title: Src family kinase inhibitor Saracatinib (AZD0530) impairs oxaliplatin uptake in colorectal cancer cells and blocks organic cation transporters.
abstract: Elevated Src family kinase (SFK) activity is associated with tumor invasion and metastasis. The SFK inhibitor saracatinib (AZD0530) is currently in phase II trials in patients including those with colorectal cancer (CRC), where links between SFK activity and poor prognosis are particularly striking. Saracatinib is likely to be used clinically in combination regimens, specifically with 5-fluorouracil (5-FU) and oxaliplatin, in CRC. The aim of this study was to determine the effect of saracatinib on oxaliplatin and 5-FU efficacy in CRC cells. Saracatinib did not modulate 5-FU efficacy but antagonized oxaliplatin in a schedule-specific manner through reduced oxaliplatin uptake via an SFK-independent mechanism. Saracatinib resembles the pharmacophore of known organic cation transporter (OCT) inhibitors and reduced oxaliplatin efficacy maximally in cells overexpressing OCT2. These data suggest that oxaliplatin uptake in CRC is attenuated by saracatinib via inhibition of OCT2, a potential consideration for the clinical development of this SFK inhibitor.
authors.affiliation: Paterson Institute for Cancer Research, University of Manchester, Manchester Cancer Research Centre and Manchester Academic Health Sciences Centre, Manchester, United Kingdom. cmorrow@picr.man.ac.uk
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Morrow
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ghattas
authors.forename: Christopher
authors.initials: C
authors.lastname: Smith
authors.forename: Heinz
authors.initials: H
authors.lastname: Bönisch
authors.forename: Richard A
authors.initials: RA
authors.lastname: Bryce
authors.forename: D Mark
authors.initials: DM
authors.lastname: Hickinson
authors.forename: Tim P
authors.initials: TP
authors.lastname: Green
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology*; D052117:Benzodioxoles / Q000008:administration & dosage / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D008958:Models, Molecular; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000077150:Oxaliplatin; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014162:Transfection; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D052117:Benzodioxoles; D004273:DNA, Neoplasm; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D009944:Organoplatinum Compounds; D011799:Quinazolines; D034741:RNA, Small Interfering; C491013:SLC22A2 protein, human; D000077150:Oxaliplatin; C515233:saracatinib; D019061:src-Family Kinases; D002945:Cisplatin; D005472:Fluorouracil