Skip to main content

Advertisement

Log in

Phenoxodiol: Isoflavone analog with antineoplastic activity

  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Phenoxodiol, a synthetic analog of the plant isoflavone genistein, represents a new generation of oncology drugs acting as multiple signal transduction regulators. Phenoxodiol exerts its effect mainly by the induction of apoptosis through multiple mechanisms resulting in degradation of antiapoptotic proteins, with increased levels being linked to chemoresistance in tumor cells. Preclinical studies with this agent showed promising anticancer activity leading to a potential role in the treatment of a wide range of solid and hematologic cancers. Early clinical studies, especially in chemotherapy-resistant ovarian cancer, showed minimal toxicity with minor antitumor activity. Hormone-refractory prostate cancer is another promising area in which phenoxodiol is being actively tested. Studies are ongoing to define the optimal use of this novel anticancer agent.

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.

Similar content being viewed by others

References and Recommended Reading

  1. Lamartiniere CA, Murrill WB, Manzolillo PA, et al.: Genistein alters the ontogeny of mammary gland development and protects against chemically-induced mammary cancer in rats. Proc Soc Exp Biol Med 1998, 217:358–364.

    PubMed  CAS  Google Scholar 

  2. Adlercreutz H, Mazur W: Phyto-oestrogens and Western diseases. Ann Med 1997, 29:95–120. Important review article about the relation between dietary isoflavone intake and lower cancer incidence, making the case for possible anticancer activity of these agents.

    PubMed  CAS  Google Scholar 

  3. Schabath MB, Hernandez LM, Wu X, et al.: Dietary phytoestrogens and lung cancer risk. JAMA 2005, 294:1493–1504. Recent case-control study about the decreased incidence of lung cancer with dietary phytoestrogens.

    Article  PubMed  CAS  Google Scholar 

  4. Rauth S, Kichina J, Green A: Inhibition of growth and induction of differentiation of metastatic melanoma cells in vitro by genistein: chemosensitivity is regulated by cellular p53. Br J Cancer 1997, 75:1559–1566.

    PubMed  CAS  Google Scholar 

  5. Spinozzi F, Pagliacci MC, Migliorati G, et al.: The natural tyrosine kinase inhibitor genistein produces cell cycle arrest and apoptosis in Jurkat T-leukemia cells. Leuk Res 1994, 18:431–439.

    Article  PubMed  CAS  Google Scholar 

  6. Peterson TG, Coward L, Kirk M, et al.: The role of metabolism in mammary epithelial cell growth inhibition by the isoflavones genistein and biochanin A. Carcinogenesis 1996, 17:1861–9.

    Article  PubMed  CAS  Google Scholar 

  7. Yanagihara K, Ito A, Toge T, Numoto M: Antiproliferative effects of isoflavones on human cancer cell lines established from the gastrointestinal tract. Cancer Res 1993, 53:5815–21.

    PubMed  CAS  Google Scholar 

  8. Naik HR, Lehr JE, Pienta KJ: An in vitro and in vivo study of antitumor effects of genistein on hormone refractory prostate cancer. Anticancer Res 1994, 14:2617–2619.

    PubMed  CAS  Google Scholar 

  9. Schweigerer L, Christeleit K, Fleischmann G, et al.: Identification in human urine of a natural growth inhibitor for cells derived from solid paediatric tumours. Eur J Clin Invest 1992, 22:260–264.

    Article  PubMed  CAS  Google Scholar 

  10. Choi YH, Zhang L, Lee WH, Park KY: Genistein-induced G2/M arrest is associated with the inhibition of cyclin B1 and the induction of p21 in human breast carcinoma cells. Int J Oncol 1998, 13:391–396.

    PubMed  CAS  Google Scholar 

  11. Harper A, Kerr DJ, Gescher A, Chipman JK: Antioxidant effects of isoflavonoids and lignans, and protection against DNA oxidation. Free Radic Res 1999, 31:149–160.

    Article  PubMed  CAS  Google Scholar 

  12. Kyle E, Neckers L, Takimoto C, et al.: Genistein-induced apoptosis of prostate cancer cells is preceded by a specific decrease in focal adhesion kinase activity. Mol Pharmacol 1997, 51:193–200.

    PubMed  CAS  Google Scholar 

  13. Fotsis T, Pepper M, Adlercreutz H, et al.: Genistein, a dietary ingested isoflavonoid, inhibits cell proliferation and in vitro angiogenesis. J Nutr 1995, 125:790S-797S.

    PubMed  CAS  Google Scholar 

  14. Joussen AM, Rohrschneider K, Reichling J, et al.: Treatment of corneal neovascularization with dietary isoflavonoids and flavonoids. Exp Eye Res 2000, 71:483–487.

    Article  PubMed  CAS  Google Scholar 

  15. Bergan R, Kyle E, Nguyen P, et al.: Genistein-stimulated adherence of prostate cancer cells is associated with the binding of focal adhesion kinase to beta-1-integrin. Clin Exp Metastasis 1996, 14:389–398.

    Article  PubMed  CAS  Google Scholar 

  16. Swanton C: Cell-cycle targeted therapies. Lancet Oncol 2004, 5:27–36.

    Article  PubMed  CAS  Google Scholar 

  17. Newcomb EW: Flavopiridol: pleiotropic biological effects enhance its anti-cancer activity. Anticancer Drugs 2004, 15:411–419.

    Article  PubMed  CAS  Google Scholar 

  18. Schwartz GK, Ilson D, Saltz L, et al.: Phase II study of the cyclin-dependent kinase inhibitor flavopiridol administered to patients with advanced gastric carcinoma. J Clin Oncol 2001, 19:1985–1992.

