Skip to main content

Advertisement

SpringerLink
Log in

Dynamic analysis of metabolic effects of chloroacetaldehyde and cytochalasin B on tumor cells using bioelectronic sensor chips

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

Abstract

Purpose: To study the interplay of drugs and energy metabolism of tumor cells, metabolic changes induced by chloroacetaldehyde and cytochalasin B were analyzed in colon carcinoma cells LS174T. Methods: O2-consumption and extracellular acidification were recorded using a bioelectronic sensor-chip system, which monitors these parameters in a culture continuously for at least 24 h. In parallel cultures cell number, cellular ATP-content, mitochondrial transmembrane potential, and the content of reactive oxygen species (ROS) were determined. Results: When cell death was induced by chloroacetaldehyde (50 μM), the rate of acidification declined gradually for the next 15 h, while O2-consumption decreased rapidly within 30 min. This correlated with a loss in mitochondrial potential. However, cellular ATP-level showed a transient increase at 2 h; also ROS levels increased up to 6 h. In cells treated with cytochalasin B (2 μM), which inhibits glucose uptake, the rate of O2-consumption increased and the acidification activity dropped, even upon glutamine depletion. Mitochondrial membrane potential transiently increased after 1 h, while ATP-content decreased; there was no change in the level of ROS. Conclusion: The pattern of changes in basic energy metabolism differs with the type of cell death and growth inhibition involved in the cytotoxic action of two different drugs.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Ahmed N, Williams JF, Weidemann MJ (1993) Glycolytic, glutaminolytic and pentose-phosphate pathways in promyelocytic HL60 and DMSO-differentiated HL60 cells. Biochem Mol Biol Int 29:1055–1067

    PubMed  CAS  Google Scholar 

  • Blancher C, Moore JW, Talks KL, Houlbrook S, Harris AL (2000) Relationship of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression to vascular endothelial growth factor induction and hypoxia survival in human breast cancer cell lines. Cancer Res 60:7106–7113

    PubMed  CAS  Google Scholar 

  • Brischwein M, Motrescu E, Cabala E, Otto AM, Grothe H, Wolf B (2003) Functional cellular assays with multiparametric silicon sensor chips. Lab Chip 3:234–240

    Article  PubMed  CAS  Google Scholar 

  • Butler WB (1984) Preparing nuclei from cells in monolayer cultures suitable for counting and for following synchronized cells through the cell cycle. Anal Biochem 141:70–73

    Article  PubMed  CAS  Google Scholar 

  • Casciari JJ, Sotirchos SV, Sutherland RM (1992) Variations in tumor cell growth rates and metabolism with oxygen concentration, glucose concentration, and extracellular pH. J Cell Physiol 151:386–394

    Article  PubMed  CAS  Google Scholar 

  • Dang CV, Semenza GL (1999) Oncogenic alterations of metabolism. Trends Bioch Sci 24:68–72

    Article  CAS  Google Scholar 

  • Degli Esposti M (2002) Measuring mitochondrial reactive oxygen species. Methods (San Diego, Calif) 26:335–340

    CAS  Google Scholar 

  • Delarue J, Lerebours E, Tilly H, Rimbert A, Hochain P, Guedon C, Piguet H, Colin R (1990) Effect of chemotherapy on resting energy expenditure in patients with non-Hodgkin’s lymphoma. Results of a sequential study. Cancer 65:2455–2459

    Article  PubMed  CAS  Google Scholar 

  • Denekamp J, Dasu A, Waites A (1998) Vasculature and microenvironmental gradients: the missing links in novel approaches to cancer therapy? Adv Enzyme Regul 38:281–299

    Article  PubMed  CAS  Google Scholar 

  • Eguchi Y, Shimizu S, Tsujimoto Y (1997) Intracellular ATP levels determine cell death fate by apoptosis or necrosis. Cancer Res 57:1835–1840

    PubMed  CAS  Google Scholar 

  • Ehret R, Baumann W, Brischwein M, Lehmann M, Henning T, Freund I, Drechsler S, Friedrich U, Hubert M-L, Motrescu E, Kob A, Palzer H, Grothe H, Wolf B (2001) Multiparametric microsensor chips for screening applications. Fresenius J Anal Chem 369:30–35

    Article  PubMed  CAS  Google Scholar 

  • Fernandez-Checa JC, Garcia-Ruiz C, Colell A, Morales A, Mari M, Miranda M, Ardite E (1998) Oxidative stress: role of mitochondria and protection by glutathione. BioFactors (Oxford, England) 8:7–11

    CAS  Google Scholar 

  • Gatenby RA (1995) The potential role of transformation-induced metabolic changes in tumor-host interaction. Cancer Res 55:4151–4156

    PubMed  CAS  Google Scholar 

  • Gerweck LE (1998) Tumor pH: implications for treatment and novel drug design. Semin Radiat Oncol 8:176–182

    Article  PubMed  CAS  Google Scholar 

  • Gerweck LE, Kozin SV, Stocks SJ (1999) The pH partition theory predicts the accumulation and toxicity of doxorubicin in normal and low-pH-adapted cells. Brit J Cancer 79:838–842

