Skip to main content
Springer Nature Link
Log in

Regulation of apoptosis-related molecules by synergistic combination of all-trans retinoic acid and zoledronic acid in hormone-refractory prostate cancer cell lines

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

We report that all-trans retinoic acid (ATRA) in combination with zoledronic acid has strong synergistic cytotoxic and apoptotic effects against human hormone- and drug-refractory prostate cancer cells, PC-3 and DU-145, in a time- and dose-dependent manner. We further investigated the effect of the combination treatment on the apoptotic process by both oligoarray and protein array analysis in DU-145 cells, in which the drug combination shows much more strong synergistic effects, as compared to PC-3 cells. Moreover, we have also performed real time-PCR array analysis to validate oligoarray results. We demonstrated that the combination of ATRA and zoledronic acid is a strong inducer of apoptotic related cell death in human androgen-and drug refractory prostate cancer cells DU-145, at either transcriptional or translational levels. While expression of proapoptotic genes such as tumor necrosis factor receptor superfamily (TNFRSF), Bad, Bax, Fas, FADD are induced with the exposure of the combination, expression of antiapoptotic genes or proteins such as members of inhibitor apoptosis family (IAPs), MCL-1, LTBR, p53 and bcl-2 are reduced. Because this novel combination treatment has fewer side effects than is generally the case with conventional cytotoxic agents, this regimen may be a good option for treatment of elderly prostate cancer patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ (2008) Cancer statistics. CA Cancer J Clin 55:10–30

    Article  Google Scholar 

  2. Garnick MB (1997) Hormonal therapy in the management of prostate cancer: from Higgins to the present. Urology 49:5–15

    Article  CAS  PubMed  Google Scholar 

  3. Albertsen PC, Fryback DG, Storere BE (1995) Long term survival among men with conservatively treated localized prostate cancer. J Am Med Assoc 274:626–631

    Article  CAS  Google Scholar 

  4. Ashkenazi A, Holland P, Eckhardt (2008) Ligand based ligand-based targeting of apoptosis in cancer: the potential of recombinant human apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL). J Clin Oncol 26:3621–3630

    Article  CAS  PubMed  Google Scholar 

  5. Devlin H, Mudryj M (2009) Progression of prostate cancer: multiple pathways to androgen independence. Cancer Lett 274:177–186

    Article  CAS  PubMed  Google Scholar 

  6. Kurie JM, Hong WK (1999) Retinoids as antitumor agents: a new age of biological therapy. Cancer J Sci Am 5:150–151

    CAS  PubMed  Google Scholar 

  7. Lotan R (1996) Retinoids in cancer chemoprevention. FASEB J 10:1031–1039

    CAS  PubMed  Google Scholar 

  8. Lotan Y, Xu XC, Shalev M, Lotan R, Williams R, Wheeler TM, Thompson TC, Kadmon D (2000) Differential expression of nuclear retinoid receptors in normal and malignant prostates. J Clin Oncol 18:116–121

    CAS  PubMed  Google Scholar 

  9. Smith MA, Parkinson DR, Cheson BD, Friedman MA (1992) Retinoids in cancer therapy. J Clin Oncol 10:839–864

    CAS  PubMed  Google Scholar 

  10. Zhang XK (2002) Vitamin A and apoptosis in prostate cancer. Endocr Relat Cancer 9:87–102

    Article  CAS  PubMed  Google Scholar 

  11. Koshiuka K, Elstner E, Williamson E, Said JW, Tada Y, Koeffler HP (2000) Novel therapeutic approach: organic arsenical melarsoprol alone or with all-trans-retinoic acid markedly inhibit growth of human breast and prostate cancer cells in vitro and in vivo. Br J Cancer 82:452–458

    Article  CAS  PubMed  Google Scholar 

  12. Kucukzeybek Y, Gul MK, Cengiz E, Erten C, Karaca B, Gorumlu G, Atmaca H, Uzunoglu S, Karabulut B, Sanli UA, Uslu R (2008) Enhancement of docetaxel-induced cytotoxicity and apoptosis by all-trans retinoic acid (ATRA) through downregulation of survivin (BIRC5), MCL-1 and LTbeta-R in hormone- and drug resistant prostate cancer cell line, DU-145. J Exp Clin Cancer Res 12:27–37

