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Changes in mitochondrial function induced by dequalinium precede oxidative stress and apoptosis in the human prostate-cancer cell line PC-3

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Abstract

Mitochondria play central roles in diverse physiological and pathological conditions associated with cell survival and death. Delocalized lipophilic cations, such as dequalinium (DQA), are accumulated in cancer cells attracted by the highly negative mitochondrial transmembrane potential of these cells. DQA showed a potent anticancer activity in cells from different malignancies. Here, we report the effect of DQA on PC-3 prostate cancer cells. Incubation with DQA at concentrations between 1.5 and 100 μM from 24 to 48 h decreases cell viability. The decrease in cell viability together with a loss of mitochondrial transmembrane potential induced an increase in reactive oxygen species production and cell death via caspase-3 dependent apoptotic pathway. DQA was shown to cause moderate to strong cell death in a time and concentration dependent manner, causing a most advantageous effect at a concentration of 10 μM applied for a long 48 h time period, which might be a consequence of the kinetics of intracellular DQA accumulation in mitochondria, but also of the mechanisms of DQA-induced cell death. This data shows DQA as a promising agent against the human prostate cancer PC-3 cell line, activating the caspase-3 dependent apoptotic pathway. This fact might be beneficial for possible future applications in cancer therapy.

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References

  1. Stavridi F., Karapanagiotou E.M., Syrigos K.N. 2010. Targeted therapeutic approaches for hormone-refractory prostate cancer. Cancer Treat. Rev. 36, 122–130.

    Article  CAS  PubMed  Google Scholar 

  2. Kaighn M.E., Narayan K.S., Ohnuki Y., Lechner J.F., Jones L.W. 1979. Establishment and characterization of a human prostatic carcinoma cell line (PC-3). Invest. Urol. 17, 16–23.

    CAS  PubMed  Google Scholar 

  3. Duchen M.R. 2004. Mitochondria in health and disease: Perspectives on a new mitochondrial biology. Mol. Aspects Med. 25, 365–451.

    Article  CAS  PubMed  Google Scholar 

  4. Bras M., Queenan B., Susin S.A. 2005. Programmed cell death via mitochondria: Different modes of dying. Biochemistry. 70, 231–239.

    CAS  PubMed  Google Scholar 

  5. Vanden Berghe T., Grootjans S., Goossens V., Dondelinger Y., Krysko D.V., Takahashi N., Vandenabeele P. 2013. Determination of apoptotic and necrotic cell death in vitro and in vivo. Methods. 61, 117–129.

    Article  Google Scholar 

  6. FerrÍn G., Linares C.I., Montané J. 2011. Mitochondrial drug targets in cell death and cancer. Curr. Pharm. Design. 17, 2002–2016.

    Article  Google Scholar 

  7. Wen S., Zhu D., Huang P. 2013. Targeting cancer cell mitochondria as a therapeutic approach. Future Med. Chem. 5, 53–67.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Biasutto L., Dong L.-F., Zoratti M., Neuzil J. 2010. Mitochondrially targeted anti-cancer agents. Mitochondrion. 10, 670–681.

    Article  CAS  PubMed  Google Scholar 

  9. Wang F., Ogasawara M.A., Huang P. 2010. Small mitochondria-targeting molecules as anti-cancer agents. Mol. Aspects. Med. 31, 75–92.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Zhang E., Zhang C., Su Y., Cheng T., Shi C. 2011. Newly developed strategies for multifunctional mitochondria-targeted agents in cancer therapy. Drug. Discov. Today. 16, 140–146.

    Article  CAS  PubMed  Google Scholar 

  11. Modica-Napolitano J.S., Aprille J.R. 2001. Delocalized lipophilic cations selectively target the mitochondria of carcinoma cells. Adv. Drug. Deliv. Rev. 49, 63–70.

    Article  CAS  PubMed  Google Scholar 

  12. Christman J.E., Miller D.S., Coward P., Smith L.H., Teng N. 1990. Study of the selective cytotoxic properties of cationic, lipophilic mitochondrial-specific compounds in gynecologic malignancies. Gynecol. Oncol. 39, 72–79.

