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Dirty deeds done dirt cheap: sensitization of prostate cancer cells to abiraterone treatment using hydroxylated polychlorinated biphenyls

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Summary

Effective targeting of androgen biosynthesis by the 17α-hydroxylase/17,20-lyase inhibitor abiraterone prolongs survival in a variety of prostate cancer patients. However, resistance to abiraterone treatment occurs frequently and the development of new drugs supporting or complementing abiraterone therapy is urgently needed. We recently reported antiproliferative and proapoptotic effects of hydroxylated polychlorinated biphenyls (PCBs) on various blood cell lines in vitro. Here we report the biological evaluation of the PCB28 derived OH-metabolites 3-OHCB28 or 3′-OHCB28 in prostate cancer cells. Depending on concentration, both metabolites inhibit the growth of PC3 cells, a cell line representing later stages of advanced prostate cancer. In addition 3′-OHCB28 reduced the necessary concentration of abiraterone required for the inhibition of PC3 cells by a factor of 4. Western blot analysis of cytoprotective heatshock proteins (HSP) implicated a significant reduction of HSP27 expression by 3′-OHCB28 in PC3 cells. Given the known HSP27 suppressive role of abiraterone, our results therefore suggest, that that the pharmacological interaction between abiraterone and 3′-OHCB28 in PC3 cells could be produced by the combined effect of both substances on the expression of HSPs, especially the expression of HSP27. Including the known dose response linkages and pharmacokinetic characteristics of the OH-metabolites described here, we conclude, that the use of hydroxylated PCBs can be supportive for the anti-proliferative treatment of prostate cancer and merits further investigation.

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References

  1. Ziegler S, Schettgen T, Beier F, Wilop S, Quinete N, Esser A, Masouleh BK, Ferreira MSV, Vankann L, Uciechowski P, Rink L, Kraus T, Brümmendorf TH, Ziegler P (2017) Accelerated telomere shortening in peripheral blood lymphocytes after occupational polychlorinated biphenyls exposure. Arch Toxicol 91:289–300. https://doi.org/10.1007/s00204-016-1725-8

    Article  CAS  PubMed  Google Scholar 

  2. Vasko T, Hoffmann J, Gostek S, Schettgen T, Quinete N, Preisinger C, Kraus T, Ziegler P (2018) Telomerase gene expression bioassays indicate metabolic activation of genotoxic lower chlorinated polychlorinated biphenyls. Sci Rep 8:16903. https://doi.org/10.1038/s41598-018-35043-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kimbrough RD (1987) Human health effects of polychlorinated biphenyls (PCBs) and polybrominated biphenyls (PBBs). Annu Rev Pharmacol Toxicol 27:87–111. https://doi.org/10.1146/annurev.pa.27.040187.000511

    Article  CAS  PubMed  Google Scholar 

  4. Lauby-Secretan B, Loomis D, Grosse Y, el Ghissassi F, Bouvard V, Benbrahim-Tallaa L, Guha N, Baan R, Mattock H, Straif K, WHO International Agency for Research on Cancer (2013) Carcinogenicity of polychlorinated biphenyls and polybrominated biphenyls. The Lancet Oncology 14:287–288. https://doi.org/10.1016/s1470-2045(13)70104-9

    Article  CAS  PubMed  Google Scholar 

  5. Grimm FA, Hu D, Kania-Korwel I, Lehmler HJ, Ludewig G, Hornbuckle KC, Duffel MW, Bergman Å, Robertson LW (2015) Metabolism and metabolites of polychlorinated biphenyls. Crit Rev Toxicol 45:245–272. https://doi.org/10.3109/10408444.2014.999365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Saupe M, Rauschenberger L, Preuß M, Oswald S, Fussek S, Zimmermann U, Walther R, Knabbe C, Burchardt M, Stope MB (2015) Differential expression of the multidrug resistance 1 (MDR1) protein in prostate cancer cells is independent from anticancer drug treatment and Y box binding protein 1 (YB-1) activity. World J Urol 33:1481–1486. https://doi.org/10.1007/s00345-014-1469-0

    Article  CAS  PubMed  Google Scholar 

  7. Grossebrummel H et al (2016) Cytochrome P450 17A1 inhibitor abiraterone attenuates cellular growth of prostate cancer cells independently from androgen receptor signaling by modulation of oncogenic and apoptotic pathways. Int J Oncol 48:793–800. https://doi.org/10.3892/ijo.2015.3274

