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Cytotoxic effects of the novel isoflavone, phenoxodiol, on prostate cancer cell lines

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Abstract

Phenoxodiol is an isoflavone derivative that has been shown to elicit cytotoxic effects against a broad range of human cancers. We examined the effect of phenoxodiol on cell death pathways on the prostate cell lines LNCaP, DU145 and PC3, representative of different stages of prostate cancer, and its effects on cell death pathways in these cell lines. Cell proliferation assays demonstrated a significant reduction in the rate of cell proliferation after 48 h exposure to phenoxodiol (10 and 30 μM). FACS analysis and 3′-end labelling indicated that all three prostate cancer cell lines underwent substantial levels of cell death 48 h after treatment. Mitochondrial membrane depolarization, indicative of early-stage cell death signalling, using JC-1 detection, was also apparent in all cell lines after exposure to phenoxodiol in the absence of caspase-3 activation. Caspase inhibition assays indicated that phenoxodiol operates through a caspase-independent cell death pathway. These data demonstrate that phenoxodiol elicits anti-cancer effects in prostate cancer cell lines representative of early and later stages of development through an as-yet-unknown cell death mechanism. These data warrant the further investigation of phenoxodiol as a potential treatment for prostate cancer.

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Abbreviations

AR:

androgen receptor

FACS:

fluorescence activated cell sorting

FCCP:

carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone

MTS:

(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulpophenyl)-2H-tetrazolium)

JC-1:

5,5′6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolocarbocyanine iodide

RIPA:

radioimmunoprecipitation assay

RT-PCR:

reverse transcriptase polymerase chain reaction

SDS-PAGE:

sodium dodecyl sulphate polyacrylamide gel electrophoresis

References

  • Aguero MF, Facchinetti MM, Sheleg Z and Senderowicz AM 2005 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. 65 3364–3373

    PubMed  CAS  Google Scholar 

  • Alhasan SA, Pietrasczkiwicz H, Alonso MD, Ensley J and Sarkar FH 1999 Genistein-induced cell cycle arrest and apoptosis in a head and neck squamous cell carcinoma cell line. Nutr. Cancer 34 12–19

    Article  PubMed  CAS  Google Scholar 

  • Alvero AB, O’Malley D, Brown D, Kelly G, Garg M, Chen W, Rutherford T and Mor G 2006 Molecular mechanism of phenoxodiol-induced apoptosis in ovarian carcinoma cells. Cancer 106 599–608

    Article  PubMed  CAS  Google Scholar 

  • Axanova L, Morre DJ and Morre DM 2005 Growth of LNCaP cells in monoculture and coculture with osteoblasts and response to tNOX inhibitors. Cancer Lett. 225 35–40

    Article  PubMed  CAS  Google Scholar 

  • Beecher GR 2003 Overview of dietary flavonoids: nomenclature, occurrence and intake. J. Nutr. 133 3248S–3254S

    PubMed  CAS  Google Scholar 

  • Brown JM and Attardi LD 2005 The role of apoptosis in cancer development and treatment response. Nat. Rev. Cancer 5 231–237

    Article  PubMed  CAS  Google Scholar 

  • Brown JM and Wilson G 2003 Apoptosis genes and resistance to cancer therapy: what does the experimental and clinical data tell us? Cancer Biol. Ther. 2 477–490

    PubMed  CAS  Google Scholar 

  • Brown JM and Wouters BG 1999 Apoptosis, p53, and tumor cell sensitivity to anticancer agents. Cancer Res. 59 1391–1399

    PubMed  CAS  Google Scholar 

  • Brown DM, Kelly GE and Husband AJ 2005 Flavonoid compounds in maintenance of prostate health and prevention and treatment of cancer. Mol. Biotechnol. 30 253–270

    Article  PubMed  CAS  Google Scholar 

  • Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T and Korsmeyer SJ 2001 BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol. Cell 8 705–711