    PubMed  CAS  Google Scholar 

  19. Shapiro GI, Supko JG, Patterson A, et al.: A phase II trial of the cyclin-dependent kinase inhibitor flavopiridol in patients with previously untreated stage IV non-small cell lung cancer. Clin Cancer Res 2001, 7:1590–1599.

    PubMed  CAS  Google Scholar 

  20. Kouroukis CT, Belch A, Crump M, et al.: Flavopiridol in untreated or relapsed mantle-cell lymphoma: results of a phase II study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2003, 21:1740–1745.

    Article  PubMed  CAS  Google Scholar 

  21. Byrd JC, Peterson BL, Gabrilove J, et al.: Treatment of relapsed chronic lymphocytic leukemia by 72-hour continuous infusion or 1-hour bolus infusion of flavopiridol: results from Cancer and Leukemia Group B study 19805. Clin Cancer Res 2005, 11:4176–4181.

    Article  PubMed  CAS  Google Scholar 

  22. Schwartz GK, O’Reilly E, Ilson D, et al.: Phase I study of the cyclin-dependent kinase inhibitor flavopiridol in combination with paclitaxel in patients with advanced solid tumors. J Clin Oncol 2002, 20:2157–2170.

    Article  PubMed  CAS  Google Scholar 

  23. Constantinou A, Huberman E: Genistein as an inducer of tumor cell differentiation: possible mechanisms of action. Proc Soc Exp Biol Med 1995, 208:109–115.

    PubMed  CAS  Google Scholar 

  24. Ravindranath MH, Muthugounder S, Presser N, Viswanathan S:Anticancer therapeutic potential of soy isoflavone, genistein. Adv Exp Med Biol 2004, 546:121–165.

    PubMed  Google Scholar 

  25. Constantinou AI, Husband A: Phenoxodiol (2H-1-benzopyran-7-0,1,3-(4-hydroxyphenyl)), a novel isoflavone derivative, inhibits DNA topoisomerase II by stabilizing the cleavable complex. Anticancer Res 2002, 22:2581–2585.

    PubMed  CAS  Google Scholar 

  26. Kamsteeg M, Rutherford T, Sapi E, et al.: Phenoxodiol—an isoflavone analog—induces apoptosis in chemoresistant ovarian cancer cells. Oncogene 2003, 22:2611–2620. One of the first papers to describe the in vivo antiapoptotic effects of phenoxodiol in chemoresistant malignancies.

    Article  PubMed  CAS  Google Scholar 

  27. Sapi E, Alvero AB, Chen W, et al.: Resistance of ovarian carcinoma cells to docetaxel is XIAP dependent and reversible by phenoxodiol. Oncol Res 2004, 14:567–578.

    PubMed  CAS  Google Scholar 

  28. Straszewski-Chavez SL, Abrahams VM, Funai EF, Mor G:X-linked inhibitor of apoptosis (XIAP) confers human trophoblast cell resistance to Fas-mediated apoptosis. Mol Hum Reprod 2004, 10:33–41.

    Article  PubMed  CAS  Google Scholar 

  29. Aguero MF, Facchinetti MM, Sheleg Z, Senderowicz AM:Phenoxodiol, a novel isoflavone, induces G1 arrest by specific loss in cyclin-dependent kinase 2 activity by p53-independent induction of p21WAF1/CIP1. Cancer Res 2005, 65:3364–3373.

    PubMed  CAS  Google Scholar 

  30. Min J, Stegner AL, Alexander H, Alexander S: Overexpression of sphingosine-1-phosphate lyase or inhibition of sphingosine kinase in Dictyostelium discoideum results in a selective increase in sensitivity to platinum-based chemotherapy drugs. Eukaryot Cell 2004, 3:795–805.

    Article  PubMed  CAS  Google Scholar 

  31. Constantinou AI, Mehta R, Husband A: Phenoxodiol, a novel isoflavone derivative, inhibits dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis in female Sprague-Dawley rats. Eur J Cancer 2003, 39:1012–1018.

    Article  PubMed  CAS  Google Scholar 

  32. Joshua AM, Ong S, Noney L, et al.: Phase 1 dose-escalation of phenoxodiol in patients with advanced cancer [abstract]. Proc AACR 2003, 225:902. Early phase I clinical study of phenoxodiol in refractory malignancies showing minimal toxicity.

    Google Scholar 

  33. Rutherford T, O’Malley D, Makkenchery A, et al.: Phenoxodiol phase Ib/II study in patients with recurrent ovarian cancer that are resistant to > second line chemotherapy [abstract]. Proc AACR 2004, 45:4457. Phase I/II trial of phenoxodiol in the setting of refractory/recurrent ovarian cancer showing a promising clinical benefit.

    Google Scholar 

  34. Kelly G: Interim results of a phase Ib/IIa study of oral phenoxodiol in patients with late-stage, hormonerefractory prostate cancer [abstract]. Proc AACR 2004, 45:LB-214. Phase I/II trial of phenoxodiol in the setting of hormone-refractory prostate cancer showing a promising disease stabilization at 37%.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Toni K. Choueiri MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Choueiri, T.K., Wesolowski, R. & Mekhail, T.M. Phenoxodiol: Isoflavone analog with antineoplastic activity. Curr Oncol Rep 8, 104–107 (2006). https://doi.org/10.1007/s11912-006-0044-2

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-006-0044-2

Keywords

Navigation