Characterisation and manipulation of docetaxel resistant prostate cancer cell lines

Watson, O'Neill, Prencipe Maria, Dowling Catherine, Fan Yue, Mulrane Laoighse, Gallagher, O'Connor Darran, O'Connor Robert, Devery Aoife, Corcoran Claire, Rani Sweta, O'Driscoll Lorraine, Fitzpatrick

Description

There 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. Results The 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. Conclusion This 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.

Sujets

• Docétaxel
• Prostate
• Apoptosis
• Viability

Informations

• Publié par: biomed
• Publié le: 01 janvier 2011
• Nombre de lectures: 11
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

O ’ Neill et al . Molecular Cancer 2011, 10 :126 http://www.molecular-cancer.com/content/10/1/126

R E S E A R C H Open Access Characterisation and manipulation of docetaxel resistant prostate cancer cell lines Amanda J O ’ Neill 1* † , Maria Prencipe 1 † , Catherine Dowling 1 † , Yue Fan 1 , Laoighse Mulrane 2 , William M Gallagher 2 , Darran O ’ Connor 2 , Robert O ’ Connor 3 , Aoife Devery 3 , Claire Corcoran 4 , Sweta Rani 4 , Lorraine O ’ Driscoll 4 , John M Fitzpatrick 1 and R William G Watson 1

Abstract Background: There 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. Results: The 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- B activity in the PC-3 D12 cells compared to the Parental PC-3, docetaxel induced higher NF- B activity and I  B phosphorylation at 3 and 6 hours with only minor changes in the DU-145 cells. Inhibition of NF- B with the BAY 11-7082 inhibitor reversed the resistance to Docetaxel. Conclusion: This study confirms that multiple mechanisms contribute to Docetaxel resistance and the central transcription factor NF- B plays an immensely important role in determining docetaxel-resistance which may represent an appropriate therapeutic target. Keywords: Docetaxel, Prostate, NF- ? κ ?B, Apoptosis, Viability

Background are S phase-dependent [3]. Secondly, failure of che- Unfortunately there is no effective treatment strategy for  motherapy may be caused by reduced intracellular con- advanced castration-resistant prostate cancer [1,2]. centrations of a drug through either increased efflux or Although Docetaxel (Taxotere ® ) currently represents decreased intake secondary to alterations in drug trans- the most active chemotherapeutic agent it only gives a porters, particularly P-glyco protein (P-gp). Multidrug modest survival advantage with most patients eventually resistance (MDR) mechanisms including increased progressing because of inherent or acquired drug resis-  expression of the P-gp or increased cellular metabolism tance. A number of mechanisms have been proposed to  of drug detoxifying proteins, such as glutathione-S- contribute to this resistance. Firstly, the majority of transferase, have been shown to protect the cancer cells prostate tumours are slow growing even in metastatic against cytotoxic drugs [4] . Thirdly, alterations in b - disease and thus are unlikely to respond to drugs that tublin isotypes with differe nt kinetics of microtubule formation have been shown to contribute to resistance. * Correspondence: [e-mail] With an increase in isotypes III and IV correlating with † Contributed equally 1 Bi U o C m D ol S e c c h u o la o r l a o n f d M B e i d o ic m i e ne dic a a n l d Re M s e e d ar ic c a h l , S U c n i i e v n e c r e s , ity UC C D oll C e o g n e w D a u y b I li n n s , tit D u u te bli o n f t D u o m ce o t u ax r el su re p s p is r t e a s n s c o e r i p n r v o i t t e r i o n [ s 5 , ]. su F c o h urt as hly l , os m s u o ta f ti P o T ns E i N n , Ireland which is a common event occurring in about 60% of Full list of author information is available at the end of the article © 2011 O ’ Neill et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.