    Article  PubMed  CAS  Google Scholar 

  • Gillies RJ, Bhujwalla ZM, Evelhoch J, Garwood M, Neeman M, Robinson SP, Sotak CH, van der Sanden B (2000) Applications of magnetic resonance in model systems: tumor biology and physiology. Neoplasia (New York, N Y) 2:139–151

    CAS  Google Scholar 

  • Helmlinger G, Sckell A, Dellian M, Forbes NS, Jain RK (2002) Acid production in glycolysis-impaired tumors provides new insights into tumor metabolism. Clin Cancer Res 8:1284–1291

    PubMed  CAS  Google Scholar 

  • Henning T, Brischwein M, Baumann W, Ehret R, Freund I, Kammerer R, Lehmann M, Schwinde A, Wolf B (2001) Approach to a multiparametric sensor-chip-based tumor chemosensitivity assay. Anti Cancer Drugs 12:21–32

    Article  PubMed  CAS  Google Scholar 

  • Kozin SV, Shkarin P, Gerweck LE (2001) The cell transmembrane pH gradient in tumors enhances cytotoxicity of specific weak acid chemotherapeutics. Cancer Res 61:4740–4743

    PubMed  CAS  Google Scholar 

  • Kraus M, Wolf B (1996) Implications of acidic tumor microenvironment for neoplastic growth and cancer treatment: a computer analysis. Tumor Biol 17:133–154

    Article  CAS  Google Scholar 

  • Lee YJ, Galoforo SS, Berns CM, Tong WP, Kim HR, Corry PM (1997) Glucose deprivation-induced cytotoxicity in drug resistant human breast carcinoma MCF-7/ADR cells: role of c-myc and bcl-2 in apoptotic cell death. J Cell Sci 110 (Pt 5):681–686

    PubMed  CAS  Google Scholar 

  • Mancini M, Anderson BO, Caldwell E, Sedghinasab M, Paty PB, Hockenbery DM (1997) Mitochondrial proliferation and paradoxical membrane depolarization during terminal differentiation and apoptosis in a human colon carcinoma cell line. J Cell Biol 138:449–469

    Article  PubMed  CAS  Google Scholar 

  • Mazurek S, Boschek CB, Eigenbrodt E (1997) The role of phosphometabolites in cell proliferation, energy metabolism, and tumor therapy. J Bioenerg Biomembr 29:315–330

    Article  PubMed  CAS  Google Scholar 

  • Mazurek S, Zwerschke W, Jansen-Durr P, Eigenbrodt E (2001) Effects of the human papilloma virus HPV-16 E7 oncoprotein on glycolysis and glutaminolysis: role of pyruvate kinase type M2 and the glycolytic-enzyme complex. Biochem J 356:247–256

    Article  PubMed  CAS  Google Scholar 

  • Mizel SB, Wilson L (1972) Inhibition of the transport of several hexoses in mammalian cells by cytochalasin B. J Biol Chem 247:4102–4105

    PubMed  CAS  Google Scholar 

  • Neeman M, Eldar H, Rushkin E, Degani H (1990) Chemotherapy-induced changes in the energetics of human breast cancer cells; 31P- and 13C-NMR studies. Biochim Biophys Acta 1052:255–263

    Article  PubMed  CAS  Google Scholar 

  • Otto AM, Faderl M, Schonenberger H (1991) Dissociation of estrogenic and cytotoxic properties of an estrogen receptor-binding platinum complex in human breast cancer cell lines. Cancer Res 51:3217–3223

    PubMed  CAS  Google Scholar 

  • Otto AM, Brischwein M, Niendorf A, Henning T, Motrescu E, Wolf B (2003) Microphysiological testing for chemosensitivity of living tumor cells with multiparametric microsensor chips. Cancer Detect Prevent 27:291–296

    Article  PubMed  CAS  Google Scholar 

  • Petch D, Butler M (1994) Profile of energy metabolism in a murine hybridoma: glucose and glutamine utilization. J Cell Physiol 161:71–76

    Article  PubMed  CAS  Google Scholar 

  • Pfister DG, McCaffrey J, Zahalsky AJ, Schwartz GK, Lis E, Gerald W, Huvos A, Shah J, Kraus D, Shaha A, Singh B, Wolden S, Zelefsky M, Palgi I (2002) A phase II trial of bryostatin-1 in patients with metastatic or recurrent squamous cell carcinoma of the head and neck. Invest New Drugs 20:123–127

    Article  PubMed  CAS  Google Scholar 

  • Rempel A, Mathupala SP, Griffin CA, Hawkins AL, Pedersen PL (1996) Glucose catabolism in cancer cells: amplification of the gene encoding type II hexokinase. Cancer Res 56:2468–2471

    PubMed  CAS  Google Scholar 

  • Richter C, Schweizer M, Cossarizza A, Franceschi C (1996) Control of apoptosis by the cellular ATP level. FEBS Lett 378:107–110

