In vivo activity and pharmacokinetics of nemorosone on pancreatic cancer xenografts

• Verfasst von: Wolf, Robert [VerfasserIn]
• Verfasst von: Hoheisel, Jörg D. [VerfasserIn]
• Titel: In vivo activity and pharmacokinetics of nemorosone on pancreatic cancer xenografts
• Verf.angabe: Robert J. Wolf, Ralf A. Hilger, Jörg D. Hoheisel, Jens Werner, Frank Holtrup
• E-Jahr: 2013
• Jahr: September 5, 2013
• Umfang: 8 S.
• Teil: volume:8
• Teil: year:2013
• Teil: number:9
• Teil: elocationid:e74555
• Teil: pages:1-8
• Teil: extent:8
• Fussnoten: Gesehen am 22.07.2021
• Titel Quelle: Enthalten in: PLOS ONE
• Ort Quelle: San Francisco, California, US : PLOS, 2006
• Jahr Quelle: 2013
• Band/Heft Quelle: 8(2013), 9, Artikel-ID e74555, Seite 1-8
• ISSN Quelle: 1932-6203
• DOI: doi:10.1371/journal.pone.0074555
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Blood plasma
• Sach-SW: Cancer treatment
• Sach-SW: Cancers and neoplasms
• Sach-SW: Drug metabolism
• Sach-SW: Enzyme metabolism
• Sach-SW: Hepatocytes
• Sach-SW: Metabolites
• Sach-SW: Pancreatic cancer
• K10plus-PPN: 1764145070

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.