Skip to main content
SpringerLink
Log in

Expression of apoptosis-related oncoproteins and modulation of apoptosis by caffeine in human leukemic cells

  • Original Paper
  • Experimental Oncology
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

We investigated the modulation of radio- and chemoresistance by caffeine and mechanisms of resistance in human leukemic cell lines and mononuclear cells from 18 leukemic patients. Caffeine synergistically potentiated cytotoxicity and apoptosis induced by ionizing radiation or carboplatin (CPt), but attenuated induction of apoptosis by daunorubicin (DNR) in KG-1a cells. Since caffeine released irradiated as well as DNR-treated KG-1a cells from G2M cell cycle arrest and CPt-treated cells from S-phase arrest, this release does not fully explain the different effects of caffeine. Caffeine synergistically reduced the level of the apoptosis inhibitor glutatione after irradiation or CPt treatment. In contrast, treatment with DNR plus caffeine diminished glutathione levels to a lesser extent than DNR alone. We conclude that the effect of caffeine on glutathione depletion represents a mechanism of action by which caffeine can modulate apoptosis. Caffeine increased CPt cytotoxicity in K562 cells and its doxorubicin-resistant subline (K562/ADM), but little effect was seen in HL-60 cells or mononuclear cells from leukemic patients. Multivariate cluster analysis revealed an association of CPt resistance with the expression of c-Fos, c-N-Ras, and p53 oncoproteins and with proliferative activity (S-phase of cell cycle), but not with Bcl-2 expression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Angel P, Karin M (1991) The role of Jun, Fos, and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta 1072:129–157

    PubMed  Google Scholar 

  • Arends MJ, Morris RJ, Wyllie AH (1990) Apoptosis: the role of the endonuclease. Am J Pathol 136:593–608

    PubMed  Google Scholar 

  • Askew DS, Ihle JN, Cleveland JL (1993) Activation of apoptosis with enforcedmyc expression in myeloid progenitor cells is dominant to the expression of apoptosis by interleukin-3 or erythropoietin. Blood 82:2079–2087

    PubMed  Google Scholar 

  • Bergeron C, Ferenczy A, Toft DO, Shymala G (1988) Immunocytochemical study of progesterone receptors in hyperplastic and neoplastic endometrial tissues. Cancer Res 48:6132–6136

    PubMed  Google Scholar 

  • Bissonette RP, Echeverri F, Mahboubi A, Green DR (1992) Apoptotic cel death induced by c-myc is inhibited bybcl-2,. Nature 359:552–554

    PubMed  Google Scholar 

  • Brown R, Clugston C, Burns P, Edlin P, Vasey P, Vojtesek B, Kaye SB (1993) Increased accumulation of p53 protein in cisplatin-resistant ovarian cell lines. Int J Cancer 55:678–684

    PubMed  Google Scholar 

  • Collins SJ, Gallo CG, Gallagher RE (1977) Continuous growth and differentiation of huma myeloid leukaemic cells in suspension culture. Nature 270:347–349

    PubMed  Google Scholar 

  • Colotta F, Polentarutti N, Sironi M, Mantovani A (1992) Expression and involvement of c-fos and c-jun protooncogenes in programmed cell death induced by growth factor deprivation in lymphoid cell lines. J Biol Chem 267:18278–18283

    PubMed  Google Scholar 

  • Darzynkiewicz Z, Bruno S, Del Bino G, Gorczyka W, Hotz MA, Lassota P, Traganos F (1992) Features of apoptotic cells measured by flow cytometry. Cytometry 13:795–808

    PubMed  Google Scholar 

  • Fertil B, Malaise EP (1981) Inherent cellular radiosensitivity as a basic concept for human tumor radiotherapy. Int J Radiat Oncol Biol 7:621–629

    Google Scholar 

  • Ganapathi R, Grabowski D, Schmidt H, Yen A, Iliakis G (1986) Modulation of Adriamycin andN-trifluoroacetyladriamycin-14-valerate induced effects on cell cycle traverse and cytotoxicity in P388 mouse leukemia cells by caffeine and the calmodulin inhibitor trifluoperazine. Cancer Res 46:5553–5557

