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Potentiation of docetaxel cytotoxicity by conjugated linoleic acid (CLA) in prostate cancer cells
Potentiation of docetaxel prostate cancer cells.
cytotoxicity
by conjugated
linoleic acid (CLA) in
KP Lim, S McClinton, HJ Kirk, KWJ Wahle, SD Heys, AC Schofield University of Aberdeen Introduction: Prostate cancer is the second commonest cancer in men in the UK with a 5 year survival rate of 68.5%. Despite this, the treatment options have remained largely unchanged with little progress being made over the last 50 years. The chemotherapeutic agent, docetaxel, has recently attracted interest for use in advanced hormone insensitive prostate cancer. Initial studies have shown response rates of up to 46 % when used as a monotherapy. Hence, more than half of patients still fail to respond. One novel approach has been the use of fatty acids to potentiate other chemotherapeutic agents. Recent interest has arisen regarding the fatty acid, conjugated linoleic acid (CLA), which has shown to be able to potentiate taxane cytotoxicity against breast cancer cell lines in vitro. The aim of our study was to investigate the potential enhancement effect of docetaxel-induced apoptosis by CLA in prostate cancer cell lines. Materials & Methods: The 2 human prostate cancer cell lines LNCaP (hormone sensitive) and PC3 (hormone insensitive) were studied. Each cell line was treated with docetaxel (O-32 pM) with and without a range of fatty acids (concentrations O-100 uM). The range of fatty acids used included 2 isomers of conjugated linoleic acid (CLA cis-9,trans-11 and CLA trans-10, cis12 as well as a mixture containing the 2 isomers). Cell viability was quantified with standard MTT assay and the effects expressed as lCSO (the concentration of drug required to cause 50 % cell growth inhibition) The degree of enhancement was expressed as a sensitization factor (ratio of ICso[docetaxel alone] against ICso[docetaxel fatty acid]). The nature of the interaction was then analysed using the isobologram method. Apoptosis assessed morphologically following DAPI staining, and expressed as an apoptotic index. Results: The I& for docetaxel in LNCaP cells was 3.55 x 10m6(95% Cl 2.1 x 10m6 to 5.9 x 10m6). This was reduced to an lCSO to 1.02 x 10m6 (95% Cl 5.0 x 1 Om7 to 2.0 x 10m6 ) when docetaxel was used in combination with CLA 9,ll. The sensitization factor was 3.47 (p = 0.005) therefore representing a 3.47 fold enhancement of docetaxel cytotoxicity by CLA 9,ll. CLA 9,ll was not cytotoxic to LNCaP cells when used alone. No potentiation of docetaxel was achieved when CLA IO,12 or a mixture of both isomers was used. Assessment of the effects of CLA 9,ll on docetaxel-induced apoptosis, as assessed by DAPI, resulted in an increase of apoptosis. The apoptotic index was 38.8 % f 6.1 for docetaxel alone and 51 .O % f 4.6 for docetaxel with CLA 9,ll in LNCaP cells. Conclusion: We have shown that CLA is able to enhance the effect of docetaxel in both hormone sensitive and insensitive cell lines. This enhancement is synergistic with CLA 9,ll and LNCaP. Apoptosis has been shown to be a potential mechanism for this effect and this may have important implications for future clinical practice.
cytotoxicity
by conjugated
linoleic acid (CLA) in
KP Lim, S McClinton, HJ Kirk, KWJ Wahle, SD Heys, AC Schofield University of Aberdeen Introduction: Prostate cancer is the second commonest cancer in men in the UK with a 5 year survival rate of 68.5%. Despite this, the treatment options have remained largely unchanged with little progress being made over the last 50 years. The chemotherapeutic agent, docetaxel, has recently attracted interest for use in advanced hormone insensitive prostate cancer. Initial studies have shown response rates of up to 46 % when used as a monotherapy. Hence, more than half of patients still fail to respond. One novel approach has been the use of fatty acids to potentiate other chemotherapeutic agents. Recent interest has arisen regarding the fatty acid, conjugated linoleic acid (CLA), which has shown to be able to potentiate taxane cytotoxicity against breast cancer cell lines in vitro. The aim of our study was to investigate the potential enhancement effect of docetaxel-induced apoptosis by CLA in prostate cancer cell lines. Materials & Methods: The 2 human prostate cancer cell lines LNCaP (hormone sensitive) and PC3 (hormone insensitive) were studied. Each cell line was treated with docetaxel (O-32 pM) with and without a range of fatty acids (concentrations O-100 uM). The range of fatty acids used included 2 isomers of conjugated linoleic acid (CLA cis-9,trans-11 and CLA trans-10, cis12 as well as a mixture containing the 2 isomers). Cell viability was quantified with standard MTT assay and the effects expressed as lCSO (the concentration of drug required to cause 50 % cell growth inhibition) The degree of enhancement was expressed as a sensitization factor (ratio of ICso[docetaxel alone] against ICso[docetaxel fatty acid]). The nature of the interaction was then analysed using the isobologram method. Apoptosis assessed morphologically following DAPI staining, and expressed as an apoptotic index. Results: The I& for docetaxel in LNCaP cells was 3.55 x 10m6(95% Cl 2.1 x 10m6 to 5.9 x 10m6). This was reduced to an lCSO to 1.02 x 10m6 (95% Cl 5.0 x 1 Om7 to 2.0 x 10m6 ) when docetaxel was used in combination with CLA 9,ll. The sensitization factor was 3.47 (p = 0.005) therefore representing a 3.47 fold enhancement of docetaxel cytotoxicity by CLA 9,ll. CLA 9,ll was not cytotoxic to LNCaP cells when used alone. No potentiation of docetaxel was achieved when CLA IO,12 or a mixture of both isomers was used. Assessment of the effects of CLA 9,ll on docetaxel-induced apoptosis, as assessed by DAPI, resulted in an increase of apoptosis. The apoptotic index was 38.8 % f 6.1 for docetaxel alone and 51 .O % f 4.6 for docetaxel with CLA 9,ll in LNCaP cells. Conclusion: We have shown that CLA is able to enhance the effect of docetaxel in both hormone sensitive and insensitive cell lines. This enhancement is synergistic with CLA 9,ll and LNCaP. Apoptosis has been shown to be a potential mechanism for this effect and this may have important implications for future clinical practice.