title: Anti-proliferative actions of N'-desmethylsorafenib in human breast cancer cells.
abstract: The multi-kinase inhibitor sorafenib is used for the treatment of renal and hepatic carcinomas and is undergoing evaluation for treatment of breast cancer in combination with other agents. Cytochrome P450 (CYP) 3A4 converts sorafenib to multiple metabolites that have been detected in patient plasma. However, recent clinical findings suggest that combination therapy may elicit inhibitory pharmacokinetic interactions involving sorafenib that increase toxicity. While sorafenib N-oxide is an active metabolite, information on the anti-tumor actions of other metabolites is unavailable. The present study evaluated the actions of sorafenib and its five major metabolites in human breast cancer cell lines. All agents, with the exception of N'-hydroxymethylsorafenib N-oxide, decreased ATP formation in four breast cancer cell lines (MDA-MB-231, MDA-MB-468, MCF-7 and T-47D). Prolonged treatment of MDA-MB-231 cells with N'-desmethylsorafenib, N'-desmethylsorafenib N-oxide and sorafenib (10 μM, 72 h) produced small increases in caspase-3 activity to 128-139% of control. Sorafenib and its metabolites, again with the exception of N'-hydroxymethylsorafenib N-oxide, impaired MEK/ERK signaling in MDA-MB-231 cells and modulated the expression of cyclin D1 and myeloid cell leukemia sequence-1, which regulate cell viability. When coadministered with doxorubicin (0.5 or 1 μM), sorafenib and N'-desmethylsorafenib (25 μM) produced greater effects on ATP production than either treatment alone. Thus, it emerges that, by targeting the MEK/ERK pathway, multiple sorafenib metabolites may contribute to the actions of sorafenib in breast cancer. Because N'-desmethylsorafenib is not extensively metabolized and does not inhibit major hepatic CYPs, this metabolite may have a lower propensity to precipitate pharmacokinetic drug interactions than sorafenib.
authors.affiliation: Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, University of Sydney, NSW 2006, Australia.
authors.forename: Pei H
authors.initials: PH
authors.lastname: Cui
authors.forename: Tristan
authors.initials: T
authors.lastname: Rawling
authors.forename: Tina B
authors.initials: TB
authors.lastname: Gillani
authors.forename: Kirsi
authors.initials: K
authors.lastname: Bourget
authors.forename: Xiao-Suo
authors.initials: XS
authors.lastname: Wang
authors.forename: Fanfan
authors.initials: F
authors.lastname: Zhou
authors.forename: Michael
authors.initials: M
authors.lastname: Murray
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D061986:MCF-7 Cells; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib
keywords: Breast cancer cells; CYP; DMEM; Dulbecco's Modified Eagle Medium; ERK; ERK kinase; LC–MS–MS; MEK; MEK/ERK signaling; Mcl-1; N′-Desmethylsorafenib; PBS; Pharmacokinetic drug interactions; RIPA; Sorafenib; VEGF; cytochrome P450; extracellular signal-regulated kinase; liquid chromatography–tandem mass spectrometry; myeloid cell leukemia sequence-1; phosphate-buffered saline; radioimmunoprecipitation; vascular endothelial growth factor