In vivo activity and pharmacokinetics of nemorosone on pancreatic cancer xenografts.

Abstract

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.

• Authors: Robert J Wolf, Ralf A Hilger, Jörg D Hoheisel, Jens Werner, Frank Holtrup
• Journal: PloS one (PLoS One) Vol. 8 Issue 9 Pg. e74555 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24040280 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzophenones
• Ki-67 Antigen
• Terpenes
• nemorosone
• Deoxycytidine
• Phloroglucinol
• Cytochrome P-450 CYP3A
• Caspase 3
• hyperforin
• Gemcitabine

Topics

• Animals
• Antineoplastic Agents (administration & dosage, blood, pharmacokinetics)
• Benzophenones (administration & dosage, blood, pharmacokinetics)
• Biological Availability
• Biotransformation
• Carcinoma (blood, drug therapy, pathology)
• Caspase 3 (genetics, metabolism)
• Cytochrome P-450 CYP3A (genetics, metabolism)
• Deoxycytidine (administration & dosage, analogs & derivatives)
• Drug Administration Schedule
• Female
• Gene Expression
• Half-Life
• Hepatocytes (cytology, drug effects, metabolism)
• Humans
• Injections, Subcutaneous
• Ki-67 Antigen (genetics, metabolism)
• Mice
• Mice, Nude
• Pancreatic Neoplasms (blood, drug therapy, pathology)
• Phloroglucinol (administration & dosage, analogs & derivatives)
• Primary Cell Culture
• Terpenes (administration & dosage)
• Transplantation, Heterologous
• Xenograft Model Antitumor Assays
• Gemcitabine