    Google Scholar 

  13. Russell RGG, Rogers MJ (1999) Bisphosphonates: from the laboratory to the clinic and back again. Bone 25:97–106

    Article  CAS  PubMed  Google Scholar 

  14. Green JR (2003) Antitumor effects of bisphosphonates. Cancer 97:840–847

    Article  PubMed  Google Scholar 

  15. Cengiz E, Karaca B, Kucukzeybek Y, Gorumlu G, Gul MK, Erten C, Atmaca H, Uzunoglu S, Karabulut B, Sanli UA, Uslu R (2010) Overcoming drug resistance in hormone- and drug-refractory prostate cancer cell line, PC-3 by docetaxel and gossypol combination. Mol Biol Rep 37(3):1269–1277. Epub 2009 Mar 14

    Google Scholar 

  16. Zaidman BZ, Wasser SP, Nevo E, Mahajna J (2008) Coprinus comatus and Ganoderma lucidum interfere with androgen receptor function in LNCaP prostate cancer cells. Mol Biol Rep 35(2):107–117. Epub 2007 Mar 13

    Google Scholar 

  17. Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs on enzyme inhibitors. Adv Enzyme Regul 22:27–55

    Article  CAS  PubMed  Google Scholar 

  18. Hsu H, Shu HB, Pan MG, Goeddel DV (1996) TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 84:299–306

    Article  CAS  PubMed  Google Scholar 

  19. Muzio M, Chinnaiyan AM, Kischkel FC, O’Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME, Dixit VM (1996) FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85:817–827

    Article  CAS  PubMed  Google Scholar 

  20. Chopra DP, Menard RE, Januszewski J, Mattingly RR (2004) TNF-α mediated apoptosis in normal human prostate epithelial cells and tumor cell lines. Cancer Lett 203:145–154

    Article  CAS  PubMed  Google Scholar 

  21. Boldin MP, Goncharov TM, Goltsev Y, Wallach D (1996) Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1 and TNF receptor-induced cell death. Cell 85:803–815

    Article  CAS  PubMed  Google Scholar 

  22. Manna SK, Aggarwal BB (2000) All-trans-retinoic acid upregulates TNF receptors and potentiates TNF-induced activation of nuclear factors-κB, activated protein-1 and apoptosis in human lung cancer cells. Oncogene 19:2110–2119

    Article  CAS  PubMed  Google Scholar 

  23. McEleny KR, Watson RWG, Coffey RNT, O’Neill AJ, Fitzpatrick JM (2002) Inhibitors of apoptosis proteins in prostate cancer cell lines. Prostate 51:133–140

    Article  CAS  PubMed  Google Scholar 

  24. Tamm I, Wang Y, Sausville E, Scudiero DA, Vigna N, Oltersdorf T, Reed J (1998) IAP Family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Res 58:5315–5320

    CAS  PubMed  Google Scholar 

  25. Suzuki A, Tsutomi Y, Akahane K, Araki T, Miura M (1998) Resistance to Fas-mediated apoptosis: activation of caspase 3 is regulated by cell cycle regulator p21WAF1 and IAP gene family ILP. Oncogene 17:931–939

    Article  CAS  PubMed  Google Scholar 

  26. Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, Alnemri ES, Salvesen GS, Reed J (1998) IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J 17:2215–2223

    Article  CAS  PubMed  Google Scholar 

  27. Chu ZL, McKinsey TA, Liu L, Gentry JJ, Malim MH, Ballard DW (1997) Suppression of tumour necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-kappa B control. Proc Natl Acad Sci USA 94:10057–10062

    Article  CAS  PubMed  Google Scholar 

  28. Stehlik C, de Martin R, Kumabashiri I, Schmid JA, Binder BR, Lipp J (1998) Nuclear Factor (NF)-kB-regulated X-chromosome linked iap gene expression protects endothelial cells from tumor necrosis factor a-induced apoptosis. J Exp Med 188:211–216

    Article  CAS  PubMed  Google Scholar 

  29. Manji GA, Hozak RR, LaCount DJ, Friesen PD (1997) Baculovirus inhibitor of apoptosis functions at or upstream of the apoptotic suppressor p35 to prevent programmed cell death. J Virol 71:4509–4516

