Shaw Greg, Prowse David M
Institute of Cancer, Bart's and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK.
Cancer Cell Int. 2008 Mar 18;8:3. doi: 10.1186/1475-2867-8-3.
Prostate 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.
We 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.
Androgen-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.
前列腺癌是男性癌症特异性死亡的主要原因。当无法通过根治性前列腺切除术治愈时，前列腺癌的下一步治疗是雄激素剥夺。然而，长期的雄激素剥夺往往会导致复发和雄激素非依赖性前列腺癌，尽管进行了最佳化疗，这种癌症仍不可避免地致命。刺猬信号通路最近被认为与前列腺癌的发生和转移有关。表皮生长因子受体（EGFR）或ErbB2的表达也与雄激素非依赖性、较短生存期和转移相关。
我们确定刺猬信号通路和ErbB信号通路在从雄激素非依赖性前列腺癌患者分离出的循环肿瘤细胞以及雄激素非依赖性前列腺癌细胞系LNCaP C4-2B中是活跃的。作为协同化疗方案的基础，本研究测试了刺猬信号特异性抑制剂环杷明与ErbB信号抑制剂吉非替尼或拉帕替尼的联合使用。雄激素非依赖性前列腺癌细胞的生长受到一种阻断刺猬信号通路的平滑肌瘤蛋白（SMO）抑制剂（环杷明）以及ErbB抑制剂（吉非替尼和拉帕替尼）的抑制。采用Chou和Talalay的等效线图和联合指数法评估药物相互作用。当刺猬信号抑制剂和ErbB抑制剂联合使用时，观察到协同的抗增殖作用。
雄激素非依赖性前列腺癌细胞增殖与刺猬信号通路和ErbB信号通路的活性相关。环杷明、吉非替尼或拉帕替尼治疗显著降低了雄激素非依赖性前列腺癌细胞的增殖。因此，刺猬信号通路是雄激素非依赖性前列腺癌一个有前景的新治疗靶点。当刺猬信号抑制剂和ErbB抑制剂一起使用时观察到协同效应。本研究可能对改善晚期前列腺癌的治疗具有临床意义。
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