Phosphodiesterase 4D inhibitors limit prostate cancer growth potential.
Phosphodiesterase 4D inhibitors limit prostate cancer growth potential.
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磷酸二酯酶4D抑制剂限制了前列腺癌的生长潜力。
DOI：
10.1158/1541-7786.mcr-14-0110
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发表时间：
2015-01
期刊：
影响因子：
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通讯作者：
Marker PC
中科院分区：
文献类型：
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作者：
Powers GL;Hammer KD;Domenech M;Frantskevich K;Malinowski RL;Bushman W;Beebe DJ;Marker PC
磷酸二酯酶4D(PDE4D)最近被认为是前列腺癌中的一种促增殖因子，在人类前列腺癌中过表达。然而，使用药物抑制剂抑制PDE4D的效果尚未在前列腺癌中得到检验。这些研究检验了选择性PDE4D抑制剂NVP-ABE171和西洛司特在体外和体内模型中作为抗前列腺癌治疗方法的效果。研究了PDE4D抑制剂对前列腺癌关键通路和/或环磷酸腺苷(CAMP)下游的影响。NVP-ABE171和西洛司特均抑制细胞生长。在体外，PDE4D抑制剂导致sonic hedgehog(SHH)、雄激素受体(AR)和MAPK通路信号减弱，但生长抑制与sonic hedgehog通路最相关。PDE4D抑制也减少了共同培养的基质细胞激活Hedgehog信号的旁分泌信号诱导的上皮细胞增殖。此外，PDE4D抑制剂还减轻了野生型小鼠的前列腺重量。与赋形剂治疗的对照组相比，西洛司特或NVP-ABE171治疗的裸鼠体内生长的前列腺癌异种移植瘤湿重减轻，细胞凋亡率增加。这些研究表明，使用小分子抑制剂对PDE4D进行药理抑制是前列腺癌治疗的有效选择。PDE4D抑制剂在体内和体外都能抑制前列腺癌细胞的生长，PDE4D抑制剂对前列腺癌具有治疗潜力。
Phosphodiesterase 4D (PDE4D) has recently been implicated as a proliferation-promoting factor in prostate cancer and is over-expressed in human prostate carcinoma. However, the effects of PDE4D inhibition using pharmacological inhibitors have not been examined in prostate cancer. These studies examined the effects of selective PDE4D inhibitors, NVP-ABE171 and cilomilast, as anti-prostate cancer therapies in both in vitro and in vivo models. The effects of PDE4D inhibitors on pathways that are critical in prostate cancer and/or downstream of cyclic AMP (cAMP) were examined. Both NVP-ABE171 and cilomilast decreased cell growth. In vitro, PDE4D inhibitors lead to decreased signaling of the sonic hedgehog (SHH), Androgen Receptor (AR), and MAPK pathways, but growth inhibition was best correlated to the sonic hedgehog pathway. PDE4D inhibition also reduced proliferation of epithelial cells induced by paracrine signaling from co-cultured stromal cells that had activated hedgehog signaling. In addition, PDE4D inhibitors decreased the weight of the prostate in wild-type mice. Prostate cancer xenografts grown in nude mice that were treated with cilomilast or NVP-ABE171 had decreased wet weight and increased apoptosis compared to vehicle treated controls. These studies suggest the pharmacological inhibition of PDE4D using small molecule inhibitors is an effective option for prostate cancer therapy. PDE4D inhibitors decrease the growth of prostate cancer cells in vivo and in vitro, and PDE4D inhibition has therapeutic potential in prostate cancer.