Characterisation and manipulation of docetaxel resistant prostate cancer cell lines

Amanda J O'Neill,R William G Watson,Catherine Dowling,John M Fitzpatrick,Yue Fan,William M Gallagher,Maria Prencipe,Darran O'Connor,Laoighse Mulrane,Claire Corcoran,Robert O'Connor,Lorraine O'Driscoll,Sweta Rani,Aoife Devery

doi:10.1186/1476-4598-10-126

Abstract

BackgroundThere is no effective treatment strategy for advanced castration-resistant prostate cancer. Although Docetaxel (Taxotere®) represents the most active chemotherapeutic agent it only gives a modest survival advantage with most patients eventually progressing because of inherent or acquired drug resistance. The aims of this study were to further investigate the mechanisms of resistance to Docetaxel. Three Docetaxel resistant sub-lines were generated and confirmed to be resistant to the apoptotic and anti-proliferative effects of increasing concentrations of Docetaxel.ResultsThe resistant DU-145 R and 22RV1 R had expression of P-glycoprotein and its inhibition with Elacridar partially and totally reversed the resistant phenotype in the two cell lines respectively, which was not seen in the PC-3 resistant sublines. Resistance was also not mediated in the PC-3 cells by cellular senescence or autophagy but multiple changes in pro- and anti-apoptotic genes and proteins were demonstrated. Even though there were lower basal levels of NF-κB activity in the PC-3 D12 cells compared to the Parental PC-3, docetaxel induced higher NF-κB activity and IκB phosphorylation at 3 and 6 hours with only minor changes in the DU-145 cells. Inhibition of NF-κB with the BAY 11-7082 inhibitor reversed the resistance to Docetaxel.ConclusionThis study confirms that multiple mechanisms contribute to Docetaxel resistance and the central transcription factor NF-κB plays an immensely important role in determining docetaxel-resistance which may represent an appropriate therapeutic target.

Highlights

There is no effective treatment strategy for advanced castration-resistant prostate cancer
Even though there were lower basal levels of Nuclear factor kappa B (NF-B) activity in the PC-3 D12 cells compared to the Parental PC-3, docetaxel induced higher levels of NF-B activity and IB phosphorylation with only minor changes in the DU-145 cells
The PC-3 Ag cells had an IC50@ 48 hrs = 10 nM, the PC-3 D8 an IC50@ 48 hrs = 20 nM and the PC-3 D12 an IC50@ 48 hrs = 100 nM following treatment with Docetaxel (Figure 1B). This confirmed that the PC-3 D8 and PC-3 D12 sublines had a resistance to Docetaxel treatment

Summary

Introduction

There is no effective treatment strategy for advanced castration-resistant prostate cancer. Docetaxel (Taxotere®) represents the most active chemotherapeutic agent it only gives a modest survival advantage with most patients eventually progressing because of inherent or acquired drug resistance. Docetaxel (Taxotere®) currently represents the most active chemotherapeutic agent it only gives a modest survival advantage with most patients eventually progressing because of inherent or acquired drug resistance. The identification and manipulation of these multiple mechanisms represents a significant challenge as targeting individual proteins has little clinical impact This was demonstrated in a recent phase II clinical trial with oblimersen sodium, a Bcl-2 antisense oligonucleotide and Docetaxel which did not achieve its primary endpoint of reducing PSA and was associated with increased toxicity [10]. Strategies to block multiple Bcl-2 family members are under way with AT101, a small molecular inhibitor of Bcl-2, Bcl-xl, Bcl-w and Mcl-1 (clinicaltrials.gov ID: NCT00571675)

Objectives

Methods

Results

Discussion

Conclusion