Abstract B237: Sorafenib decreases proliferation and induces apoptosis of prostate cancer cells by inhibition of the androgen receptor and Akt signaling pathways.
Authors: Oh Su Jung , Erb Holger H. H. , Hobisch Alfred , Santer Frédéric R. , Culig Zoran 
Published: June 2012

Prostate cancer is one of the most common male cancers in the western world. When the tumor is organ-confined the disease can in most cases be cured by radical prostatectomy or radiotherapy. For non-organ-confined prostate cancer standard treatments are androgen ablation therapies by orchiectomy, luteinizing hormone releasing hormone agonists or anti-androgens (e.g. bicalutamide) and doxetaxel-based chemotherapy for castration-resistant prostate cancer. However, the response duration of these therapies is limited and the development of alternative approaches is in need. Sorafenib is an oral multikinase inhibitor that targets a number of serine/threonine and tyrosine kinases and has been approved for the treatment of unresectable hepatocellular and advanced renal cell carcinoma. In regard of a possible application of sorafenib in prostate cancer we set out to investigate its effects in a panel of androgen-sensitive (LNCaP and CWR22Rv1) and castration-resistant (PC3 and LNCaP-IL-6+) prostate cancer cell lines as well as in their derivatives mimicking anti-androgen (LNCaP-Bic) and chemotherapy (PC3-DR) resistance. Proliferation was measured by 3H-thymidine incorporation assay and apoptosis by Annexin V flow cytometry and caspase 3/7 activity assays. Cell cycle- and apoptosis-regulating proteins were determined by Western blotting. Secreted prostate-specific antigen was used to monitor androgen receptor activity. 3H-thymidine incorporation assays revealed that sorafenib causes a dose-dependent inhibition of proliferation of all cell lines associated with down-regulation of cyclin-dependent kinase 2 and cyclin D1 expression. Apoptosis was induced at 2 μM sorafenib in androgen-sensitive cells, whereas a higher dose of the drug was needed in castration-resistant cell lines. Apoptosis induction was associated with inhibition of Akt and GSK-3beta phosphorylation as well as down-regulation of the Bcl-2 family member Mcl-1. In contrast to treatments with bicalutamide or docetaxel, therapy-resistant cells were still sensitive to the anti-cancer effects of sorafenib. Yet, a higher dose was needed to induce apoptosis in the therapy-resistant sublines compared to parental cell lines. Most interestingly, sorafenib was able to reduce expression levels of androgen receptor and prostate-specific antigen. In cells in which androgen receptor expression was down-regulated by siRNA, treatment with sorafenib increased apoptosis in an additive manner. In summary, the results of the present study indicate that there is a potential to use sorafenib in prostate cancers as an adjuvant therapy option to current androgen ablation treatments, but also in progressed prostate cancers that become unresponsive to standard therapies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B237.