CH5137291, an androgen receptor nuclear translocation-inhibiting compound, inhibits the growth of castration-resistant prostate cancer cells.

Resistance of prostate cancer to castration is currently an unavoidable problem. The major mechanisms underlying such resistance are androgen receptor (AR) overexpression, androgen-independent activation of AR, and AR mutation. To address this problem, we developed an AR pure antagonist, CH5137291, with AR nuclear translocation-inhibiting activity, and compared its activity and characteristics with that of bicalutamide.

Biological properties of androgen receptor pure antagonist for treatment of castration-resistant prostate cancer: optimization from lead compound to CH5137291.

Background: Castration-resistant prostate cancer (CRPC) is still dependent on androgen receptor (AR) signaling. We previously reported that a novel nonsteroidal AR pure antagonist, CH4933468, which is a thiohydantoin derivative with a sulfonamide side chain, provided in vitro proof of concept but did not in vivo.

Methods: We developed other derivatives, CH5137291, CH5138514, and CH5166623, and their pharmacological properties were compared with CH4933468 and bicalutamide.

Design and synthesis of an androgen receptor pure antagonist (CH5137291) for the treatment of castration-resistant prostate cancer.

A series of 5,5-dimethylthiohydantoin derivatives were synthesized and evaluated for androgen receptor pure antagonistic activities for the treatment of castration-resistant prostate cancer. Since CH4933468, which we reported previously, had a problem with agonist metabolites, novel thiohydantoin derivatives were identified by applying two strategies. One was the replacement of the alkylsulfonamide moiety by a phenylsulfonamide to avoid the production of agonist metabolites.

Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity.

Background: Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen-depletion independent status. However, the mechanism of bicalutamide resistance remains unclear because few cell models have been generated.

Methods: We generated a bicalutamide-resistant subline, LNCaP-BC2, from LNCaP after prolonged treatment with bicalutamide.

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

Background: 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.

Methods: 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.

Cell sheet engineering: recreating tissues without biodegradable scaffolds.

While tissue engineering has long been thought to possess enormous potential, conventional applications using biodegradable scaffolds have limited the field's progress, demonstrating a need for new methods. We have previously developed cell sheet engineering using temperature-responsive culture dishes in order to avoid traditional tissue engineering approaches, and their related shortcomings. Using temperature-responsive dishes, cultured cells can be harvested as intact sheets by simple temperature changes, thereby avoiding the use of proteolytic enzymes.