Advertisement

Pharmaceutical Research

, Volume 23, Issue 7, pp 1509–1516 | Cite as

Cytotoxic Properties of Tyloxapol

  • Jung-hua Steven KuoEmail author
  • Ming-shiou Jan
  • Hsuan Wen Chiu
Research Paper

Purpose

Tyloxapol, a viscous polymer of the alkyl aryl polyether alcohol type, is classified as a nonionic surfactant and is widely used in biomedical applications. Although tyloxapol has been reported to be cytotoxic in various cell lines, there is no published information about its possible mechanisms of cell death. Hence, the objective of this study was to determine whether tyloxapol causes apoptosis or necrosis. These data could be helpful for a better understanding of the action of tyloxapol in cellular systems.

Methods

RAW 264.7 (murine macrophage-like) cells and NIH/3T3 (mouse fibroblast) cells were treated with tyloxapol, and the activity of dehydrogenases in those cells, an indicator of cell viability, was assessed. The cell morphology changes induced by tyloxapol treatment were detected using propidium iodide nuclear staining. The hallmarks of apoptotic cells were characterized using DNA fragmentation assays, DNA fluorescence staining, and then flow analysis.

Results

Tyloxapol treatment produced dose- and time-dependent cytotoxicity. Tyloxapol treatment damaged RAW 264.7 cells more than it damaged NIH/3T3 cells. All the cells exposed to tyloxapol showed some morphological features of apoptosis, such as chromatin condensation and cell shrinkage. Typical apoptotic ladders were observed in DNA extracted from tyloxapol-treated cells. Flow cytometric analysis revealed an increase in the hypodiploid DNA population (sub-G1), indicating that DNA cleavage occurred after tyloxapol treatment. In addition, we showed that pretreating cells with zVAD-fmk, a general caspase inhibitor, did not prevent tyloxapol-induced apoptosis. The cytotoxicity of tyloxapol can be reduced by adding a nontoxic lipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine to attenuate the interaction of tyloxapol with the cell membrane.

Conclusions

Our results indicate that tyloxapol induces apoptosis in RAW 264.7 and NIH/3T3 cells. These data provide a novel insight into the cytotoxic action of tyloxapol at the molecular level.

Key words

apoptosis cytotoxicity surfactant tyloxapol 

Notes

Acknowledgment

This work was supported by grant NSC 94-2216-E-041-001 from the National Science Council, Taiwan.