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Cory S and Adams JM 2002 The Bcl2 family: regulators of the cellular life-or-death switch. Nat. Rev. Cancer 2 647–656

    Article  PubMed  CAS  Google Scholar 

  • De Luca T, Morre DM, Zhao H and Morre DJ 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 25 43–60

    Article  PubMed  Google Scholar 

  • Dharmarajan AM, Goodman SB, Tilly KI and Tilly JL 1994 Apoptosis during functional corpus luteum regression: evidence of a role for chorionic gonadotropin in promoting luteal cell survival. Endocrine J. 2 295–303

    CAS  Google Scholar 

  • Feldman BJ and Feldman D 2001 The development of androgen-independent prostate cancer. Nat. Rev. Cancer 1 34–45

    Article  PubMed  CAS  Google Scholar 

  • Fojo T and Bates S 2003 Strategies for reversing drug resistance. Oncogene 22 7512–7523

    Article  PubMed  CAS  Google Scholar 

  • Gamble JR, Xia P, Hahn CN, Drew JJ, Drogemuller CJ, Brown D and Vadas MA 2005 Phenoxodiol, an experimental anticancer drug, shows potent antiangiogenic properties in addition to its antitumour effects. Int. J. Cancer 118 2412–2420

    Article  Google Scholar 

  • Georgaki S, Skopeliti M, Tsiatas M, Nicolaou KA, Ioannou K, Husband A, Bamias A, Dimopoulos MA, et al. 2009 Phenoxodiol, an anticancer isoflavene, induces immunomodulatory effects in vitro and in vivo. J. Cell Mol. Med. 13 3929–3938

    Article  PubMed  Google Scholar 

  • Gleave M, Miyake H and Chi K 2005 Beyond simple castration: targeting the molecular basis of treatment resistance in advanced prostate cancer. Cancer Chemother. Pharmacol. 56 47–57

    Article  PubMed  Google Scholar 

  • Hong SJ, Dawson TM and Dawson VL 2004 Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling. Trends Pharmacol. Sci. 25 259–264

    Article  PubMed  CAS  Google Scholar 

  • Hsing AW, Tsao L and Devesa SS 2000 International trends and patterns of prostate cancer incidence and mortality. Int. J. Cancer 85 60–67

    Article  PubMed  CAS  Google Scholar 

  • Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ and Thun MJ 2005 Cancer statistics 2005 CA Cancer J. Clin. 55 10–30

    Article  PubMed  Google Scholar 

  • Kamsteeg M, Rutherford T, Sapi E, Hanczaruk B, Shahabi S, Flick M, Brown D and Mor G 2003 Phenoxodiol—an isoflavone analog—induces apoptosis in chemoresistant ovarian cancer cells. Oncogene 22 2611–2620

    Article  PubMed  CAS  Google Scholar 

  • Korsmeyer SJ, Wei MC, Saito M, Weiler S, Oh KJ and Schlesinger PH 2000 Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ. 7 1166–1173

    Article  PubMed  CAS  Google Scholar 

  • McPherson RA, Galettis PT and de Souza PL 2009 Enhancement of the activity of phenoxodiol by cisplatin in prostate cancer cells. Br. J. Cancer 100 649–655

    Article  PubMed  CAS  Google Scholar 

  • Middleton E Jr, Kandaswami C and Theoharides TC 2000 The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev. 52 673–751

    PubMed  CAS  Google Scholar 

  • Morre DJ, Chueh PJ, Yagiz K, Balicki A, Kim C and Morre DM 2007 ECTO-NOX target for the anticancer isoflavene phenoxodiol. Oncol. Res. 16 299–312

    PubMed  Google Scholar 

  • Puthalakath H and Strasser A 2002 Keeping killers on a tight leash: transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins. Cell Death Differ. 9 505–512

    Article  PubMed  CAS  Google Scholar 

  • Ruth AC and Roninson IB 2000 Effects of the multidrug transporter P-glycoprotein on cellular responses to ionizing radiation. Cancer Res. 60 2576–2578

