Phenoxodiol: Pharmacology and clinical experience in cancer monotherapy and in combination with chemotherapeutic drugs

Expert Opinion on Pharmacotherapy

Volumn 10, Issue 6, 2009, Pages 1059-1067

  Silasi, Dan Arin ^a   Alvero, Ayesha B ^a   Rutherford, Thomas J ^a   Brown, David ^b   Mor, Gil ^a  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b Novogen Ltd   (Australia)

Author keywords

Apoptosis; Cancer therapy; Chemoresistance; Phenoxodiol

Indexed keywords

3 (4 HYDROXYPHENYL) 2H CHROMEN 7 OL; ANTINEOPLASTIC AGENT; CARBOPLATIN; CISPLATIN; DOCETAXEL; GEMCITABINE; GENISTEIN; PACLITAXEL; PLACEBO; PLATINUM; TAXANE DERIVATIVE; TOPOTECAN; UNCLASSIFIED DRUG;

ADD ON THERAPY; ADENOCARCINOMA; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ALKALINE PHOSPHATASE BLOOD LEVEL; ANTIANGIOGENIC ACTIVITY; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; AREA UNDER THE CURVE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; BLADDER TUMOR; BLEEDING TIME; BLOOD TOXICITY; CANCER CELL; CANCER COMBINATION CHEMOTHERAPY; CANCER GROWTH; CANCER INHIBITION; CANCER MODEL; CANCER PATIENT; CANCER RESISTANCE; CHEMICAL MODIFICATION; CHEMOSENSITIZATION; CHEMOTHERAPY INDUCED EMESIS; CLINICAL PHARMACOLOGY; CLINICAL TRIAL; COLORECTAL TUMOR; CONTINUOUS INFUSION; COUGHING; DIARRHEA; DRUG ABSORPTION; DRUG BINDING SITE; DRUG CYTOTOXICITY; DRUG DOSE ESCALATION; DRUG EFFECT; DRUG EFFICACY; DRUG ERUPTION; DRUG HALF LIFE; DRUG HYPERSENSITIVITY; DRUG MECHANISM; DRUG SAFETY; DRUG STRUCTURE; DRUG TOLERABILITY; DRUG WITHDRAWAL; FATIGUE; GASTROINTESTINAL SYMPTOM; HUMAN; KIDNEY CARCINOMA; KIDNEY TUMOR; LEIOMYOSARCOMA; LETHARGY; LYMPHOCYTOPENIA; MELANOMA; MESOTHELIOMA; MONOTHERAPY; MULTIPLE CYCLE TREATMENT; NAUSEA; NONHUMAN; OVARY CANCER; OVARY CARCINOMA; PERITONEUM CANCER; PROSTATE CANCER; PROSTATE TUMOR; REVIEW; SIDE EFFECT; SQUAMOUS CELL CARCINOMA; THYMOMA; TIME TO MAXIMUM PLASMA CONCENTRATION; TREATMENT DURATION; TREATMENT OUTCOME; TREATMENT RESPONSE; UTERINE CERVIX CARCINOMA; UTERINE TUBE CARCINOMA; UTERUS TUMOR; VAGINA CARCINOMA; VULVA CARCINOMA;

ANIMALS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; CLINICAL TRIALS AS TOPIC; DNA TOPOISOMERASES, TYPE II; HUMANS; ISOFLAVONES; NEOPLASMS;

EID: 67649619170     PISSN: 14656566     EISSN: None     Source Type: Journal    
DOI: 10.1517/14656560902837980     Document Type: Review

References (37)

