Targeting Aurora kinases for the treatment of prostate cancer.

Inappropriate expression of the Aurora kinases can induce aberrant mitosis, centrosome irregularities, and chromosomal instability, which lead to anueploidy and cell transformation. Here, we report that Aurora-A and Aurora-B are highly expressed in primary human and mouse prostate cancers and prostate cancer cell lines. In clinical samples, levels of Aurora-A and Aurora-B were significantly elevated in prostatic intraepithelial neoplasia lesions and prostate tumors when compared with the non-neoplastic samples. Interestingly, expression of Aurora-A in non-neoplastic prostates correlated with seminal vesicle invasion (rho = 0.275, P = 0.0169) and in prostate tumor with positive surgical margins (rho = 0.265, P = 0.0161). In addition, nuclear expression of Aurora-B in prostatic intraepithelial neoplasia lesions correlated with clinical staging of the tumor (rho = -0.4, P = 0.0474) whereas cytoplasmic expression in tumors correlated with seminal vesicle invasion (rho = 0.282, P = 0.0098). Cell lines and primary tumors derived from the TRAMP model were also found to express high levels of Aurora-A and Aurora-B. When human PC3, LNCaP, and mouse C1A cells were treated with the potent Aurora kinase inhibitor VX680, which attenuates phosphorylation of histone H3, cancer cell survival was reduced. VX680 could further reduce cell viability >2-fold when used in combination with the chemotherapy drug doxorubicin. Our findings support a functional relationship between Aurora kinase expression and prostate cancer and the application of small-molecule inhibitors in therapeutic modalities.

Emergence of metastatic hormone-refractory disease in prostate cancer after anti-androgen therapy.

The anti-androgens used in prostate cancer therapy have been designed to interfere with the normal androgen receptor (AR)-mediated processes that ensure prostate cell survival, triggering tumor cells to undergo programmed cell death. While anti-androgens were originally designed to treat advanced disease, they have recently been used to debulk organ-confined prostate tumors, to improve positive margins prior to surgery, and for chemoprevention in patients at high risk for prostate cancer. However, tumors treated with anti-androgens frequently become hormone refractory and acquire a more aggressive phenotype. Progression toward metastatic hormone-refractory disease has often been regarded as the outgrowth of a small number of hormone-independent cells that emerge from a hormone-dependent tumor during anti-androgen treatment by natural selection. While a number of selective advantages have recently been identified, there is also considerable evidence suggesting that the progression toward metastatic hormone-refractory disease is an dynamic process which involves abrogation of programmed cell death as a result of the attenuation of DNA fragmentation and maintenance of mitochondrial membrane potential in tumor cells; the upregulation of stromal-mediated growth factor signaling pathways; and the upregulation of extracellular matrix (ECM) protease expression.

Induction of invasive phenotype by Casodex in hormone-sensitive prostate cancer cells.

The cellular mechanisms of anti-androgen-induced tumor regression have not been investigated in great detail. We have compared the induction of cell death in the androgen-dependent, non-invasive LNCaP prostate cancer cell line by Casodex and TNF-alpha. Both agents induce a dose and time-dependent decrease in cell viability in vitro. However, Casodex does not induce classical DNA fragmentation to oligonucleosomes typically induced by TNF-alpha, but rather induces cleavage to form intermediate 60 kb DNA fragments. RT-PCR based analysis demonstrates that in LNCaP cells Casodex coordinately alters the expression of steady-state level of mRNAs of several matrix metalloproteases and their cognate inhibitors (most notably MMP2 and TIMP1). Zymography and reverse zymography confirm that the ratio of metalloprotease(s) to inhibitor(s) is altered in favor of activation of the proteases. In a small percentage of the treated LNCaP cells, the activation of the extracellular matrix (ECM)-proteases by Casodex also induces an invasive phenotype. The acquisition of an invasive phenotype is not seen when LNCaP cells are treated with TNF-alpha, and is not seen when the LNCaP cells are treated with both compounds simultaneously, suggesting that the phenomenon may be specific to particular classes of compounds. These observations have significant implications in the treatment of prostate cancer, since the appearance of a more aggressive phenotype following treatment is clearly undesirable.