Novel therapeutic strategies in development for prostate cancer
University of California, Department of Medicine, Box 1711, San Francisco,1600 Divisadero Street, San Francisco, CA 94115, USA. Expert Opinion on Investigational Drugs
(Impact Factor: 5.53).
02/2008; 17(1):13-22. DOI: 10.1517/13543718.104.22.168
Relatively few therapy options exist for patients with prostate cancer that has become resistant to androgen-deprivation therapy and has metastasized to distant sites. Survival for such patients is poor with a median survival of approximately 20 months from the time of initiation of standard docetaxel-based chemotherapy. Promising new treatments are needed, and several are currently being evaluated, including those that target the hormonal axis, such as abiraterone, chemotherapies, such as satraplatin and ixabepilone, combinations of chemotherapy with other agents, such as bevacizumab and calcitriol, as well as a variety of immunotherapeutic approaches. This review will highlight recent and current studies for many of the promising developments for advanced disease, as well as novel early stage approaches.
Available from: Justine Rudner
- "Despite the use of classical chemotherapy (mainly taxanes), hormone ablation therapy, radiopharmaceuticals, and refined radiation methods, no curative treatment for advanced stages is available to date. Thus, novel approaches are needed particularly for the treatment of patients with hormone-refractory disease [3,4]. "
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ABSTRACT: The phosphatidylinositol-3-kinase (PI3K)/Akt pathway is frequently deregulated in prostate cancer and associated with neoplastic transformation, malignant progression, and enhanced resistance to classical chemotherapy and radiotherapy. Thus, it is a promising target for therapeutic intervention. In the present study, the cytotoxic action of the Akt inhibitor Erufosine (ErPC3) was analyzed in prostate cancer cells and compared to the cytotoxicity of the PI3K inhibitor LY294002. Moreover, the efficacy of combined treatment with Akt inhibitors and ionizing radiation in prostate cancer cells was examined.
Prostate cancer cell lines PC3, DU145, and LNCaP were treated with ErPC3 (1-100 µM), LY294002 (25-100 µM), irradiated (0-10 Gy), or subjected to combined treatments. Cell viability was determined by the WST-1 assay. Apoptosis induction was analyzed by flow cytometry after staining with propidium iodide in a hypotonic citrate buffer, and by Western blotting using antibodies against caspase-3 and its substrate PARP. Akt activity and regulation of the expression of Bcl-2 family members and key downstream effectors involved in apoptosis regulation were examined by Western blot analysis.
The Akt inhibitor ErPC3 exerted anti-neoplastic effects in prostate cancer cells, however with different potency. The anti-neoplastic action of ErPC3 was associated with reduced phosphoserine 473-Akt levels and induction of apoptosis. PC3 and LNCaP prostate cancer cells were also sensitive to treatment with the PI3K inhibitor LY294002. However, the ErPC3-sensitive PC3-cells were less susceptible to LY294002 than the ErPC3-refractory LNCaP cells. Although both cell lines were largely resistant to radiation-induced apoptosis, both cell lines showed higher levels of apoptotic cell death when ErPC3 was combined with radiotherapy.
Our data suggest that constitutive Akt activation and survival are controlled by different different molecular mechanisms in the two prostate cancer cell lines - one which is sensitive to the Akt-inhibitor ErPC3 and one which is more sensitive to the PI3K-inhibitor LY294002. Our findings underline the importance for the definition of predictive biomarkers that allow the selection patients that may benefit from the treatment with a specific signal transduction modifier.
Available from: tua.org.tw
Available from: ruor.uottawa.ca
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