Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany ; Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
PLoS One. 2013 Sep 5;8(9):e74555. doi: 10.1371/journal.pone.0074555. eCollection 2013.
Pancreatic cancer is one of the leading cancer-related causes of death in the western world with an urgent need for new treatment strategies. Recently, hyperforin and nemorosone have been described as promising anti-cancer lead compounds. While hyperforin has been thoroughly investigated in vitro and in vivo, in vivo data for nemorosone are still missing. Thus, we investigated the growth-inhibitory potential of nemorosone on pancreatic cancer xenografts in NMRI nu/nu mice and determined basic pharmacokinetic parameters. Xenograft tumors were treated with nemorosone and gemcitabine, the current standard of care. Tumor sections were subjected to H&E as well as caspase 3 and Ki-67 staining. Nemorosone plasma kinetics were determined by HPLC and mass spectrometry. Induction of CYP3A4 and other metabolizing enzymes by nemorosone and hyperforin was tested on primary hepatocytes using qRT-PCR. At a dose of 50 mg/kg nemorosone per day, a significant growth-inhibitory effect was observed in pancreatic cancer xenografts. The compound was well tolerated and rapidly absorbed into the bloodstream with a half-life of approximately 30 min. Different metabolites were detected, possibly resembling CYP3A4-independent oxidation products. It is concluded that nemorosone is a potential anti-cancer lead compound with good bioavailability, little side-effects and promising growth-inhibitory effects, thus representing a valuable compound for a combination therapy approach.
胰腺癌是西方世界主要的癌症相关死亡原因之一，因此迫切需要新的治疗策略。最近，贯叶金丝桃素和毛蕊异黄酮已被描述为有前途的抗癌先导化合物。虽然贯叶金丝桃素在体外和体内都进行了彻底的研究，但毛蕊异黄酮的体内数据仍然缺失。因此，我们研究了毛蕊异黄酮对 NMRI nu/nu 小鼠胰腺癌异种移植物的生长抑制潜力，并确定了基本的药代动力学参数。异种移植肿瘤用毛蕊异黄酮和吉西他滨（目前的标准治疗方法）治疗。肿瘤切片进行 H&E 以及 caspase 3 和 Ki-67 染色。通过 HPLC 和质谱法测定毛蕊异黄酮的血浆动力学。使用 qRT-PCR 在原代肝细胞上测试毛蕊异黄酮和贯叶金丝桃素对 CYP3A4 和其他代谢酶的诱导作用。每天给予 50mg/kg 毛蕊异黄酮的剂量，可显著抑制胰腺癌异种移植物的生长。该化合物耐受性良好，可迅速被吸收到血液中，半衰期约为 30 分钟。检测到不同的代谢物，可能类似于 CYP3A4 非依赖性氧化产物。因此，可以得出结论，毛蕊异黄酮是一种具有良好生物利用度、副作用小且具有有前途的生长抑制作用的潜在抗癌先导化合物，因此是联合治疗方法的有价值的化合物。
