]
  23. Holmgren A. Thioredoxin. Annu Rev Biochem. 1985;54:237–271. doi: 10.1146/annurev.bi.54.070185.001321. [DOI] [PubMed] [Google Scholar]
  24. Hori K., Katayama M., Sato N., Ishii K., Waga S., Yodoi J. Neuroprotection by glial cells through adult T cell leukemia-derived factor/human thioredoxin (ADF/TRX). Brain Res. 1994 Aug 1;652(2):304–310. doi: 10.1016/0006-8993(94)90241-0. [DOI] [PubMed] [Google Scholar]
  25. Hurta R. A., Wright J. A. Alterations in the activity and regulation of mammalian ribonucleotide reductase by chlorambucil, a DNA damaging agent. J Biol Chem. 1992 Apr 5;267(10):7066–7071. [PubMed] [Google Scholar]
  26. Israël N., Gougerot-Pocidalo M. A., Aillet F., Virelizier J. L. Redox status of cells influences constitutive or induced NF-kappa B translocation and HIV long terminal repeat activity in human T and monocytic cell lines. J Immunol. 1992 Nov 15;149(10):3386–3393. [PubMed] [Google Scholar]
  27. Iwata S., Hori T., Sato N., Ueda-Taniguchi Y., Yamabe T., Nakamura H., Masutani H., Yodoi J. Thiol-mediated redox regulation of lymphocyte proliferation. Possible involvement of adult T cell leukemia-derived factor and glutathione in transferrin receptor expression. J Immunol. 1994 Jun 15;152(12):5633–5642. [PubMed] [Google Scholar]
  28. Kane D. J., Sarafian T. A., Anton R., Hahn H., Gralla E. B., Valentine J. S., Ord T., Bredesen D. E. Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science. 1993 Nov 19;262(5137):1274–1277. doi: 10.1126/science.8235659. [DOI] [PubMed] [Google Scholar]
  29. Kelley S. L., Basu A., Teicher B. A., Hacker M. P., Hamer D. H., Lazo J. S. Overexpression of metallothionein confers resistance to anticancer drugs. Science. 1988 Sep 30;241(4874):1813–1815. doi: 10.1126/science.3175622. [DOI] [PubMed] [Google Scholar]
  30. Kitaoka Y., Sorachi K., Nakamura H., Masutani H., Mitsui A., Kobayashi F., Mori T., Yodoi J. Detection of adult T-cell leukemia-derived factor/human thioredoxin in human serum. Immunol Lett. 1994 Jul;41(2-3):155–161. doi: 10.1016/0165-2478(94)90126-0. [DOI] [PubMed] [Google Scholar]
  31. Luthman M., Holmgren A. Rat liver thioredoxin and thioredoxin reductase: purification and characterization. Biochemistry. 1982 Dec 21;21(26):6628–6633. doi: 10.1021/bi00269a003. [DOI] [PubMed] [Google Scholar]
  32. Makino S., Masutani H., Maekawa N., Konishi I., Fujii S., Yamamoto R., Yodoi J. Adult T-cell leukaemia-derived factor/thioredoxin expression on the HTLV-I transformed T-cell lines: heterogeneous expression in ALT-2 cells. Immunology. 1992 Aug;76(4):578–583. [PMC free article] [PubMed] [Google Scholar]
  33. Masuda H., Tanaka T., Takahama U. Cisplatin generates superoxide anion by interaction with DNA in a cell-free system. Biochem Biophys Res Commun. 1994 Sep 15;203(2):1175–1180. doi: 10.1006/bbrc.1994.2306. [DOI] [PubMed] [Google Scholar]
  34. Matsuda M., Masutani H., Nakamura H., Miyajima S., Yamauchi A., Yonehara S., Uchida A., Irimajiri K., Horiuchi A., Yodoi J. Protective activity of adult T cell leukemia-derived factor (ADF) against tumor necrosis factor-dependent cytotoxicity on U937 cells. J Immunol. 1991 Dec 1;147(11):3837–3841. [PubMed] [Google Scholar]
  35. McClarty G. A., Chan A. K., Wright J. A. Hydroxyurea-induced conversion of mammalian ribonucleotide reductase to a form hypersensitive to bleomycin. Cancer Res. 1986 Sep;46(9):4516–4521. [PubMed] [Google Scholar]
