Skip to main content
Log in

Phenoxodiol Treatment Alters the Subsequent Response of ENOX2 (tNOX) and Growth of HeLa Cells to Paclitaxel and Cisplatin

  • Research
  • Published:
Molecular Biotechnology Aims and scope Submit manuscript

Abstract

Phenoxodiol is an experimental anticancer drug under development as a chemosensitizer intended to reverse multidrug resistance mechanisms in ovarian and prostate cancer cells to most standard cytotoxics. The putative molecular target of phenoxodiol is a cell-surface, tumor-specific NADH oxidase, ENOX2 (tNOX), with phenoxodiol having no apparent effect on the constitutive form of this enzyme ENOX1 (CNOX). Using ENOX2 as the target, this study was conducted to explore the temporal relationship between phenoxodiol and paclitaxel or cisplatin in achieving chemosensitization in HeLa cells which are relatively resistant to both paclitaxel and cisplatin. Sequential addition of phenoxodiol and paclitaxel or phenoxodiol and cisplatin showed greater inhibition of HeLa cell ENOX1 activity and growth compared to adding the drugs simultaneously or individually. In parallel, a similar chemosensitizing response of phenoxodiol for cisplatin was observed. ENOX1 was not affected and trans-platinum had no effect. With spent media from phenoxodiol-treated cells sensitivity was enhanced to both paclitaxel and cisplatin if the cells were first pretreated with phenoxodiol. Similar results were obtained with ENOX2-enriched preparations stripped from the surfaces of phenoxodiol-treated cells. In keeping with a speculative prion model, it seems as though the ENOX2 “remembers” the phenoxodiol and “teaches” other ENOX2 molecules to respond to paclitaxel and cisplatin as if phenoxodiol were still present.

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

Access this article

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

Similar content being viewed by others

References

  1. Brown, D. M., Kelly, G. E., & Husband, A. J. (2005). Flavanoid compounds in maintenance of prostate health and prevention and treatment of cancer. Molecular Biotechnology, 30, 253–270. doi:10.1385/MB:30:3:253.

    Article  CAS  Google Scholar 

  2. De Luca, T., Morré, D. M., Zhao, H., & Morré, D. J. (2005). NAD+/NADH and/or CoQ/CoQH2 ratios from plasma membrane electron transport may determine ceramide and sphingosine-1-phosphate levels accompanying G1 arrest and apoptosis. BioFactors (Oxford, England), 25, 43–60.

    Google Scholar 

  3. Kamsteeg, J., Rutherford, T., Sapi, E., Hanczaruk, B., Shahabi, S., Flick, M., et al. (2003). Phenoxodiol—an isoflavone analog—induces apoptosis in chemoresistant ovarian cancer cells. Oncogene, 22, 2611–2620. doi:10.1038/sj.onc.1206422.

    Article  CAS  Google Scholar 

  4. Morré, D. J., Chueh, P.-J., Yagiz, K., Balicki, A., Kim, C., & Morré, D. M. (2007). ECTO-NOX target for the anticancer isoflavene phenoxodiol. Oncology Research, 16, 299–312. doi:10.1159/000102153.

    Google Scholar 

  5. Goss, G., Quinn, M., Rutherford, T., & Kelly, G. A. (2005). A randomized Phase II study of phenoxodiol with platinum or taxane chemotherapy in chemoresistant epithelial ovarian cancer, fallopian tube cancer and primary peritoneal cancer. European Journal of Cancer (Suppl. 3), 261.

  6. Morré, D. J., & Morré, D. M. (2003). Spectroscopic analyses of oscillation in ECTO-NOX-catalyzed oxidation of NADH. Nonlinearity in Biology Toxicology and Medicine, 1, 345–362. doi:10.1080/15401420390249916.

    Article  Google Scholar 

  7. Lyles, M. M., & Gilbert, H. F. (1991). Catalysis of the oxidative folding of ribonuclease A by protein disulfide isomerase dependence of the rate on the composition of the redox buffer. Biochemistry, 3, 613–619. doi:10.1021/bi00217a004.

