Abstract
BackgroundProstate cancer is a leading cause of male cancer specific mortality. When cure by radical prostatectomy is not possible the next line of prostate cancer treatment is androgen deprivation. However prolonged androgen deprivation often results in relapse and androgen-independent prostate cancer that is inevitably fatal despite optimal chemotherapy. The Hedgehog signalling pathway has recently been implicated in prostate cancer development and metastasis. EGFR or ErbB2 expression has been also correlated with androgen independence, shorter survival and metastasis.ResultsWe determined that the Hedgehog and ErbB signalling pathways are active in circulating tumour cells isolated from androgen-independent prostate cancer patients and in the androgen-independent prostate cancer cell line LNCaP C4-2B. As a basis for synergistic chemotherapy protocols combinations of the Hedgehog specific inhibitor cyclopamine and the ErbB signalling inhibitors gefitinib or lapatinib were tested in this study. Androgen-independent prostate cancer cell growth was inhibited by a SMO inhibitor (cyclopamine) which blocks Hedgehog signalling and by ErbB inhibitors (gefitinib and lapatinib). The isobologram and combination index method of Chou and Talalay was used to evaluate drug interactions. Synergistic antiproliferation effects were observed when the Hedgehog and ErbB inhibitors were combined.ConclusionAndrogen-independent prostate cancer cell proliferation was associated with activity of the Hedgehog and ErbB signalling pathways. Cyclopamine, gefitinib or lapatinib treatment significantly decreased the proliferation of androgen-independent prostate cancer cells. The Hedgehog pathway therefore represents a promising new therapeutic target in androgen-independent prostate cancer. Synergistic effects were observed when Hedgehog and ErbB inhibitors were used together. This study may have clinical implications for improving the treatment of advanced prostate cancer.
Highlights
Prostate cancer is a leading cause of male cancer specific mortality
The use of circulating tumour cells (CTC) is advantageous as biopsies are rarely performed on patients at this cancer stage and obtaining CTC is a low risk minimally invasive technique compared to biopsy
Immunofluorescence analysis showed that each prostate cancer patient sample contained more than 5 nucleated, EpCAM positive CTC, which has been associated with a poor prognosis in breast and prostate cancer [13,14]
Summary
Prostate cancer is a leading cause of male cancer specific mortality. When cure by radical prostatectomy is not possible the line of prostate cancer treatment is androgen deprivation. Decreasing circulating testosterone with androgen deprivation therapy is currently used to treat metastatic prostate cancer and those cancers that are not suitable for attempts at cure with radiotherapy or surgery. This effectively shrinks androgen-dependent tumours, both in the prostate and at distant sites. Many men fail this therapy and continuous androgen deprivation usually leads to recurrent androgen-independent prostate cancer (AIPC)[3]. The high mortality rate associated with prostate cancer is linked to the development of AIPC and the current lack of effective therapies. Developing new therapeutic approaches that target AIPC has considerable potential for improving quality of life and survival of patients with advanced prostate cancer
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