    Article  PubMed  CAS  Google Scholar 

  • Salvioli S, Ardizzoni A, Franceschi C, Cossarizza A (1997) JC-1, but not DiOC6(3) or rhodamine 123, is a reliable fluorescent probe to assess delta psi changes in intact cells: implications for studies on mitochondrial functionality during apoptosis. FEBS Lett 411:77–82

    Article  PubMed  CAS  Google Scholar 

  • Sanchez-Alcazar JA, Ruiz-Cabello J, Hernandez-Munoz I, Pobre PS, De La Torre P, Siles-Rivas E, Garcia I, Kaplan O, Munoz-Yague MT, Solis-Herruzo JA (1997) Tumor necrosis factor-alpha increases ATP content in metabolically inhibited L929 cells preceding cell death. J Biol Chem 272:30167–30177

    Article  PubMed  CAS  Google Scholar 

  • Serafino A, Sinibaldi-Vallebona P, Lazzarino G, Tavazzi B, Di Pierro D, Rasi G, Ravagnan G (2000) Modifications of mitochondria in human tumor cells during anthracycline-induced apoptosis. Anticancer Res 20:3383–3394

    PubMed  CAS  Google Scholar 

  • Singer B (1996) DNA damage: chemistry, repair, and mutagenic potential. Regul Toxicol Pharmacol 23:2–13

    Article  PubMed  CAS  Google Scholar 

  • Smiley ST, Reers M, Mottola-Hartshorn C, Lin M, Chen A, Smith TW, Steele GD Jr, Chen LB (1991) Intracellular heterogeneity in mitochondrial membrane potentials revealed by a J-aggregate-forming lipophilic cation JC-1. Proc Natl Acad Sci USA 88:3671–3675

    Article  PubMed  CAS  Google Scholar 

  • Sood C, O’Brien PJ (1993) Molecular mechanisms of chloroacetaldehyde-induced cytotoxicity in isolated rat hepatocytes. Biochem Pharmacol 46:1621–1626

    Article  PubMed  CAS  Google Scholar 

  • Tan S, Sagara Y, Liu Y, Maher P, Schubert D (1998) The regulation of reactive oxygen species production during programmed cell death. J Cell Biol 141:1423–1432

    Article  PubMed  CAS  Google Scholar 

  • Vaupel P, Hockel M (2000) Blood supply, oxygenation status and metabolic micromilieu of breast cancers: characterization and therapeutic relevance. Int J Oncol 17:869–879

    PubMed  CAS  Google Scholar 

  • Visarius TM, Stucki JW, Lauterburg BH (1997) Stimulation of respiration by methylene blue in rat liver mitochondria. FEBS Lett 412:157–160

    Article  PubMed  CAS  Google Scholar 

  • Visarius TM, Stucki JW, Lauterburg BH (1999) Inhibition and stimulation of long-chain fatty acid oxidation by chloroacetaldehyde and methylene blue in rats. J Pharmacol Exp Therapeutics 289:820–824

    CAS  Google Scholar 

  • Walenta S, Feigk B, Wachsmuth I, Dunkern T, Degani H, Mueller-Klieser W (2002) Differential changes in purine nucleotides after Doxorubicin treatment of human cancer cells in vitro. Int J Oncol 21:289–296

    PubMed  CAS  Google Scholar 

  • Wolf B, Brischwein M, Baumann W, Ehret R, Kraus M (1998) Monitoring of cellular signalling and metabolism with modular sensor-technique: the PhysioControl-Microsystem (PCM). Biosens Bioelectron 13:501–509

    Article  PubMed  CAS  Google Scholar 

  • Zamzami N, Marchetti P, Castedo M, Decaudin D, Macho A, Hirsch T, Susin SA, Petit PX, Mignotte B, Kroemer G (1995) Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death. J Exp Med 182:367–377

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The technical assistance of Gudrun Teschner and Alfred Michelfelder is gratefully acknowledged. We thank Dr. Lisa Sprague for fruitful discussions on the manuscript.

Author information

Author notes

  1. E. R. Motrescu

    Present address: Department of Molecular Pathology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), C.U. Strasbourg, 67404, Illkirch Cedex, France

  2. S. Zahler

    Present address: Department of Pharmacy, Center of Drug Research, Pharmaceutical Biology, Butenandtstr. 5-13, Building B, 81377, Munich, Germany

Authors and Affiliations

  1. Heinz-Nixdorf-Chair for Medical Electronics, Technical University of Munich, Theresienstr. 90, 80333, Munich, Germany

    E. R. Motrescu, A. M. Otto, M. Brischwein & B. Wolf

  2. Institute of Physiology, Ludwig-Maximilian-University of Munich, Schillerstr. 44, 80336, Munich, Germany

    S. Zahler

Authors
  1. E. R. Motrescu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. M. Otto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Brischwein
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. Zahler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B. Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. M. Otto.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Motrescu, E.R., Otto, A.M., Brischwein, M. et al. Dynamic analysis of metabolic effects of chloroacetaldehyde and cytochalasin B on tumor cells using bioelectronic sensor chips. J Cancer Res Clin Oncol 131, 683–691 (2005). https://doi.org/10.1007/s00432-005-0015-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-005-0015-2

Keywords

Search

Navigation