    Article  CAS  PubMed  Google Scholar 

  13. Helige C., Smolle J., Zellnig G., Fink-Puches R., Kerl H., Tritthart H.A. 1992. Effect of dequalinium on K1735-M2 melanoma cell growth, directional migration and invasion in vitro. Eur. J. Cancer. 29A, 124–128.

    CAS  PubMed  Google Scholar 

  14. Abdul M., Hoosein N. 2002. Expression and activity of potassium ion channels in human prostate cancer. Cancer Lett. 186, 99–105.

    Article  CAS  PubMed  Google Scholar 

  15. Modica-Napolitano J.S., Nalbandian R., Kidd M.E., Nalbandian A., Nguyen C.C. 2003. The selective in vitro cytotoxicity of carcinoma cells by AZT is enhanced by concurrent treatment with delocalized lipophilic cations. Cancer Lett. 198, 59–68.

    Article  CAS  PubMed  Google Scholar 

  16. Sancho P., Galeano E., Nieto E., Delgado M.D., Garcia-Perez A.I. 2007. Dequalinium induces cell death in human leukemia cells by early mitochondrial alterations which enhance ROS production. Leuk. Res. 31, 969–978.

    Article  CAS  PubMed  Google Scholar 

  17. Pajuelo L., Calviño E., Diez J.C., Boyano-Adánez M.C., Gil J., Sancho P. 2010. Dequalinium induces apoptosis in peripheral blood mononuclear cells isolated from human chronic lymphocytic leukemia. Invest. New Drugs. 29, 1156–1163.

    Article  PubMed  Google Scholar 

  18. Garcia-Perez A.I., Galeano E., Nieto E., Sancho P. 2011. Dequalinium induces human leukemia cell death by affecting the redox balance. Leuk. Res. 35, 1395–1401.

    Article  CAS  PubMed  Google Scholar 

  19. Weissig V., Torchilin V.P. 2001. Towards mitochondria gene therapy: DQAsomes as a strategy. J. Drug Target. 9, 1–13.

    Article  CAS  PubMed  Google Scholar 

  20. Lyrawati D., Trounson A., Cram D. 2011. Expression of GFP in the mitochondrial compartment using DQAsome-mediated delivery of an artificial minimitochondrial genome. Pharm. Res. 28, 2848–862.

    Article  CAS  PubMed  Google Scholar 

  21. Weissig V., Lizano C., Torchilin V. 1998. Micellar delivery system for dequalinium A lipophilic cationic drug with anticarcinoma activity. J. Liposome Res. 8, 391–400.

    Article  Google Scholar 

  22. Green M.R., Sambrook J. 2012. Molecular Cloning: A Laboratory Manual, 4th ed. Cold Spring Harbor, NY: Cold Spring Harbor Lab. Press.

    Google Scholar 

  23. Gonzalez-Guerrico A.M., Meshki J., Xiao L., Benavides F., Conti C.J., Kazanietz M.G. 2005. Molecular mechanisms of protein kinase C-induced apoptosis in prostate cancer cells. J. Biochem. Mol. Biol. 38, 639–645.

    Article  CAS  PubMed  Google Scholar 

  24. Decker P., Muller S. 2002. Modulating poly (ADPribose) polymerase activity: Potential for the prevention and therapy of pathogenic situations involving DNA damage and oxidative stress. Curr. Pharm. Biotechnol. 3, 275–283.

    Article  CAS  PubMed  Google Scholar 

  25. Huang Y.T., Chueh S.C., Teng C.M., Guh J.H. 2004. Investigation of ouabain-induced anticancer effect in human androgen-independent prostate cancer PC-3 cells. Biochem. Pharmacol. 67, 727–733.

    Article  CAS  PubMed  Google Scholar 

  26. Liu H., Liu Y.Q., Liu Y.Q., Xu A.H., Young C.Y., Yuan H.Q., Lou H.X. 2010. A novel anticancer agent, retigeric acid B, displays proliferation inhibition, S phase arrest and apoptosis activation in human prostate cancer cells. Chem. Biol. Interact. 188, 598–606.

    Article  CAS  PubMed  Google Scholar 

  27. Xu A.H., Hu Z.M., Qu J.B., Liu S.M., Syed A.K., Yuan H.Q., Lou H.X. 2010. Cyclic bisbibenzyls induce growth arrest and apoptosis of human prostate cancer PC-3 cells. Acta Pharmacol. Sin. 31, 609–615.

