Tumor Biology

, Volume 36, Issue 6, pp 4861–4869 | Cite as

Effects of zoledronic acid and docetaxel on small GTP-binding proteins in prostate cancer

  • Rachel M. Jones
  • Claire Morgan
  • Gianfilippo Bertelli
Research Article

Abstract

Increasingly, in castration-resistant prostate cancer, patients are often treated with docetaxel and the bisphosphonate zoledronic acid concurrently, yet there is still a paucity in the literature regarding the molecular basis of how this drug combination works. The study was performed on the hormone-resistant cell line PC-3. Cells were treated with clinically relevant concentrations of docetaxel and zoledronic acid either as single agents or in sequence and combination. Cell viability and apoptosis were assessed along with the prenylation status of the GTPases Ras and RhoA. Following 1-mM zoledronic acid treatment, inhibition of the prenylation of H-Ras and Rho A was observed along with an increase in the unprenylated form in the cytoplasm. Docetaxel 1 nM and zoledronic acid 1 mM also showed an increase in the unprenylated form of both small GTP-binding proteins in the cytoplasm and a reduction of protein in the membrane fraction. Overall, zoledronic acid followed by docetaxel was the best regimen producing the greatest reduction in cell viability and increase in apoptosis. At the highest concentrations of zoledronic acid and docetaxel, zoledronic acid followed by docetaxel was also the most effective at reducing the prenylation of both H-Ras and RhoA at the membrane. We have demonstrated that clinically achievable concentrations of zoledronic acid and docetaxel cause a reduction in the prenylation of both H-Ras and Rho A and a reduction of protein movement into the membrane. The most effective regimen overall was high-dose zoledronic acid followed by docetaxel, suggesting that this regimen may be of benefit in clinical practice.

Keywords

Castration resistant Prostate cancer RhoA Ras Zoledronic acid Docetaxel 

Notes

Conflicts of interest

None

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Rachel M. Jones
    • 1
  • Claire Morgan
    • 2
  • Gianfilippo Bertelli
    • 3
  1. 1.Gynaecology DepartmentVelindre Cancer CentreCardiffUK
  2. 2.College of MedicineSwansea UniversitySwanseaUK
  3. 3.South West Wales Cancer InstituteSingleton HospitalSwanseaUK

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