Powers Ginny L, Hammer Kimberly D P, Domenech Maribella, Frantskevich Katsiaryna, Malinowski Rita L, Bushman Wade, Beebe David J, Marker Paul C
Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin.
Department of Biomedical Engineering and Wisconsin Institute for Medical Research, University of Wisconsin-Madison, Madison, Wisconsin. Department of Chemical Engineering, University of Puerto Rico, Mayaguez, Puerto Rico.
Mol Cancer Res. 2015 Jan;13(1):149-60. doi: 10.1158/1541-7786.MCR-14-0110. Epub 2014 Aug 22.
Phosphodiesterase 4D (PDE4D) has recently been implicated as a proliferation-promoting factor in prostate cancer and is overexpressed in human prostate carcinoma. However, the effects of PDE4D inhibition using pharmacologic 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 SHH pathway. PDE4D inhibition also reduced proliferation of epithelial cells induced by paracrine signaling from cocultured 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 with vehicle-treated controls. These studies suggest the pharmacologic 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.
磷酸二酯酶4D（PDE4D）最近被认为是前列腺癌中的一种增殖促进因子，并且在人类前列腺癌中过表达。然而，使用药物抑制剂抑制PDE4D的作用尚未在前列腺癌中进行研究。这些研究在体外和体内模型中研究了选择性PDE4D抑制剂NVP-ABE171和西洛司特作为抗前列腺癌疗法的作用。研究了PDE4D抑制剂对前列腺癌关键通路和/或环磷酸腺苷（cAMP）下游通路的影响。NVP-ABE171和西洛司特均降低了细胞生长。在体外，PDE4D抑制剂导致音猬因子（SHH）、雄激素受体（AR）和丝裂原活化蛋白激酶（MAPK）通路的信号传导减少，但生长抑制与SHH通路的相关性最好。PDE4D抑制还减少了由激活刺猬信号的共培养基质细胞旁分泌信号诱导的上皮细胞增殖。此外，PDE4D抑制剂降低了野生型小鼠前列腺的重量。与载体处理的对照组相比，用西洛司特或NVP-ABE171处理的裸鼠中生长的前列腺癌异种移植物湿重降低且凋亡增加。这些研究表明，使用小分子抑制剂对PDE4D进行药物抑制是前列腺癌治疗的有效选择。
PDE4D抑制剂在体内和体外均降低前列腺癌细胞的生长，并且PDE4D抑制在前列腺癌中具有治疗潜力。
