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Nucleic Acids Res. Nov 1, 1996; 24(21): 4242–4248.
PMCID: PMC146228

Topoisomerase poisons activate the transcription factor NF-kappaB in ACH-2 and CEM cells.


The nuclear factor kappaB (NF-kappaB) is involved in T cell activation and enhances HIV-1 gene expression. It is activated in response to numerous stimuli, including oxidative stress. Oxidative stress damages membrane lipids, proteins and nucleic acids. We have shown previously that oxidative DNA damage generated by photosensitization could trigger activation of NF-kappaB. We now show that a series of topoisomerase poisons (actinomycin D, camptothecin, daunomycin and etoposide) also activate NF-kappaB (NFKB1/RelA dimer) in ACH-2 and CEM cells. This activation is inhibited by pyrrolidine dithiocarbamate. In ACH-2 cells latently infected by HIV-1, camptothecin, daunomycin and etoposide are able to enhance virus production. Since topoisomerase poisons cause the formation of single- and double-strand breaks in DNA, these lesions might be capable of triggering NF-kappaB activation. Indeed, DNA damaging agents generating adducts (trans-platin and 4-nitroquinoline 1-oxide) and/or crosslinks in DNA (cisplatin and mitomycin C) do not or only weakly activate NF-kappaB in T cell lines.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Miyamoto S, Verma IM. Rel/NF-kappa B/I kappa B story. Adv Cancer Res. 1995;66:255–292. [PubMed]
  • Baldwin AS., Jr The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 1996;14:649–683. [PubMed]
  • Chen Z, Hagler J, Palombella VJ, Melandri F, Scherer D, Ballard D, Maniatis T. Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway. Genes Dev. 1995 Jul 1;9(13):1586–1597. [PubMed]
  • Chen ZJ, Parent L, Maniatis T. Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity. Cell. 1996 Mar 22;84(6):853–862. [PubMed]
  • Alcamí J, Laín de Lera T, Folgueira L, Pedraza MA, Jacqué JM, Bachelerie F, Noriega AR, Hay RT, Harrich D, Gaynor RB, et al. Absolute dependence on kappa B responsive elements for initiation and Tat-mediated amplification of HIV transcription in blood CD4 T lymphocytes. EMBO J. 1995 Apr 3;14(7):1552–1560. [PMC free article] [PubMed]
  • Kim JY, Gonzalez-Scarano F, Zeichner SL, Alwine JC. Replication of type 1 human immunodeficiency viruses containing linker substitution mutations in the -201 to -130 region of the long terminal repeat. J Virol. 1993 Mar;67(3):1658–1662. [PMC free article] [PubMed]
  • Antoni BA, Stein SB, Rabson AB. Regulation of human immunodeficiency virus infection: implications for pathogenesis. Adv Virus Res. 1994;43:53–145. [PubMed]
  • Schulze-Osthoff K, Los M, Baeuerle PA. Redox signalling by transcription factors NF-kappa B and AP-1 in lymphocytes. Biochem Pharmacol. 1995 Sep 7;50(6):735–741. [PubMed]
  • Anderson MT, Staal FJ, Gitler C, Herzenberg LA, Herzenberg LA. Separation of oxidant-initiated and redox-regulated steps in the NF-kappa B signal transduction pathway. Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11527–11531. [PMC free article] [PubMed]
  • Schreck R, Rieber P, Baeuerle PA. 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. [PMC free article] [PubMed]
  • Piret B, Legrand-Poels S, Sappey C, Piette J. NF-kappa B transcription factor and human immunodeficiency virus type 1 (HIV-1) activation by methylene blue photosensitization. Eur J Biochem. 1995 Mar 1;228(2):447–455. [PubMed]
  • Martínez-Cayuela M. Oxygen free radicals and human disease. Biochimie. 1995;77(3):147–161. [PubMed]
  • Pace GW, Leaf CD. The role of oxidative stress in HIV disease. Free Radic Biol Med. 1995 Oct;19(4):523–528. [PubMed]
  • Legrand-Poels S, Bours V, Piret B, Pflaum M, Epe B, Rentier B, Piette J. Transcription factor NF-kappa B is activated by photosensitization generating oxidative DNA damages. J Biol Chem. 1995 Mar 24;270(12):6925–6934. [PubMed]
  • Quinto I, Ruocco MR, Baldassarre F, Mallardo M, Dragonetti E, Scala G. The human immunodeficiency virus type 1 long terminal repeat is activated by monofunctional and bifunctional DNA alkylating agents in human lymphocytes. J Biol Chem. 1993 Dec 15;268(35):26719–26724. [PubMed]
