In vivo activity and pharmacokinetics of nemorosone on pancreatic cancer xenografts

• Published in: PloS one 2013-09, Vol.8 (9), p.e74555
• Main Authors: Wolf, Robert J, Hilger, Ralf A, Hoheisel, Jörg D, Werner, Jens, Holtrup, Frank
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Apoptosis; Benzophenones - administration & dosage; Benzophenones - blood; Benzophenones - pharmacokinetics; Bioavailability; Biological Availability; Biotransformation; Cancer; Cancer treatment; Carcinoma - blood; Carcinoma - drug therapy; Carcinoma - pathology; Caspase; Caspase 3 - genetics; Caspase 3 - metabolism; Caspase-3; Cytochrome; Cytochrome P-450; Cytochrome P-450 CYP3A - genetics; Cytochrome P-450 CYP3A - metabolism; Cytotoxicity; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Dosage; Drug Administration Schedule; Female; Gemcitabine; Gene Expression; Genomes; Half-Life; Health aspects; Hepatocytes; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - metabolism; High-performance liquid chromatography; Humans; Hypericum perforatum; In vivo methods and tests; Injections, Subcutaneous; Ki-67 Antigen - genetics; Ki-67 Antigen - metabolism; Kinetics; Laboratory animals; Lead compounds; Leukemia; Liquid chromatography; Mass spectrometry; Mass spectroscopy; Medical research; Metabolism; Metabolites; Mice; Mice, Nude; Neuroblastoma; Oxidation; Pancreatic cancer; Pancreatic Neoplasms - blood; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - pathology; Pharmacokinetics; Pharmacology; Phloroglucinol - administration & dosage; Phloroglucinol - analogs & derivatives; Primary Cell Culture; Proteins; Surgery; Terpenes - administration & dosage; Transplantation, Heterologous; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0074555

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.