    PubMed  Google Scholar 

  • Hariton C (1994) Ocular hypotension induced by topical dopaminergic drugs and phosphodiesterase inhibitors. Eur J Pharmacol 258:85–94

    PubMed  Google Scholar 

  • Hedley DW (1993) Assays of cancer chemotherapy resistance. Glutathione assays. In: Robinson P (ed) Handbook of flow cytometric methods. Wiley, New York, pp 221–226

    Google Scholar 

  • Kashani-Sabet M, Lu Y, Leong L, Haedicke K, Scanlon KJ (1990) Differential oncogene amplification in tumor cells from a patient treated with cisplatin and 5-fluorouracil. Eur J Cancer 26:383–390

    PubMed  Google Scholar 

  • Kaspers GJ, Pieters R, Zantwijk CH van, Laat PA de, Waal FC de, Wering ER van, Veerman AJ (1991) In vitro drug sensitivity of normal peripheral blood lymphocytes and childhood leukaemic cells from bone marrow and peripheral blood. Br J Cancer 64:469–474

    PubMed  Google Scholar 

  • Koeffler HP (1983) Induction of differentiation of human acute myelogeneous leukemia cells: therapeutic implications. Blood 62:709–721

    PubMed  Google Scholar 

  • Korsmeyer SJ (1992) Bcl-2 inhibits a new category of oncogenes: regulators of cell death. Blood 80:879–886

    PubMed  Google Scholar 

  • Lau CC, Pardee AB (1982) Mechanism by which caffeine potentiates lethality of nitrogen mustard. Proc Natl Acad Sci USA 79:2942–2946

    PubMed  Google Scholar 

  • Leoncini L, del Vecchio MT, Megha T, Barbini P, Galieni P, Pileri S, Sabattini E, Gherlinzoni F, Tosi P, Kraft R, Cottier (1993) Correlations between apoptotic and proliferative indices in malignant non-Hodkin's lymphomas. Am J Pathol 142:755–763

    PubMed  Google Scholar 

  • Lozzio CB, Lozzio BB (1975) Human myelogenous leukemia cell-line with positive Philadelphia chromosome. Blood 45:321–334

    PubMed  Google Scholar 

  • Lücke-Huhle C (1982) Alpha-irradiation-induced G2 delay: a period of cell recovery. Radiat Res 89:298–308

    PubMed  Google Scholar 

  • Miura M, Zhu H, Rotello R, Hartwieg EA, Yuan J (1993) Induction of apoptosis in fibroblasts by IL-1β-converting enzyme, a mammalian homolog of the C elegans cell death gene ced-3. Cell 75:653–660

    PubMed  Google Scholar 

  • Miyashita T, Reed JC (1993) Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line. Blood 81:151–157

    PubMed  Google Scholar 

  • Moore J, Boswell S, Hoffman R, Burgess G, Hromas R (1993) Mutant H-ras overexpression inhibits a random apoptotic nuclease in myeloid leukemia cells. Leukemia Res 17:703–709

    Google Scholar 

  • Muller R, Bravo R, Burckhardt J, Curran T (1984) Induction of c-fos gene and protein by growth factors precedes activation of c-myc. Nature 312:716–720

    PubMed  Google Scholar 

  • Oberhammer F, Wilson JW, Dive C, Morris ID, Hickman JA, Wakeling AE, Walker PR, Sikorska M (1993) Apoptotic death in epithelial cells: cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation. EMBO J 12:3679–3684

    PubMed  Google Scholar 

  • Osieka R, Glatte P, Schmidt CG (1989) Chemosensitization by chlorpromazine (CPZ) and caffeine (C) in human melanoma xenografts sensitive or resistant to methyl-CCNU (semustine). Strahlenther Onkol 165:526–528

    PubMed  Google Scholar 

  • Sandstrom PA, Mannie MD, Buttke TM (1994) Inhibition of activation-induced death in T cell hybridomas by thiol antioxidants: oxidative stress as a mediator of apoptosis. J Leukoc Biol 55:221–226

    PubMed  Google Scholar 

  • Sato T, Hanada M, Bodrug S, Irie S, Iwama N, Boise LH, Thompson CB Golemis E, Fong L, Whang HG, Reed JC (1994) Interactions among members of the Bcl-2 protein family analyzed with yeast two-hybrid system. Proc Natl Acad Sci USA 91:9238–9242