    CAS  PubMed  Google Scholar 

  30. Adida C, Berrebi D, Peuchmaur M, Reyes-Mugica M, Altieri DC (1998) Anti-apoptosis gene, survivin, and prognosis of neuroblastoma. Lancet 351:882–883

    Article  CAS  PubMed  Google Scholar 

  31. Monzo M, Rosell R, Felip E, Astudillo J, Sanchez JJ, Maestre J et al (1999) A novel anti-apoptosis gene: re-expression of survivin messenger RNA as a prognosis marker in non-small-cell lung cancers. J Clin Oncol 17:2100–2104

    CAS  PubMed  Google Scholar 

  32. Sarela AI, Macadam RC, Farmery SM, Markham AF, Guillou PJ (2000) Expression of the antiapoptosis gene, survivin, predicts death from recurrent colorectal carcinoma. Gut 46:645–650

    Article  CAS  PubMed  Google Scholar 

  33. Tanaka K, Iwamoto S, Gon G, Nohara T, Iwamoto M, Tanigawa N (2000) Expression of survivin and its relationship to loss of apoptosis in breast carcinomas. Clin Cancer Res 6:127–134

    CAS  PubMed  Google Scholar 

  34. Kato J, Kuwabara Y, Mitani M, Shinoda N, Sato A, Toyama T et al (2001) Expression of survivin in esophageal cancer: correlation with the prognosis and response to chemotherapy. Int J Cancer 95:92–95

    Article  CAS  PubMed  Google Scholar 

  35. Aichberger KJ, Mayerhofer M, Gleixner KV, Krauth MT, Gruze A, Pickl WF et al (2007) Identification of MCL1 as a novel target in neoplastic mast cells in systemic mastocytosis: inhibition of mast cell survival by MCL1 antisense oligonucleotides and synergism with PKC412. Blood 109:3031–3041

    CAS  PubMed  Google Scholar 

  36. gli-Esposti MA, vis-Smith T, Din WS, Smolak PJ, Goodwin RG, Smith CA (1997) Activation of the lymphotoxin beta receptor by cross-linking induces chemokine production and growth arrest in A375 melanoma cells. J Immunol 158:1756–1762

    Google Scholar 

  37. Lukashev M, LePage D, Wilson C, Bailly V, Garber E, Lukashin A et al (2006) Targeting the lymphotoxin-beta receptor with agonist antibodies as a potential cancer therapy. Cancer Res 66:9617–9624

    Article  CAS  PubMed  Google Scholar 

  38. Winter H, van den Engel NK, Poehlein CH, Hatz RA, Fox BA, Hu HM (2007) Tumor-specific T cells signal tumor destruction via the lymphotoxin beta receptor. J Transl Med 5:14–26

    Article  PubMed  Google Scholar 

  39. Zhao M, Begum S, Ha PK, Westra W, Califano J (2008) Downregulation of rad17 in head and neck cancer. Head&Neck 30:35–42

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Medical Oncology, Tulay Aktas Oncology Hospital, School of Medicine, Ege University, Bornova, Izmir, Turkey

    Bulent Karabulut, Burcak Karaca, Canfeza Sezgin & Ruchan Uslu

  2. Section of Molecular Biology, Department of Biology, Faculty of Science and Arts, Celal Bayar University, Muradiye, Manisa, Turkey

    Harika Atmaca, Asli Kisim & Selim Uzunoglu

Authors
  1. Bulent Karabulut
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Burcak Karaca
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Harika Atmaca
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Asli Kisim
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Selim Uzunoglu
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Canfeza Sezgin
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Ruchan Uslu
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Ruchan Uslu.

Electronic supplementary material

Below is the link to the electronic supplementary material.

(DOC 30.5 kb)

(DOC 38.5 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Karabulut, B., Karaca, B., Atmaca, H. et al. Regulation of apoptosis-related molecules by synergistic combination of all-trans retinoic acid and zoledronic acid in hormone-refractory prostate cancer cell lines. Mol Biol Rep 38, 249–259 (2011). https://doi.org/10.1007/s11033-010-0102-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-010-0102-6

Keywords