    Article  Google Scholar 

  8. Morré, D. J., Gomez-Rey, M. L., Schramke, C., Em, O., Lawler, J., Hobeck, J., et al. (1999). Use of dipyridyl-dithio substrates to measure directly the protein disulfide-thiol interchange activity of the auxin stimulated NADH, protein disulfide reductase of soybean plasma membranes. Molecular and Cellular Biochemistry, 200, 7–13. doi:10.1023/A:1006916116297.

    Article  Google Scholar 

  9. Kishi, T., Morré, D. M., & Morré, D. J. (1999). The plasma membrane NADH oxidase of HeLa cells has hydroquinone oxidase activity. Biochimica et Biophysica Acta, 1412, 66–77. doi:10.1016/S0005-2728(99)00049-3.

    Article  CAS  Google Scholar 

  10. Smith, P. K., Krohn, R. I., Hermanson, G. T., Mailia, A. K., Gartner, F. H., Provenzano, M. D., et al. (1985). Measurement of protein using bicinchoninic acid. Analytical Biochemistry, 150, 76–85. doi:10.1016/0003-2697(85)90442-7.

    Article  CAS  Google Scholar 

  11. Tompa, P., & Friedrich, P. (1998). Prion proteins as memory molecules: A hypothesis. Neuroscience, 86, 1037–1043. doi:10.1016/S0306-4522(98)00148-1.

    Article  CAS  Google Scholar 

  12. Morré, D. J., Morré, D. M., Stevenson, J., MacKellar, W., & McClure, D. (1995). HeLa plasma membranes bind the antitumor sulfonylurea LY181984 with high affinity. Biochimica et Biophysica Acta, 1244, 133–140.

    Google Scholar 

  13. Sedlak, D., Morré, D. M., & Morré, D. J. (2001). A drug-unresponsive and protease-resistant CNOX protein from human sera. Archives of Biochemistry and Biophysics, 386, 106–116. doi:10.1006/abbi.2000.2180.

    Article  CAS  Google Scholar 

  14. Hostetler, B., Weston, N., Kim, C., Morré, D. M., & Morré, D. J. (2008). Cancer site-specific isoforms of ENOX2 (tNOX), a cancer-specific cell surface oxidase. Clinical Proteomics. doi:10.1007/s12014-008-9016-x.

  15. del Castillo-Olivares, A., Yantiri, F., Chueh, P.-J., Wang, S., Sweeting, M., Sedlak, D., et al. (1998). A drug-responsive and protease-resistant 34 kD NADH oxidase from the surface of HeLa cells. Archives of Biochemistry and Biophysics, 358, 125–140. doi:10.1006/abbi.1998.0823.

    Article  Google Scholar 

  16. Morré, D. J. (1995). NADH oxidase activity of HeLa plasma membranes inhibited by the antitumor sulfonylurea N-(4-methylphenylsulfonyl)-N′-(4-chlorophenyl)urea (LY181984) at an external site. Biochimica et Biophysica Acta, 1240, 201–208. doi:10.1016/0005-2736(95)00164-7.

    Article  Google Scholar 

  17. Morré, D. J., Chueh, P.-J., Lawler, J., & Morré, D. M. (1998). The sulfonylurea-inhibited NADH oxidase activity of HeLa cell plasma membranes has properties of a protein disulfide-thiol oxidoreductase with protein disulfide-thiol interchange activity. Journal of Bioenergetics and Biomembranes, 30, 477–487. doi:10.1023/A:1020594214379.

    Article  Google Scholar 

  18. Morré, D. J. (1998). NADH oxidase: A multifunctional ectoprotein of the eukaryotic cell surface. In H. Asard, A. Bérczi, & R. Caubergs (Eds.), Plasma membrane redox systems and their role in biological stress and disease (pp. 121–156). Dordrecht, The Netherlands: Kluwer Academic Publishers.