    Article  CAS  PubMed  Google Scholar 

  28. Zhang X.Q., Huang X.F., Mu S.J., An Q.X., Xia A.J., Chen R., Wu D.C. 2010. Inhibition of proliferation of prostate cancer cell line, PC-3, in vitro and in vivo using (−)-gossypol. Asian J. Androl. 12, 390–399.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Patra N., De U., Kang J.A., Kim J.M., Ahn M.Y., Lee J., Jung J.H., Chung H.Y., Moon H.R., Kim H.S. 2011. A novel epoxypropoxy flavonoid derivative and topoisomerase II inhibitor, MHY336, induces apoptosis in prostate cancer cells. Eur. J. Pharmacol. 658, 98–107.

    Article  CAS  PubMed  Google Scholar 

  30. Samarghandian S., Afshari J.T., Davoodi S. 2011. Chrysin reduces proliferation and induces apoptosis in the human prostate cancer cell line PC-3. Clinics (São Paulo). 66, 1073–1079.

    Article  Google Scholar 

  31. Senthilkumar K., Arunkumar R., Elumalai P., Sharmila G., Gunadharini D.N., Banudevi S., Krishnamoorthy G., Benson C.S., Arunakaran J. 2011. Quercetin inhibits invasion, migration and signalling molecules involved in cell survival and proliferation of prostate cancer cell line (PC-3). Cell Biochem. Funct. 29, 87–95.

    Article  CAS  PubMed  Google Scholar 

  32. Martin S.J., Reutelingsperger C.P., McGahon A.J., Rader J.A., van Schie R.C., LaFace D.M., Green D.R. 1995. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J. Exp. Med. 182, 1545–1556.

    Article  CAS  PubMed  Google Scholar 

  33. Pradelli L.A., Bénéteau M., Ricci J.E. 2010. Mitochondrial control of caspase-dependent and -independent cell death. Cell. Mol. Life Sci. 67, 1589–1597.

    Article  CAS  PubMed  Google Scholar 

  34. Agarwal A., Mahfouz R.Z., Sharma R.K., Sarkar O., Mangrola D., Mathur P.P. 2009. Potential biological role of poly (ADP-ribose) polymerase (PARP) in male gametes. Reprod. Biol. Endocrinol. 7, 143–163.

    Article  PubMed Central  PubMed  Google Scholar 

  35. Bataller M., Portugal J. 2005. Apoptosis and cell recovery in response to oxidative stress in p53-deficient prostate carcinoma cells. Arch. Biochem. Biophys. 437, 151–158.

    Article  CAS  PubMed  Google Scholar 

  36. Valko M., Rhodes C.J., Moncol J., Izakovic M., Mazur M. 2006. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem. Biol. Interact. 160, 1–40.

    Article  CAS  PubMed  Google Scholar 

  37. Paschos A., Pandya R., Duivenvoorden W.C., Pinthus J.H. 2013. Oxidative stress in prostate cancer: Changing research concepts towards a novel paradigm for prevention and therapeutics. Prostate Cancer Prostatic Dis. 16, 217–225.

    Article  CAS  PubMed  Google Scholar 

  38. Pelicano H., Carney D., Huang P. 2004. ROS stress in cancer cells and therapeutic implications. Drug Resist. Update. 7, 97–110.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Biology of Systems, University of Alcalá, Alcalá de Henares (Madrid), 28871, Spain

    K. Makowska, M. C. Estañ, I. Gañán-Gómez, M. C. Boyano-Adánez, A. I. García-Pérez & P. Sancho

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  1. K. Makowska
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  2. M. C. Estañ
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  3. I. Gañán-Gómez
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  4. M. C. Boyano-Adánez
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  5. A. I. García-Pérez
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  6. P. Sancho
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Correspondence to P. Sancho.

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Published in Russian in Molekulyarnaya Biologiya, 2014, Vol. 48, No. 3, pp. 416–428.

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Makowska, K., Estañ, M.C., Gañán-Gómez, I. et al. Changes in mitochondrial function induced by dequalinium precede oxidative stress and apoptosis in the human prostate-cancer cell line PC-3. Mol Biol 48, 359–370 (2014). https://doi.org/10.1134/S0026893314030133

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  • DOI: https://doi.org/10.1134/S0026893314030133

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