  36. McGinness J. E., Proctor P. H., Demopoulos H. B., Hokanson J. A., Kirkpatrick D. S. Amelioration of cis-platinum nephrotoxicity by orgotein (superoxide dismutase). Physiol Chem Phys. 1978;10(3):267–277. [PubMed] [Google Scholar]
  37. Meijer C., Mulder N. H., Hospers G. A., Uges D. R., de Vries E. G. The role of glutathione in resistance to cisplatin in a human small cell lung cancer cell line. Br J Cancer. 1990 Jul;62(1):72–77. doi: 10.1038/bjc.1990.232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Mitsui A., Hirakawa T., Yodoi J. Reactive oxygen-reducing and protein-refolding activities of adult T cell leukemia-derived factor/human thioredoxin. Biochem Biophys Res Commun. 1992 Aug 14;186(3):1220–1226. doi: 10.1016/s0006-291x(05)81536-0. [DOI] [PubMed] [Google Scholar]
  39. Miyashita T., Reed J. C. Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line. Blood. 1993 Jan 1;81(1):151–157. [PubMed] [Google Scholar]
  40. Nakamura H., Masutani H., Tagaya Y., Yamauchi A., Inamoto T., Nanbu Y., Fujii S., Ozawa K., Yodoi J. Expression and growth-promoting effect of adult T-cell leukemia-derived factor. A human thioredoxin homologue in hepatocellular carcinoma. Cancer. 1992 Apr 15;69(8):2091–2097. doi: 10.1002/1097-0142(19920415)69:8<2091::aid-cncr2820690814>3.0.co;2-x. [DOI] [PubMed] [Google Scholar]
  41. Nakamura H., Matsuda M., Furuke K., Kitaoka Y., Iwata S., Toda K., Inamoto T., Yamaoka Y., Ozawa K., Yodoi J. Adult T cell leukemia-derived factor/human thioredoxin protects endothelial F-2 cell injury caused by activated neutrophils or hydrogen peroxide. Immunol Lett. 1994 Sep;42(1-2):75–80. doi: 10.1016/0165-2478(94)90038-8. [DOI] [PubMed] [Google Scholar]
  42. Oblong J. E., Gasdaska P. Y., Sherrill K., Powis G. Purification of human thioredoxin reductase: properties and characterization by absorption and circular dichroism spectroscopy. Biochemistry. 1993 Jul 20;32(28):7271–7277. doi: 10.1021/bi00079a025. [DOI] [PubMed] [Google Scholar]
  43. Okamoto T., Ogiwara H., Hayashi T., Mitsui A., Kawabe T., Yodoi J. Human thioredoxin/adult T cell leukemia-derived factor activates the enhancer binding protein of human immunodeficiency virus type 1 by thiol redox control mechanism. Int Immunol. 1992 Jul;4(7):811–819. doi: 10.1093/intimm/4.7.811. [DOI] [PubMed] [Google Scholar]
  44. Rubin E., Kharbanda S., Gunji H., Weichselbaum R., Kufe D. cis-Diamminedichloroplatinum(II) induces c-jun expression in human myeloid leukemia cells: potential involvement of a protein kinase C-dependent signaling pathway. Cancer Res. 1992 Feb 15;52(4):878–882. [PubMed] [Google Scholar]
  45. Sachi Y., Hirota K., Masutani H., Toda K., Okamoto T., Takigawa M., Yodoi J. Induction of ADF/TRX by oxidative stress in keratinocytes and lymphoid cells. Immunol Lett. 1995 Jan;44(2-3):189–193. doi: 10.1016/0165-2478(95)00213-o. [DOI] [PubMed] [Google Scholar]
  46. Sato N., Iwata S., Nakamura K., Hori T., Mori K., Yodoi J. Thiol-mediated redox regulation of apoptosis. Possible roles of cellular thiols other than glutathione in T cell apoptosis. J Immunol. 1995 Apr 1;154(7):3194–3203. [PubMed] [Google Scholar]
  47. Schreck R., Rieber P., Baeuerle P. A. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J. 1991 Aug;10(8):2247–2258. doi: 10.1002/j.1460-2075.1991.tb07761.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Schulze-Osthoff K., Beyaert R., Vandevoorde V., Haegeman G., Fiers W. Depletion of the mitochondrial electron transport abrogates the cytotoxic and gene-inductive effects of TNF. EMBO J. 1993 Aug;12(8):3095–3104. doi: 10.1002/j.1460-2075.1993.tb05978.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Smith S. L., Douglas K. T. Stereoselective, strong inhibition of ribonucleotide reductase from E. coli by cisplatin. Biochem Biophys Res Commun. 1989 Jul 31;162(2):715–723. doi: 10.1016/0006-291x(89)92369-3. [DOI] [PubMed] [Google Scholar]
