Phenoxodiol: Isoflavone Analog with Antineoplastic Activity

Overview

Journal Curr Oncol Rep

Publisher Current Science

Specialty Oncology

Date 2006 Mar 2

PMID 16507219

Citations 6

Authors

Toni K Choueiri

Robert Wesolowski

Tarek M Mekhail

Affiliations

Soon will be listed here.

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.

Citing Articles

NOX66 as Monotherapy, and in Combination With Carboplatin, in Patients With Refractory Solid Tumors: Phase Ia/b Study.

Kiknavelidze K, Shavdia M, Chikhladze N, Abshilava L, Messina M, Mautner G Curr Ther Res Clin Exp. 2021; 94:100631.

PMID: 34306271 PMC: 8296080. DOI: 10.1016/j.curtheres.2021.100631.

Synthesis of Dextran-Phenoxodiol and Evaluation of Its Physical Stability and Biological Activity.

Yee E, Cirillo G, Brandl M, Black D, Vittorio O, Kumar N Front Bioeng Biotechnol. 2019; 7:183.

PMID: 31440502 PMC: 6694440. DOI: 10.3389/fbioe.2019.00183.

Triggering of eryptosis, the suicidal erythrocyte death, by phenoxodiol.

Fink M, Mamun Bhuyan A, Nurnberg B, Faggio C, Lang F Naunyn Schmiedebergs Arch Pharmacol. 2019; 392(10):1311-1318.

PMID: 31280326 DOI: 10.1007/s00210-019-01681-8.

Lesson learned from nature for the development of novel anti-cancer agents: implication of isoflavone, curcumin, and their synthetic analogs.

Sarkar F, Li Y, Wang Z, Padhye S Curr Pharm Des. 2010; 16(16):1801-12.

PMID: 20345353 PMC: 3093025. DOI: 10.2174/138161210791208956.

The continuing search for antitumor agents from higher plants.

Pan L, Chai H, Kinghorn A Phytochem Lett. 2010; 3(1):1-8.

PMID: 20228943 PMC: 2836022. DOI: 10.1016/j.phytol.2009.11.005.

References

Joussen A, Rohrschneider K, Reichling J, Kirchhof B, Kruse F . Treatment of corneal neovascularization with dietary isoflavonoids and flavonoids. Exp Eye Res. 2000; 71(5):483-7. DOI: 10.1006/exer.2000.0900. View

Kouroukis C, Belch A, Crump M, Eisenhauer E, Gascoyne R, Meyer R . 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(9):1740-5. DOI: 10.1200/JCO.2003.09.057. View

Schabath M, Hernandez L, Wu X, Pillow P, Spitz M . Dietary phytoestrogens and lung cancer risk. JAMA. 2005; 294(12):1493-504. DOI: 10.1001/jama.294.12.1493. View

Newcomb E . Flavopiridol: pleiotropic biological effects enhance its anti-cancer activity. Anticancer Drugs. 2004; 15(5):411-9. DOI: 10.1097/01.cad.0000127332.06439.47. View

Naik H, Lehr J, Pienta K . An in vitro and in vivo study of antitumor effects of genistein on hormone refractory prostate cancer. Anticancer Res. 1994; 14(6B):2617-9. View

Schwartz G, Ilson D, Saltz L, OReilly E, Tong W, Maslak P . Phase II study of the cyclin-dependent kinase inhibitor flavopiridol administered to patients with advanced gastric carcinoma. J Clin Oncol. 2001; 19(7):1985-92. DOI: 10.1200/JCO.2001.19.7.1985. View

Ravindranath M, Muthugounder S, Presser N, Viswanathan S . Anticancer therapeutic potential of soy isoflavone, genistein. Adv Exp Med Biol. 2004; 546:121-65. DOI: 10.1007/978-1-4757-4820-8_11. View

Fotsis T, Pepper M, Adlercreutz H, Hase T, Montesano R, Schweigerer L . Genistein, a dietary ingested isoflavonoid, inhibits cell proliferation and in vitro angiogenesis. J Nutr. 1995; 125(3 Suppl):790S-797S. DOI: 10.1093/jn/125.suppl_3.790S. View

Kyle E, Neckers L, Takimoto C, Curt G, Bergan R . Genistein-induced apoptosis of prostate cancer cells is preceded by a specific decrease in focal adhesion kinase activity. Mol Pharmacol. 1997; 51(2):193-200. DOI: 10.1124/mol.51.2.193. View

10.

Constantinou A, Huberman E . Genistein as an inducer of tumor cell differentiation: possible mechanisms of action. Proc Soc Exp Biol Med. 1995; 208(1):109-15. DOI: 10.3181/00379727-208-43841. View

11.

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(11):1559-66. PMC: 2223540. DOI: 10.1038/bjc.1997.268. View

12.

Straszewski-Chavez S, Abrahams V, Funai E, Mor G . X-linked inhibitor of apoptosis (XIAP) confers human trophoblast cell resistance to Fas-mediated apoptosis. Mol Hum Reprod. 2003; 10(1):33-41. DOI: 10.1093/molehr/gah001. View

13.

PETERSON T, Coward L, Kirk M, Falany C, Barnes S . The role of metabolism in mammary epithelial cell growth inhibition by the isoflavones genistein and biochanin A. Carcinogenesis. 1996; 17(9):1861-9. DOI: 10.1093/carcin/17.9.1861. View

14.

Schwartz G, OReilly E, Ilson D, Saltz L, Sharma S, Tong W . 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(8):2157-70. DOI: 10.1200/JCO.2002.08.080. View

15.

Harper A, Kerr D, Gescher A, Chipman J . Antioxidant effects of isoflavonoids and lignans, and protection against DNA oxidation. Free Radic Res. 1999; 31(2):149-60. DOI: 10.1080/10715769900301661. View

16.

Byrd J, Peterson B, Gabrilove J, Odenike O, Grever M, Rai K . 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(11):4176-81. DOI: 10.1158/1078-0432.CCR-04-2276. View

17.

Choi Y, Zhang L, Lee W, Park K . 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(2):391-6. DOI: 10.3892/ijo.13.2.391. View

18.

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(23):5815-21. View

19.

Constantinou A, 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. 2003; 22(5):2581-5. View

20.

Aguero M, Facchinetti M, Sheleg Z, Senderowicz A . 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(8):3364-73. DOI: 10.1158/0008-5472.CAN-04-2429. View