  • Woloschak GE, Panozzo J, Schreck S, Libertin CR. Salicylic acid inhibits ultraviolet- and cis-platinum-induced human immunodeficiency virus expression. Cancer Res. 1995 Apr 15;55(8):1696–1700. [PubMed]
  • Brach MA, Kharbanda SM, Herrmann F, Kufe DW. Activation of the transcription factor kappa B in human KG-1 myeloid leukemia cells treated with 1-beta-D-arabinofuranosylcytosine. Mol Pharmacol. 1992 Jan;41(1):60–63. [PubMed]
  • O'Brien MC, Ueno T, Jahan N, Zajac-Kaye M, Mitsuya H. HIV-1 expression induced by anti-cancer agents in latently HIV-1-infected ACH2 cells. Biochem Biophys Res Commun. 1995 Feb 27;207(3):903–909. [PubMed]
  • Zmudzka BZ, Beer JZ. Activation of human immunodeficiency virus by ultraviolet radiation. Photochem Photobiol. 1990 Dec;52(6):1153–1162. [PubMed]
  • Brach MA, Hass R, Sherman ML, Gunji H, Weichselbaum R, Kufe D. Ionizing radiation induces expression and binding activity of the nuclear factor kappa B. J Clin Invest. 1991 Aug;88(2):691–695. [PMC free article] [PubMed]
  • Vile GF, Tanew-Ilitschew A, Tyrrell RM. Activation of NF-kappa B in human skin fibroblasts by the oxidative stress generated by UVA radiation. Photochem Photobiol. 1995 Sep;62(3):463–468. [PubMed]
  • Simon MM, Aragane Y, Schwarz A, Luger TA, Schwarz T. UVB light induces nuclear factor kappa B (NF kappa B) activity independently from chromosomal DNA damage in cell-free cytosolic extracts. J Invest Dermatol. 1994 Apr;102(4):422–427. [PubMed]
  • Devary Y, Rosette C, DiDonato JA, Karin M. NF-kappa B activation by ultraviolet light not dependent on a nuclear signal. Science. 1993 Sep 10;261(5127):1442–1445. [PubMed]
  • Bailleul B, Daubersies P, Galiègue-Zouitina S, Loucheux-Lefebvre MH. Molecular basis of 4-nitroquinoline 1-oxide carcinogenesis. Jpn J Cancer Res. 1989 Aug;80(8):691–697. [PubMed]
  • Brabec V, Kleinwächter V, Butour JL, Johnson NP. Biophysical studies of the modification of DNA by antitumour platinum coordination complexes. Biophys Chem. 1990 Apr;35(2-3):129–141. [PubMed]
  • Tomasz M, Lipman R, Chowdary D, Pawlak J, Verdine GL, Nakanishi K. Isolation and structure of a covalent cross-link adduct between mitomycin C and DNA. Science. 1987 Mar 6;235(4793):1204–1208. [PubMed]
  • Roca J. The mechanisms of DNA topoisomerases. Trends Biochem Sci. 1995 Apr;20(4):156–160. [PubMed]
  • Slichenmyer WJ, Rowinsky EK, Donehower RC, Kaufmann SH. The current status of camptothecin analogues as antitumor agents. J Natl Cancer Inst. 1993 Feb 17;85(4):271–291. [PubMed]
  • Potmesil M. Camptothecins: from bench research to hospital wards. Cancer Res. 1994 Mar 15;54(6):1431–1439. [PubMed]
  • Froelich-Ammon SJ, Osheroff N. Topoisomerase poisons: harnessing the dark side of enzyme mechanism. J Biol Chem. 1995 Sep 15;270(37):21429–21432. [PubMed]
  • Baguley BC. DNA intercalating anti-tumour agents. Anticancer Drug Des. 1991 Feb;6(1):1–35. [PubMed]
  • Wassermann K, Markovits J, Jaxel C, Capranico G, Kohn KW, Pommier Y. Effects of morpholinyl doxorubicins, doxorubicin, and actinomycin D on mammalian DNA topoisomerases I and II. Mol Pharmacol. 1990 Jul;38(1):38–45. [PubMed]
  • Franzoso G, Bours V, Park S, Tomita-Yamaguchi M, Kelly K, Siebenlist U. The candidate oncoprotein Bcl-3 is an antagonist of p50/NF-kappa B-mediated inhibition. Nature. 1992 Sep 24;359(6393):339–342. [PubMed]
  • Solary E, Bertrand R, Kohn KW, Pommier Y. Differential induction of apoptosis in undifferentiated and differentiated HL-60 cells by DNA topoisomerase I and II inhibitors. Blood. 1993 Mar 1;81(5):1359–1368. [PubMed]
  • Sinha BK, Mimnaugh EG. Free radicals and anticancer drug resistance: oxygen free radicals in the mechanisms of drug cytotoxicity and resistance by certain tumors. Free Radic Biol Med. 1990;8(6):567–581. [PubMed]
  • Povirk LF, Austin MJ. Genotoxicity of bleomycin. Mutat Res. 1991 Mar;257(2):127–143. [PubMed]
  • Jensen PB, Sørensen BS, Demant EJ, Sehested M, Jensen PS, Vindeløv L, Hansen HH. Antagonistic effect of aclarubicin on the cytotoxicity of etoposide and 4'-(9-acridinylamino)methanesulfon-m-anisidide in human small cell lung cancer cell lines and on topoisomerase II-mediated DNA cleavage. Cancer Res. 1990 Jun 1;50(11):3311–3316. [PubMed]