1. Lopez-Lazaro M. Flavonoids as anticancer agents: structure-activity relationship study. Curr Med Chem Anti-Cancer Agents 2002;2:691-714 (Pubitemid 35175268)
2. Brown DM, Kelly GE, Husband A. Flavonoid compounds in maintenance of prostate health and prevention and treatment of cancer. Mol Biotechnol 2005;30:253-270 (Pubitemid 41272813)
3. Sarkar FH, Li Y. Soy isoflavones and cancer prevention. Cancer Invest 2003;21:744-757 (Pubitemid 37377330)
4. Dakora FD, Phillips DA. Diverse functions of isoflavonoids in legumes transcend anti-microbial definitions of phytoalexins. Physiol Mol Plant Pathol 1996;49:1-20 (Pubitemid 26350850)
5. Akiyama T, Ishida J, Nakagawa S, et al. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem 1987;262:5592-5595
6. Alhasan SA, Aranha O, Sarkar FH. Genistein elicits pleiotropic molecular effects on head and neck cancer cells. Clin Cancer Res 2001;7:4174-4181 (Pubitemid 34044643)
7. Elattar TM, Virji AS. The inhibitory effect of curcumin, genistein, quercetin and cisplatin on the growth of oral cancer cells in vitro. Anticancer Res 2000;20:1733-1738 (Pubitemid 30628195)
8. 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
9. Available from: http://www.marshalledwardsinc.com/pdf/mei-may-03-web.pdf
10. Morré DJ, Chueh PJ, Yagiz K, et al. ECTO-NOX target for the anticancer isoflavene phenoxodiol. Oncol Res 2007;16:299-312 (Pubitemid 47488074)
11. Alvero AB, Rossi P, Brown D, et al. Phenoxodiol - a chemosensitizer in the midst of cancer chemoresistance. US Oncol 2008;39-41
12. Scarlett DJ, Herst P, Tan A, et al. Mitochondrial gene-knockout (rho0) cells: a versatile model for exploring the secrets of trans-plasma membrane electron transport. Biofactors 2004;20:199-206
13. Morré DJ, Dick S, Bosneaga E, et al. tNOX (ENOX2) target for chemosensitization-low-dose responses in the hormetic concentration range. Am J Pharm Toxicol 2008;3(1):16-26
14. Jin Z, El-Deiry WS. Overview of cell death signaling pathways. Cancer Biol Ther 2005;4(2):139-163 (Pubitemid 41351311)
15. Alvero AB, O'malley D, Brown D, et al. Molecular mechanism of phenoxodiol-induced apoptosis in ovarian carcinoma cells. Cancer 2006;106(3):599-608
16. Alvero AB, Kelly MG, Rossi P, et al. Anti-tumor activity of phenoxodiol: from bench to clinic. Future Oncol 2008;4(4):475-482
17. 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 (Pubitemid 40178958)
18. Kluger HM, McCarthy MM, Alvero AB, et al. The X-linked inhibitor of apoptosis protein (XIAP) is up-regulated in metastatic melanoma, and XIAP cleavage by phenoxodiol is associated with carboplatin sensitization. J Transl Med 2007;5:6 (Pubitemid 46243459)
19. Straszewski-Chavez SL, Abrahams VM, Funai EF, et al. X-linked inhibitor of apoptosis (XIAP) confers human trophoblast cell resistance to Fas-mediated apoptosis. Mol Hum Reprod 2004;10:33-41 (Pubitemid 38195963)
20. Cabot MC, Yu JY, Kelly GE, et al. Phenoxodiol, a synthetic analog of genistein, generates ceramide and is equipotent in wild-type and multidrug-resistant human tumor cells. J Clin Oncol 2005;23(S16):2075
21. Yu F, Watts RN, Borrow JM, et al. Involvement of BH3-only proapoptotic proteins in mitochondrial-dependent phenoxodiol-induced apoptosis of human melanoma cells. Anticancer drugs 2006;17(10):1151-1161 (Pubitemid 44673395)
22. 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 (Pubitemid 36428635)
23. Aguero MF, Facchinetti MM, Sheleg Z, et al. 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 (Pubitemid 40524621)
24. de Luca T, Morre DM, Zhao H, et al. 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 2005;25:43-60 (Pubitemid 44070832)
25. Herst PM, Petersen T, Jerram P, et al. The antiproliferative effects of phenoxodiol are associated with inhibition of plasma membrane electron transport in tumor cell lines and primary immune cells. Biochem Pharmacol 2007;74:1587-1595 (Pubitemid 47614971)
26. Klein R, Brown D, Turnley AM. Phenoxodiol protects against cisplatin induced neurite toxicity in a PC-12 cell model. BMC Neuroscience 2007;8:61 (Pubitemid 47300043)
27. Kamsteeg M, Rutherford T, Sapi E, et al. Phenoxodiol - an isoflavone analog - induces apoptosis in chemoresistant ovarian cancer cells. Oncogene 2003;22:2611-2620 (Pubitemid 36605609)
28. Gamble JR, Xia P, Hahn CN, et al. Phenoxodiol, an experimental anticancer drug, shows potent antiangiogenic properties in addition to its antitumour effects. Int J Cancer 2006;118:2412-2420
29. Choueiri TK, Mekhail1 T, Hutson TE, et al. Phase I trial of phenoxodiol delivered by continuous intravenous infusion in patients with solid cancer. Ann Oncol 2006;17:860-865
30. Hutson TE, Plavney D, Mekhail T, et al. A dose finding and pharmacokinetic study of the novel isoflavanoid phenoxodiol in patients with refractory malignancies [abstract 886]. Proc Am Soc Clin Oncol 2003;22
31. Joshua AM, Ong S, Noney L, et al. Phase 1 dose-escalation of phenoxodiol in patients with advanced cancer [abstract 902]. Proc Am Soc Clin Oncol 2003;225:
32. de Souza PL, Liauw W, Links M, et al. Phase I and pharmacokinetic study of weekly NV06 (Phenoxodiol), a novel isoflav-3-ene, in patients with advanced cancer. Cancer Chemother Pharmacol 2006;58(4):427-433 (Pubitemid 43999790)
33. Kelly MG, Mor G, Goss G, et al. Phase II evaluation of phenoxodiol in combination with cisplatin or paclitaxel in women with a history of platinum/taxane refractory/resistant epithelial ovarian, fallopian tube or primary peritoneal cancers. Manuscript in preparation
34. 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 4457]. Proc Am Assoc Cancer Res 2004;45
35. Available from: www.novogen.com/uploads/Newsletter-2004.pdfy-03-web.pdf
36. Kelly G. Interim results of a phase Ib/IIa study of oral phenoxodiol in patients with late-stage, hormone-refractory prostate cancer [abstract LB-214]. Proc Am Assoc Cancer Res 2004;45
37. Alvero AB, Brown D, Montagna M, et al. Phenoxodiol-topotecan co-administration exhibit significant anti-tumor activity without major adverse side effects. Cancer Biol Ther 2007;6(4):612-617 (Pubitemid 47328337)