    Google Scholar 

  19. Morré, D. J., Bridge, A., Wu, L.-Y., & Morré, D. M. (2000). Preferential inhibition by (−)-epigallocatechin-3-gallate of the cell surface NADH oxidase and growth of transformed cells in culture. Biochemical Pharmacology, 60, 937–946. doi:10.1016/S0006-2952(00)00426-3.

    Article  Google Scholar 

  20. Morré, D. J., Chueh, P.-J., & Morré, D. M. (1995). Capsaicin inhibits preferentially the NADH oxidase and growth of transformed cells in culture. Proceedings of the National Academy of Sciences of the United States of America, 92, 1831–1835. doi:10.1073/pnas.92.6.1831.

    Article  Google Scholar 

  21. Morré, D. J., Kim, C., Paulik, M., Morré, D. M., & Faulk, W. P. (1997). Is the drug-responsive NADH oxidase of the cancer cell plasma membrane a molecular target for adriamycin? Journal of Bioenergetics and Biomembranes, 29, 269–280. doi:10.1023/A:1022414228013.

    Article  Google Scholar 

  22. Morré, D. J., Wu, L.-Y., & Morré, D. M. (1995). The antitumor sulfonylurea N-(4-methylphenylsulfonyl)-N’-(chlorophenyl)urea (LY181984) inhibits NADH oxidase activity of HeLa plasma membrane. Biochimica et Biophysica Acta, 1240, 11–17. doi:10.1016/0005-2736(95)00164-7.

    Article  Google Scholar 

  23. Morré, D. J., Sedlak, D., Tang, X., Chueh, P.-J., Geng, T., & Morré, D. M. (2001). Surface NADH oxidase of HeLa cells lacks intrinsic membrane binding motifs. Archives of Biochemistry and Biophysics, 392, 251–256. doi:10.1006/abbi.2001.2436.

    Article  Google Scholar 

  24. Griffith, J. S. (1967). Self-replication and scrapie. Nature, 315, 1043–1044. doi:10.1038/2151043a0.

    Article  Google Scholar 

  25. Prusiner, S. B. (1994). Biology and genetics of prion diseases. Annual Review of Microbiology, 48, 655–686. doi:10.1146/annurev.mi.48.100194.003255.

    Article  CAS  Google Scholar 

  26. Robertson, E. D., & Sweatt, J. D. (1998). A biochemical blueprint for long-term memory. Learning & Memory (Cold Spring Harbor, N.Y.), 6, 381–388.

    Google Scholar 

  27. Morré, D. J., Morré, D. M., & Ternes, P. (2003). Auxin-activated NADH oxidase activity of soybean plasma membranes is distinct from the constitutive plasma membrane NADH oxidase and exhibits prion-like properties. In Vitro Cellular & Developmental Biology. Plant, 39, 368–376. doi:10.1079/IVP2003417.

    Article  Google Scholar 

  28. Kelker, M., Kim, C., Chueh, P.-J., Guimont, R., Morré, D. M., & Morré, D. J. (2001). Cancer isoforms of a tumor-associated cell surface NADH oxidase (tNOX) has properties of a prion. Biochemistry, 40, 7351–7354. doi:10.1021/bi010596i.

    Article  CAS  Google Scholar 

  29. Morré, D. J., Dick, S., Bosneaga, E., Balicki, A., Wu, L.-Y., McClain, N., et al. (2008). tNOX (ENOX1) target for chemosensitization—low-dose responses in the hormetic concentration range. American Journal of Pharmacology and Toxicology, 3, 16–26.

    Google Scholar 

Download references

Acknowledgment

We thank Peggy Runck for manuscript preparation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to D. James Morré.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Morré, D.J., McClain, N., Wu, LY. et al. Phenoxodiol Treatment Alters the Subsequent Response of ENOX2 (tNOX) and Growth of HeLa Cells to Paclitaxel and Cisplatin. Mol Biotechnol 42, 100–109 (2009). https://doi.org/10.1007/s12033-008-9132-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12033-008-9132-x

Keywords

Navigation