Establishment and characterization of an androgen receptor-dependent, androgen-independent human prostate cancer cell line, LNCaP-CS10.

Hormone refractoriness is a lethal event for advanced prostate cancer patients, but the mechanisms of the disease are not well elucidated, especially for the so-called "outlaw" pathways of androgen receptor (AR)-dependent, androgen-independent hormone-refractory prostate cancer. Androgen-dependent prostate cancer LNCaP cells were treated with bicalutamide under an androgen-depleted condition to obtain refractory cells. In the obtained cell line, LNCaP-CS10, we analyzed the effects of androgen and bicalutamide on cell growth and prostate-specific antigen (PSA) production. In addition, AR gene mutation, AR expression levels, and AR subcellular localizations were analyzed. In LNCaP-CS10, cell growth and PSA production were found under an androgen-depleted condition and were induced by both R1881 and bicalutamide. Knocking down AR by siRNAs did suppress the growth and PSA production of LNCaP-CS10 cells in the androgen-depleted condition. In comparison to LNCaP, amplification or additional new mutations were not found in the AR genes, but AR nuclear translocation induced by bicalutamide was identified in the LNCaP-CS10 cells. The growth and PSA production of xenografted LNCaP-CS10 tumors, which secrete PSA not only in non-castrated SCID mice but also in castrated SCID mice, were not inhibited by bicalutamide. We have generated a bicalutamide-resistant and androgen-independent prostate cancer cell line, LNCaP-CS10, with outlaw activation both in vitro and in vivo. The LNCaP-CS10 cell line is beneficial for elucidating outlaw pathway mechanisms and evaluating the efficacy of new therapeutics for hormone-refractory prostate cancer.

Ishikura N ，Kawata H ，Nishimoto A ，Nakamura R ，Ishii N ，Aoki Y ... -  《-》

Switch from antagonist to agonist of the androgen receptor bicalutamide is associated with prostate tumour progression in a new model system.

Culig Z ，Hoffmann J ，Erdel M ，Eder IE ，Hobisch A ，Hittmair A ，Bartsch G ，Utermann G ，Schneider MR ，Parczyk K ，Klocker H ... -  《-》

Antagonistic interaction between bicalutamide (Casodex) and radiation in androgen-positive prostate cancer LNCaP cells.

Bicalutamide (Casodex) reportedly improves high-risk prostate cancer survival as an adjuvant treatment following radiotherapy. However, biological data for the interaction between bicalutamide and ionizing radiation in concomitant association are lacking. To explore this issue, androgen-dependent (LNCaP) and -independent (DU145) human prostate cancer cells were exposed for 48 hr to 20, 40, or 80 microM bicalutamide introduced before (neoadjuvant), during (concomitant), or following (adjuvant) radiation. Growth inhibition and cytotoxicity, cell cycle distribution and expression of the prostate serum antigen (PSA) and androgen receptor (AR), were measured as endpoints. Bicalutamide-induced cytotoxic and cytostatic effects were found to be correlated with a marked G1 phase arrest and S phase depression. The drug down-regulated PSA and AR proteins and psa mRNA in LNCaP cells. However, transient up-regulation of the expression of ar mRNA was observed in the presence of 40 microM drug. DU145 cells did not express PSA and proved to be comparatively resistant to the drug from both cytostatic and cytotoxic effects. Bicalutamide dose-dependently induced a significant decrease of radiation susceptibility among drug survivors in LNCaP cells, whilst the interaction appeared to be additive in DU145 cells. The antagonistic radiation-drug interaction observed in LNCaP cells is of significance in relation to combined radiotherapy-bicalutamide treatments directed against tumors expressing the AR. The results suggest that bicalutamide is amenable to combined schedule with radiotherapy provided the drug and radiation are not given in close temporal proximity.

Quéro L ，Giocanti N ，Hennequin C ，Favaudon V ... -  《-》

Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome.

Hara T ，Miyazaki J ，Araki H ，Yamaoka M ，Kanzaki N ，Kusaka M ，Miyamoto M ... -  《CANCER RESEARCH》

Changes in androgen receptor nongenotropic signaling correlate with transition of LNCaP cells to androgen independence.

Unni E ，Sun S ，Nan B ，McPhaul MJ ，Cheskis B ，Mancini MA ，Marcelli M ... -  《CANCER RESEARCH》