    PubMed  CAS  Google Scholar 

  • Sapi E, Alvero AB, Chen W, O'Malley D, Hao XY, Dwipoyono B, Garg M, Kamsteeg M, et al. 2004. Resistance of ovarian carcinoma cells to docetaxel is XIAP dependent and reversible by phenoxodiol. Oncol. Res. 14 567–578

    PubMed  CAS  Google Scholar 

  • Scherr DS, Vaughan ED Jr, Wei J, Chung M, Felsen D, Allbright R and Knudsen BS 1999 BCL-2 and p53 expression in clinically localized prostate cancer predicts response to external beam radiotherapy. J. Urol. 162 12–16; discussion 16–17

    Article  PubMed  CAS  Google Scholar 

  • Silasi DA, Alvero AB, Rutherford TJ, Brown D and Mor G 2009 Phenoxodiol: pharmacology and clinical experience in cancer monotherapy and in combination with chemotherapeutic drugs. Expert Opin. Pharmacother. 10 1059–1067

    Article  PubMed  CAS  Google Scholar 

  • Tang Y, Khan MA, Goloubeva O, Lee DI, Jelovac D, Brodie AM and Hussain A 2006 Docetaxel followed by castration improves outcomes in LNCaP prostate cancer-bearing severe combined immunodeficient mice. Clin. Cancer Res. 12 169–174

    Article  PubMed  CAS  Google Scholar 

  • Tannock IF and Lee C 2001 Evidence against apoptosis as a major mechanism for reproductive cell death following treatment of cell lines with anti-cancer drugs. Br. J. Cancer 84 100–105

    Article  PubMed  CAS  Google Scholar 

  • Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Theodore C, et al. 2004 Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. New Engl. J. Med. 351 1502–1512

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors would like to acknowledge the technical help of Mr Greg Cozens from the School of Anatomy and Human Biology, University of Western Australia, and Dr Kathy Heel from the Centre for Microscopy, Characterisation and Analysis. The authors acknowledge the facilities, scientific and technical assistance of the Australian Microscopy & Microanalysis Research Facility at the Centre for Microscopy, Characterisation & Analysis, The University of Western Australia, a facility funded by The University, State and Commonwealth Governments. AD is supported by the Cancer Council of Western Australia. This study was supported by Novogen Ltd.

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Authors and Affiliations

  1. School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Kent Street, Bentley, Western Australia, Australia, 6102

    Simon Mahoney

  2. School of Anatomy & Human Biology, The University of Western Australia, Perth, Western Australia, Australia, 6009

    Frank Arfuso, Pierra Rogers & Arun Dharmarajan

  3. Department of Medicine – Austin Health and Northern Health, The University of Melbourne, Parkville, Victoria, Australia, 3010

    Susan Hisheh

  4. Novogen Limited, 140 Wicks Road, North Ryde, NSW, Australia, 2113

    David Brown

  5. School of Medicine and Pharmacology, The University of Western Australia, Perth, Western Australia, Australia, 6009

    Michael Millward

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  1. Simon Mahoney
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  2. Frank Arfuso
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  3. Pierra Rogers
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  4. Susan Hisheh
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  5. David Brown
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  6. Michael Millward
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  7. Arun Dharmarajan
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Correspondence to Arun Dharmarajan.

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Corresponding editor: Rita Mulherkar

[Mahoney S, Arfuso F, Rogers P, Hisheh S, Brown D, Millward M and Dharmarajan A 2012 Cytotoxic effects of the novel isoflavone, phenoxodiol, on prostate cancer cell lines. J. Biosci. 37 XXX–XXX] DOI

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Mahoney, S., Arfuso, F., Rogers, P. et al. Cytotoxic effects of the novel isoflavone, phenoxodiol, on prostate cancer cell lines. J Biosci 37, 73–84 (2012). https://doi.org/10.1007/s12038-011-9170-6

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  • DOI: https://doi.org/10.1007/s12038-011-9170-6

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