    Article  CAS  PubMed  Google Scholar 

  8. Weiss M, Ahrend H, Grossebrummel H, Ziegler P, Brandenburg LO, Walther R, Zimmermann U, Burchardt M, Stope MB (2016) Cytochrome P450 17A1 inhibitor Abiraterone acetate counteracts the heat shock protein 27’s cell survival properties in prostate Cancer cells. Urol Int 97:112–117. https://doi.org/10.1159/000445251

    Article  CAS  PubMed  Google Scholar 

  9. AnvariFar H, Amirkolaie AK, Jalali AM, Miandare HK, Sayed AH, Üçüncü Sİ, Ouraji H, Ceci M, Romano N (2018) Environmental pollution and toxic substances: cellular apoptosis as a key parameter in a sensible model like fish. Aquatic toxicology (Amsterdam, Netherlands) 204:144–159. https://doi.org/10.1016/j.aquatox.2018.09.010

    Article  CAS  Google Scholar 

  10. Becker MM, Gamble W (1982) Determination of the binding of 2,4,5,2′,4′,5′-hexachlorobiphenyl by low density lipoprotein and bovine serum albumin. J Toxicol Environ Health 9:225–234. https://doi.org/10.1080/15287398209530157

    Article  CAS  PubMed  Google Scholar 

  11. Ljunggren SA, Helmfrid I, Salihovic S, van Bavel B, Wingren G, Lindahl M, Karlsson H (2014) Persistent organic pollutants distribution in lipoprotein fractions in relation to cardiovascular disease and cancer. Environ Int 65:93–99. https://doi.org/10.1016/j.envint.2013.12.017

    Article  CAS  PubMed  Google Scholar 

  12. Purkey HE, Palaninathan SK, Kent KC, Smith C, Safe SH, Sacchettini JC, Kelly JW (2004) Hydroxylated polychlorinated biphenyls selectively bind transthyretin in blood and inhibit amyloidogenesis: rationalizing rodent PCB toxicity. Chem Biol 11:1719–1728. https://doi.org/10.1016/j.chembiol.2004.10.009

    Article  CAS  PubMed  Google Scholar 

  13. Lans MC, Klasson-Wehler E, Willemsen M, Meussen E, Safe S, Brouwer A (1993) Structure-dependent, competitive interaction of hydroxy-polychlorobiphenyls, −dibenzo-p-dioxins and -dibenzofurans with human transthyretin. Chem Biol Interact 88:7–21

    Article  CAS  Google Scholar 

  14. Quinete N, Esser A, Kraus T, Schettgen T (2017) PCB 28 metabolites elimination kinetics in human plasma on a real case scenario: study of hydroxylated polychlorinated biphenyl (OH-PCB) metabolites of PCB 28 in a highly exposed German cohort. Toxicol Lett 276:100–107. https://doi.org/10.1016/j.toxlet.2017.05.025

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by a START-grant (AZ 14/16) of the Faculty of Medicine RWTH Aachen University to PZ.

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Author notes

  1. Matthias B. Stope and Patrick Ziegler contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, University Medicine Greifswald, Greifswald, Germany

    Gabriel Daragan, Martin Burchardt & Matthias B. Stope

  2. Institute for Occupational, Social and Environmental Medicine, RWTH Aachen University, Aachen, Germany

    Jenny Hoffmann, Theresa Vasko, Thomas Kraus & Patrick Ziegler

  3. Department of Gynaecology and Obstetrics, University Medicine Greifswald, Greifswald, Germany

    Alexander Mustea

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  1. Gabriel Daragan
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  2. Jenny Hoffmann
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  3. Theresa Vasko
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  4. Alexander Mustea
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  6. Thomas Kraus
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  7. Matthias B. Stope
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  8. Patrick Ziegler
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Correspondence to Patrick Ziegler.

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Supplemental Figure 1

3-OHCB28 and 3′-OHCB28 modulate heatshock protein expression in PC3 cells. A + B) Western blot analysis of relative expression of HSP40, HSP60, HSP90α and the Hsp70-Hsp90 organizing protein (HOP) in the presence of 20 μM OHCB28 or 3′-OHCB28 at the indicated timepoints. Data were standardized to vehicle treated cells (control = 1.0) with glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as loading control. Error bars indicate ± SD. *p ≤ 0.05, **p ≤ 0.01 ***p ≤ 0.001, as determined by Student’s t test. (PDF 147 kb)

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Daragan, G., Hoffmann, J., Vasko, T. et al. Dirty deeds done dirt cheap: sensitization of prostate cancer cells to abiraterone treatment using hydroxylated polychlorinated biphenyls. Invest New Drugs 38, 541–545 (2020). https://doi.org/10.1007/s10637-019-00833-0

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  • DOI: https://doi.org/10.1007/s10637-019-00833-0

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