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Effects of sorafenib on C-terminally truncated androgen receptor variants in human prostate cancer cells.

Zengerling F, Streicher W, Schrader AJ, Schrader M, Nitzsche B, Cronauer MV, Höpfner M - Int J Mol Sci (2012)

Bottom Line: In this study we demonstrate that the multikinase inhibitor sorafenib inhibits AR as well as ARΔLBD-signalling in CRPCa cells.In line with these observations, maximal antiproliferative effects of sorafenib were achieved in AR and ARΔLBD-positive PCa cells.The present findings warrant further investigations on sorafenib as an option for the treatment of advanced AR-positive PCa.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Ulm University, Ulm 89075, Germany; E-Mails: ajschrader@gmx.de (A.J.S.); mark.schrader@uniklinik-ulm.de (M.S.); marcus.cronauer@uni-ulm.de (M.V.C.) ; Department of Physiology, Charité Universitätsmedizin, Campus Benjamin Franklin, Berlin 14195, Germany; E-Mails: bianca.nitzsche@charite.de (B.N.); michael.hoepfner@charite.de (M.H.).

ABSTRACT
Recent evidence suggests that the development of castration resistant prostate cancer (CRPCa) is commonly associated with an aberrant, ligand-independent activation of the androgen receptor (AR). A putative mechanism allowing prostate cancer (PCa) cells to grow under low levels of androgens, is the expression of constitutively active, C-terminally truncated AR lacking the AR-ligand binding domain (LBD). Due to the absence of a LBD, these receptors, termed ARΔLBD, are unable to respond to any form of anti-hormonal therapies. In this study we demonstrate that the multikinase inhibitor sorafenib inhibits AR as well as ARΔLBD-signalling in CRPCa cells. This inhibition was paralleled by proteasomal degradation of the AR- and ARΔLBD-molecules. In line with these observations, maximal antiproliferative effects of sorafenib were achieved in AR and ARΔLBD-positive PCa cells. The present findings warrant further investigations on sorafenib as an option for the treatment of advanced AR-positive PCa.

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Related in: MedlinePlus

Effect of Sorafenib on prostate cancer cell proliferation. PCa cell lines PC-3 (AR−), DU-145 (AR−), LNCaP (AR+) and 22Rv1 (AR+/AR-V+) were seeded in 96-well plates and allowed to adhere overnight. Subsequently, medium was changed, and cells were grown in RPMI-1640, supplemented with 5% fetal bovine serum and antibiotics in the presence/absence of sorafenib. Cell proliferation was assessed by means of a colorimetric MTT-Assay. (A) Dose response curve of sorafenib-induced growth inhibition. PCa cells treated for 72 h with increasing concentrations of sorafenib (0–5 μM). Growth inhibition is expressed as percent of untreated controls, which were set at 100% (*p < 0.05; **p < 0.01, ***p < 0.001); (B) Time course of sorafenib-induced antiproliferative effects in PCa cells. PCa cells treated with sorafenib (5 μM) for different periods of time. Results are expressed as percent of untreated controls, which were set at 100%.
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f5-ijms-13-11530: Effect of Sorafenib on prostate cancer cell proliferation. PCa cell lines PC-3 (AR−), DU-145 (AR−), LNCaP (AR+) and 22Rv1 (AR+/AR-V+) were seeded in 96-well plates and allowed to adhere overnight. Subsequently, medium was changed, and cells were grown in RPMI-1640, supplemented with 5% fetal bovine serum and antibiotics in the presence/absence of sorafenib. Cell proliferation was assessed by means of a colorimetric MTT-Assay. (A) Dose response curve of sorafenib-induced growth inhibition. PCa cells treated for 72 h with increasing concentrations of sorafenib (0–5 μM). Growth inhibition is expressed as percent of untreated controls, which were set at 100% (*p < 0.05; **p < 0.01, ***p < 0.001); (B) Time course of sorafenib-induced antiproliferative effects in PCa cells. PCa cells treated with sorafenib (5 μM) for different periods of time. Results are expressed as percent of untreated controls, which were set at 100%.

Mentions: Based on the observation that sorafenib is able to inhibit AR as well as ARΔLBD-signalling we further investigated the antiproliferative effects of the compound on the androgen sensitive LNCaP (AR+) cells, the castration resistant 22Rv1 (AR+, AR-V+) cells as well as the androgen insensitive PC-3 (AR−) and DU-145 (AR−) cells using a MTT cell viability assay [27]. As depicted in Figure 5, the antiproliferative effects of sorafenib were more pronounced in AR-positive or AR/AR-V-positive prostate cancer cells as compared to those lacking the androgen receptor. Differences between AR+ and AR- cells were statistically significant at a sorafenib concentration of 2.5 μM (proliferation rate LNCaP: 60% ± 5% and 22Rv1: 76% ± 3% versus PC-3: 82% ± 3%, p = 0.002 and p = 0.036, respectively).