    PubMed  Google Scholar 

  • Scanlon KJ, Jiao L, Funato T, Wang W, Tone T, Rossi JJ, Kashani-Sabet M (1991) Ribozyme-mediated cleavage of c-fos mRNA reduces gene expression of DNA synthesis enzymes and metallothionein. Proc Natl Acad Sci USA 88:10591–10595

    PubMed  Google Scholar 

  • Selby CP, Sancar A (1990) Molecular mechanisms of DNA repair inhibition by caffeine. Proc Natl Acad Sci USA 87:3522–3525

    PubMed  Google Scholar 

  • Sen S, D'Incalci M (1992) Apoptosis: Biochemical events and relevance to cancer chemotherapy. FEBS Lett 307:122–127

    PubMed  Google Scholar 

  • Shi Y, Glynn JM, Guilbert LJ, Cotter TG, Bissonette RP, Green DR (1992) Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas. Science 257:212–214

    PubMed  Google Scholar 

  • Sklar MD (1988) Increased resistance to cis-diamminodichloroplatinum (II) in NIH 3T3 cells transformed by ras oncogenes. Cancer Res 48:793–797

    PubMed  Google Scholar 

  • Telford WG, King LE, Fraker PJ (1992) Comparative evaluation of several DNA binding dyes in the detection of apoptosis-associated chromatin degradation by flow cytometry. Cytometry 13:137–143

    PubMed  Google Scholar 

  • Traganos F, Kapuscinski H, Darzynkiewicz Z (1991) Caffeine modulates the effect on DNA-intercalating drugs in vitro: a flow cytometric and spectrophotometric analysis of caffeine interaction with novantrone, doxorubicin, ellipticine, and the doxorubicin analogue AD198. Cancer Res 51:3682–3689

    PubMed  Google Scholar 

  • Traganos F, Kapuscinski J, Gong J, Ardelt B, Darzynkiewicz RJ, Darzynkiewicz Z (1993) Caffeine prevents apoptosis and cell cycle effects induced by camptothecin and topotecan in HL-60 cells. Cancer Res 53:4613–4618

    PubMed  Google Scholar 

  • Trauth BC, Klas C, Peters AMJ, Matzku S, Möller P, Falk W, Debatin K-M, Krammer PH (1989) Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science 245:301–304

    PubMed  Google Scholar 

  • Tritton TR (1991) Cell surface actions of adriamycin. Pharmacol Ther 49:293–309

    PubMed  Google Scholar 

  • Tsuruo T, Iida-Saito H, Kawabata H, Oh-hara T, Hamada H, Utakoji T (1986) Characteristics of resistance to Adriamycin in human myelogenous leukemia K562 resistant to Adriamycin and in isolated clones. Jpn J Cancer Res 77:682–692

    PubMed  Google Scholar 

  • Volm M, Efferth T, Mattern J (1992) Oncoprotein (c-myc, c-erbB1, c-erB2), c-fos) and suppressor gene product (p53) expression in squamous cell carcinomas of the lung. Clinical and biological correlations. Anticancer Res 12:11–20

    PubMed  Google Scholar 

  • Warters RL, Lyons BW, Kennedy K, Li TM (1989) Topoisomerase activity in irradiated mammalian cells. Mutat Res 216:43–55

    PubMed  Google Scholar 

  • Yonish-Rouach E, Grunwald D, Wilder S, Kimchi A, May E, Lawrence JJ, May O, Oren M (1993) p53-mediated cell death: relationship to cell cycle control. Mol Cell Biol 13:1415–1423

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medizinische Klinik IV, RWTH Aachen, Pauwelsstraße 30, D-52057, Aachen, Germany

    T. Efferth, U. Fabry, P. Glatte & R. Osieka

Authors
  1. T. Efferth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. U. Fabry
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. Glatte
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Osieka
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Efferth, T., Fabry, U., Glatte, P. et al. Expression of apoptosis-related oncoproteins and modulation of apoptosis by caffeine in human leukemic cells. J Cancer Res Clin Oncol 121, 648–656 (1995). https://doi.org/10.1007/BF01218522

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01218522

Key words

Search

Navigation