  • Sappey C, Legrand-Poels S, Best-Belpomme M, Favier A, Rentier B, Piette J. Stimulation of glutathione peroxidase activity decreases HIV type 1 activation after oxidative stress. AIDS Res Hum Retroviruses. 1994 Nov;10(11):1451–1461. [PubMed]
  • Brennan P, O'Neill LA. Effects of oxidants and antioxidants on nuclear factor kappa B activation in three different cell lines: evidence against a universal hypothesis involving oxygen radicals. Biochim Biophys Acta. 1995 Jan 25;1260(2):167–175. [PubMed]
  • Zanocco AL, Pavez R, Videla LA, Lissi EA. Antioxidant capacity of diethyldithiocarbamate in a metal independent lipid peroxidative process. Free Radic Biol Med. 1989;7(2):151–156. [PubMed]
  • de Murcia G, Ménissier de Murcia J. Poly(ADP-ribose) polymerase: a molecular nick-sensor. Trends Biochem Sci. 1994 Apr;19(4):172–176. [PubMed]
  • Satoh MS, Lindahl T. Enzymatic repair of oxidative DNA damage. Cancer Res. 1994 Apr 1;54(7 Suppl):1899s–1901s. [PubMed]
  • Fram RJ, Kufe DW. DNA strand breaks caused by inhibitors of DNA synthesis: 1-beta-D-arabinofuranosylcytosine and aphidicolin. Cancer Res. 1982 Oct;42(10):4050–4053. [PubMed]
  • Jaffrézou JP, Levade T, Bettaïeb A, Andrieu N, Bezombes C, Maestre N, Vermeersch S, Rousse A, Laurent G. Daunorubicin-induced apoptosis: triggering of ceramide generation through sphingomyelin hydrolysis. EMBO J. 1996 May 15;15(10):2417–2424. [PMC free article] [PubMed]
  • Li CJ, Wang C, Pardee AB. Camptothecin inhibits Tat-mediated transactivation of type 1 human immunodeficiency virus. J Biol Chem. 1994 Mar 11;269(10):7051–7054. [PubMed]
  • Tishler RB, Calderwood SK, Coleman CN, Price BD. Increases in sequence specific DNA binding by p53 following treatment with chemotherapeutic and DNA damaging agents. Cancer Res. 1993 May 15;53(10 Suppl):2212–2216. [PubMed]
  • Nelson WG, Kastan MB. DNA strand breaks: the DNA template alterations that trigger p53-dependent DNA damage response pathways. Mol Cell Biol. 1994 Mar;14(3):1815–1823. [PMC free article] [PubMed]
  • Subler MA, Martin DW, Deb S. Activation of the human immunodeficiency virus type 1 long terminal repeat by transforming mutants of human p53. J Virol. 1994 Jan;68(1):103–110. [PMC free article] [PubMed]
  • Bortner CD, Oldenburg NB, Cidlowski JA. The role of DNA fragmentation in apoptosis. Trends Cell Biol. 1995 Jan;5(1):21–26. [PubMed]
  • Squires S, Ryan AJ, Strutt HL, Johnson RT. Hypersensitivity of Cockayne's syndrome cells to camptothecin is associated with the generation of abnormally high levels of double strand breaks in nascent DNA. Cancer Res. 1993 May 1;53(9):2012–2019. [PubMed]
  • D'Arpa P, Beardmore C, Liu LF. Involvement of nucleic acid synthesis in cell killing mechanisms of topoisomerase poisons. Cancer Res. 1990 Nov 1;50(21):6919–6924. [PubMed]
  • Weaver DT. What to do at an end: DNA double-strand-break repair. Trends Genet. 1995 Oct;11(10):388–392. [PubMed]
  • van Maanen JM, Retèl J, de Vries J, Pinedo HM. Mechanism of action of antitumor drug etoposide: a review. J Natl Cancer Inst. 1988 Dec 7;80(19):1526–1533. [PubMed]
  • Schreck R, Albermann K, Baeuerle PA. Nuclear factor kappa B: an oxidative stress-responsive transcription factor of eukaryotic cells (a review). Free Radic Res Commun. 1992;17(4):221–237. [PubMed]
  • Nobel CI, Kimland M, Lind B, Orrenius S, Slater AF. Dithiocarbamates induce apoptosis in thymocytes by raising the intracellular level of redox-active copper. J Biol Chem. 1995 Nov 3;270(44):26202–26208. [PubMed]
  • Sachsenmaier C, Radler-Pohl A, Zinck R, Nordheim A, Herrlich P, Rahmsdorf HJ. Involvement of growth factor receptors in the mammalian UVC response. Cell. 1994 Sep 23;78(6):963–972. [PubMed]
  • Steller H. Mechanisms and genes of cellular suicide. Science. 1995 Mar 10;267(5203):1445–1449. [PubMed]
  • Buttke TM, Sandstrom PA. Oxidative stress as a mediator of apoptosis. Immunol Today. 1994 Jan;15(1):7–10. [PubMed]
  • Kharbanda S, Ren R, Pandey P, Shafman TD, Feller SM, Weichselbaum RR, Kufe DW. Activation of the c-Abl tyrosine kinase in the stress response to DNA-damaging agents. Nature. 1995 Aug 31;376(6543):785–788. [PubMed]

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