  50. Sodhi A., Gupta P. Increased release of hydrogen peroxide (H2O2) and superoxide anion (O-2) by murine macrophages in vitro after cis-platin treatment. Int J Immunopharmacol. 1986;8(7):709–714. doi: 10.1016/0192-0561(86)90006-8. [DOI] [PubMed] [Google Scholar]
  51. Southern P. J., Berg P. Transformation of mammalian cells to antibiotic resistance with a bacterial gene under control of the SV40 early region promoter. J Mol Appl Genet. 1982;1(4):327–341. [PubMed] [Google Scholar]
  52. Sugihara K., Gemba M. Modification of cisplatin toxicity by antioxidants. Jpn J Pharmacol. 1986 Feb;40(2):353–355. doi: 10.1254/jjp.40.353. [DOI] [PubMed] [Google Scholar]
  53. Tagaya Y., Maeda Y., Mitsui A., Kondo N., Matsui H., Hamuro J., Brown N., Arai K., Yokota T., Wakasugi H. ATL-derived factor (ADF), an IL-2 receptor/Tac inducer homologous to thioredoxin; possible involvement of dithiol-reduction in the IL-2 receptor induction. EMBO J. 1989 Mar;8(3):757–764. doi: 10.1002/j.1460-2075.1989.tb03436.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Tagaya Y., Okada M., Sugie K., Kasahara T., Kondo N., Hamuro J., Matsushima K., Dinarello C. A., Yodoi J. IL-2 receptor(p55)/Tac-inducing factor. Purification and characterization of adult T cell leukemia-derived factor. J Immunol. 1988 Apr 15;140(8):2614–2620. [PubMed] [Google Scholar]
  55. Timmer-Bosscha H., Mulder N. H., de Vries E. G. Modulation of cis-diamminedichloroplatinum(II) resistance: a review. Br J Cancer. 1992 Aug;66(2):227–238. doi: 10.1038/bjc.1992.249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Toyokuni S., Okamoto K., Yodoi J., Hiai H. Persistent oxidative stress in cancer. FEBS Lett. 1995 Jan 16;358(1):1–3. doi: 10.1016/0014-5793(94)01368-b. [DOI] [PubMed] [Google Scholar]
  57. Wells W. W., Rocque P. A., Xu D. P., Yang Y., Deits T. L. Interactions of platinum complexes with thioltransferase(glutaredoxin), in vitro. Biochem Biophys Res Commun. 1991 Oct 31;180(2):735–741. doi: 10.1016/s0006-291x(05)81127-1. [DOI] [PubMed] [Google Scholar]
  58. Yodoi J., Uchiyama T. Diseases associated with HTLV-I: virus, IL-2 receptor dysregulation and redox regulation. Immunol Today. 1992 Oct;13(10):405–411. doi: 10.1016/0167-5699(92)90091-K. [DOI] [PubMed] [Google Scholar]
  59. Yokomizo A., Ono M., Nanri H., Makino Y., Ohga T., Wada M., Okamoto T., Yodoi J., Kuwano M., Kohno K. Cellular levels of thioredoxin associated with drug sensitivity to cisplatin, mitomycin C, doxorubicin, and etoposide. Cancer Res. 1995 Oct 1;55(19):4293–4296. [PubMed] [Google Scholar]
  60. Zelazowski A. J., Garvey J. S., Hoeschele J. D. In vivo and in vitro binding of platinum to metallothionein. Arch Biochem Biophys. 1984 Feb 15;229(1):246–252. doi: 10.1016/0003-9861(84)90150-4. [DOI] [PubMed] [Google Scholar]
  61. Zoumpourlis V., Kerr D. J., Spandidos D. A. Carboplatin as opposed to cisplatin does not stimulate the expression of the human immunodeficiency virus long terminal repeat sequences. Biochem Pharmacol. 1992 Feb 4;43(3):650–654. doi: 10.1016/0006-2952(92)90592-7. [DOI] [PubMed] [Google Scholar]

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