Effects of sorafenib on C-terminally truncated androgen receptor variants in human prostate cancer cells.

Zengerling F, Streicher W, Schrader AJ, Schrader M, Nitzsche B, Cronauer MV, Höpfner M - Int J Mol Sci (2012)

Effect of Sorafenib on prostate cancer cell proliferation. PCa cell lines PC-3 (AR−), DU-145 (AR−), LNCaP (AR+) and 22Rv1 (AR+/AR-V+) were seeded in 96-well plates and allowed to adhere overnight. Subsequently, medium was changed, and cells were grown in RPMI-1640, supplemented with 5% fetal bovine serum and antibiotics in the presence/absence of sorafenib. Cell proliferation was assessed by means of a colorimetric MTT-Assay. (A) Dose response curve of sorafenib-induced growth inhibition. PCa cells treated for 72 h with increasing concentrations of sorafenib (0–5 μM). Growth inhibition is expressed as percent of untreated controls, which were set at 100% (*p < 0.05; **p < 0.01, ***p < 0.001); (B) Time course of sorafenib-induced antiproliferative effects in PCa cells. PCa cells treated with sorafenib (5 μM) for different periods of time. Results are expressed as percent of untreated controls, which were set at 100%.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472761&req=5

f5-ijms-13-11530: Effect of Sorafenib on prostate cancer cell proliferation. PCa cell lines PC-3 (AR−), DU-145 (AR−), LNCaP (AR+) and 22Rv1 (AR+/AR-V+) were seeded in 96-well plates and allowed to adhere overnight. Subsequently, medium was changed, and cells were grown in RPMI-1640, supplemented with 5% fetal bovine serum and antibiotics in the presence/absence of sorafenib. Cell proliferation was assessed by means of a colorimetric MTT-Assay. (A) Dose response curve of sorafenib-induced growth inhibition. PCa cells treated for 72 h with increasing concentrations of sorafenib (0–5 μM). Growth inhibition is expressed as percent of untreated controls, which were set at 100% (*p < 0.05; **p < 0.01, ***p < 0.001); (B) Time course of sorafenib-induced antiproliferative effects in PCa cells. PCa cells treated with sorafenib (5 μM) for different periods of time. Results are expressed as percent of untreated controls, which were set at 100%.
Mentions: Based on the observation that sorafenib is able to inhibit AR as well as ARΔLBD-signalling we further investigated the antiproliferative effects of the compound on the androgen sensitive LNCaP (AR+) cells, the castration resistant 22Rv1 (AR+, AR-V+) cells as well as the androgen insensitive PC-3 (AR−) and DU-145 (AR−) cells using a MTT cell viability assay [27]. As depicted in Figure 5, the antiproliferative effects of sorafenib were more pronounced in AR-positive or AR/AR-V-positive prostate cancer cells as compared to those lacking the androgen receptor. Differences between AR+ and AR- cells were statistically significant at a sorafenib concentration of 2.5 μM (proliferation rate LNCaP: 60% ± 5% and 22Rv1: 76% ± 3% versus PC-3: 82% ± 3%, p = 0.002 and p = 0.036, respectively).

Bottom Line: In this study we demonstrate that the multikinase inhibitor sorafenib inhibits AR as well as ARΔLBD-signalling in CRPCa cells.In line with these observations, maximal antiproliferative effects of sorafenib were achieved in AR and ARΔLBD-positive PCa cells.The present findings warrant further investigations on sorafenib as an option for the treatment of advanced AR-positive PCa.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Ulm University, Ulm 89075, Germany; E-Mails: ajschrader@gmx.de (A.J.S.); mark.schrader@uniklinik-ulm.de (M.S.); marcus.cronauer@uni-ulm.de (M.V.C.) ; Department of Physiology, Charité Universitätsmedizin, Campus Benjamin Franklin, Berlin 14195, Germany; E-Mails: bianca.nitzsche@charite.de (B.N.); michael.hoepfner@charite.de (M.H.).

ABSTRACT
Recent evidence suggests that the development of castration resistant prostate cancer (CRPCa) is commonly associated with an aberrant, ligand-independent activation of the androgen receptor (AR). A putative mechanism allowing prostate cancer (PCa) cells to grow under low levels of androgens, is the expression of constitutively active, C-terminally truncated AR lacking the AR-ligand binding domain (LBD). Due to the absence of a LBD, these receptors, termed ARΔLBD, are unable to respond to any form of anti-hormonal therapies. In this study we demonstrate that the multikinase inhibitor sorafenib inhibits AR as well as ARΔLBD-signalling in CRPCa cells. This inhibition was paralleled by proteasomal degradation of the AR- and ARΔLBD-molecules. In line with these observations, maximal antiproliferative effects of sorafenib were achieved in AR and ARΔLBD-positive PCa cells. The present findings warrant further investigations on sorafenib as an option for the treatment of advanced AR-positive PCa.

Show MeSH
Related in: MedlinePlus