References

  1. 1.
    Reynolds, J. E. F. eds. 1996Martindale, The Extra Pharmacopoeia31st ed.Royal Pharmaceutical Soc.London1347Google Scholar
  2. 2.
    A. R. Gennaro (ed.). Remington: The Science and Practice of Pharmacy, 19th ed., Mack, Easton, PA, 1995.Google Scholar
  3. 3.
    Serikov, V. B., Glazanova, T. V., Jerome, E. H., Fleming, N. W., Higashimori, H., Staub, N. C.,Sr 2003Tyloxapol attenuates the pathologic effects of endotoxin in rabbits and mortality following cecal ligation and puncture in rats by blockade of endotoxin receptor–ligand interactionsInflammation27175190PubMedCrossRefGoogle Scholar
  4. 4.
    Gursoy, N., Garrigue, J. S., Razafindratsita, A., Lambert, G., Benita, S. 2003Excipient effects on in vitro cytotoxicity of a novel paclitaxel self-emulsifying drug delivery systemJ. Pharm. Sci.9224112418PubMedCrossRefGoogle Scholar
  5. 5.
    Kukowska-Latallo, J. F., Chen, C., Eichman, J., Bielinska, A. U., Baker, J. R. 1999Enhancement of dendrimer-mediated transfection using synthetic lung surfactant exosurf neonatal in vitro Biochem. Biophys. Res. Commun.14253261CrossRefGoogle Scholar
  6. 6.
    Yamamoto, K., Shen, B., Zarins, C., Scanu, A. M. 1984 In vitro and in vivo interactions of Triton 1339 with plasma lipoproteins of normolipidemic rhesus monkeys. Preferential effects on high density lipoproteinsArteriosclerosis4418434PubMedGoogle Scholar
  7. 7.
    Dechant, K. L., Faulds, D. 1991Colfosceril palmitate. A review of the therapeutic efficacy and clinical tolerability of a synthetic surfactant preparation (Exosurf Neonatal) in neonatal respiratory distress syndromeDrugs42877894PubMedCrossRefGoogle Scholar
  8. 8.
    Staub, N. C., Longworth, K. E., Serikov, V., Jerome, E. H., Elsasser, T. 2001Detergent inhibits 70–90% of responses to intravenous endotoxin in awake sheepJ. Appl. Physiol.9017881797PubMedCrossRefGoogle Scholar
  9. 9.
    Thomassen, M. J., Antal, J. M., Divis, L. T., Wiedemann, H. P. 1995Regulation of human alveolar macrophage inflammatory cytokines by tyloxapol: a component of the synthetic surfactant ExosurfClin. Immunol. Immunopathol.77201205PubMedCrossRefGoogle Scholar
  10. 10.
    Ghio, A. J., Marshall, B. C., Diaz, J. L., Hasegawa, T., Samuelson, W., Povia, D., Kennedy, T. P., Piantodosi, C. A. 1996Tyloxapol inhibits NF-kappa B and cytokine release, scavenges HOCI, and reduces viscosity of cystic fibrosis sputumAm. J. Respir. Crit. Care Med.154783788PubMedGoogle Scholar
  11. 11.
    Findlay, R. D., Taeusch, H. W., David-Cu, R., Walther, F. J. 1995Lysis of red blood cells and alveolar epithelial toxicity by therapeutic pulmonary surfactantsPediatr. Res.372630PubMedGoogle Scholar
  12. 12.
    Majno, G., Joris, I. 1995Apoptosis, oncosis, and necrosis. An overview of cell deathAm. J. Pathol.146315PubMedGoogle Scholar
  13. 13.
    Cummings, M. C., Winterford, C. M., Walker, N. I. 1997ApoptosisAm. J. Surg. Pathol.2188101PubMedCrossRefGoogle Scholar
  14. 14.
    Hetts, S. W. 1998To die or not to die: an overview of apoptosis and its role in diseaseJAMA279300307PubMedCrossRefGoogle Scholar
  15. 15.
    Bianchi, M. E., Manfredi, A. 2004Chromatin and cell deathBiochim. Biophys. Acta1677181186PubMedGoogle Scholar
  16. 16.
    Schott, H. 1998Comparing the surface chemical properties and the effect of salts on the cloud point of a conventional nonionic surfactant, octoxynol 9 (Triton X-100), and of its oligomer, tyloxapol (Triton WR-1339)J. Colloid Interface Sci.205496502PubMedCrossRefGoogle Scholar
  17. 17.
    Darzynkiewiz, Z., Bruno, S., Bino, G., Gorczyca, W., Hotz, M. A., Lassota, P., Traganos, F. 1992Features of apoptotic cells measured by flow cytometryCytometry13795808CrossRefGoogle Scholar
  18. 18.
    Jacobsen, M. D., Weil, M., Raff, M. C. 1996Role of Ced-3/ICE-family proteases in staurosporine-induced programmed cell deathJ. Cell Biol.13310411051PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • Jung-hua Steven Kuo
    • 1
    Email author
  • Ming-shiou Jan
    • 2
  • Hsuan Wen Chiu
    • 3
  1. 1.Graduate Institute of Pharmaceutical ScienceChia Nan University of Pharmacy and ScienceTainanTaiwan
  2. 2.Department of Microbiology and ImmunologyMedical College of Chung Shan Medical UniversityTaichungTaiwan
  3. 3.Department of BiotechnologyChia Nan University of Pharmacy and ScienceTainanTaiwan

Personalised recommendations