PURPOSE: Geldanamycin and its analogues belong to a new class of anticancer agents that inhibit the molecular chaperone heat shock protein 90. We hypothesized that membrane transporters expressed on tumor cells may contribute at least in part to cellular sensitivity to these agents. The purpose of this study is to identify novel transporters as determinant for sensitivity and resistance to geldanamycins. METHODS: To facilitate a systematic study of chemosensitivity across multiple geldanamycin analogues, we correlated mRNA expression profiles of majority of transporters with anticancer drug activities in 60 human tumor cell lines (NCI-60). We subsequently validated the gene-drug correlations using cytotoxicity and transport assays. RESULTS: The GA analogues displayed negative correlations with mRNA expression levels of the multidrug resistance protein 1 (MRP1, ABCC1). Suppressing MRP1 efflux using the inhibitor MK-571 and small interfering RNA in cell lines with intrinsic and acquired MRP1 overexpression (A549 and HL-60/ADR) and in cell lines stably transduced with MRP1 (MCF7/MRP1) increased intracellular drug accumulation and increased tumor cell sensitivity to geldanamycin analogues. CONCLUSIONS: These results suggest that elevated expression of MRP1, like the alternative efflux transporter MDR1 (ABCB1, P-glycoprotein), can significantly influence tumor cell sensitivity to geldanamycins as a potential chemoresistance factor.
PURPOSE:Geldanamycin and its analogues belong to a new class of anticancer agents that inhibit the molecular chaperone heat shock protein 90. We hypothesized that membrane transporters expressed on tumor cells may contribute at least in part to cellular sensitivity to these agents. The purpose of this study is to identify novel transporters as determinant for sensitivity and resistance to geldanamycins. METHODS: To facilitate a systematic study of chemosensitivity across multiple geldanamycin analogues, we correlated mRNA expression profiles of majority of transporters with anticancer drug activities in 60 humantumor cell lines (NCI-60). We subsequently validated the gene-drug correlations using cytotoxicity and transport assays. RESULTS: The GA analogues displayed negative correlations with mRNA expression levels of the multidrug resistance protein 1 (MRP1, ABCC1). Suppressing MRP1 efflux using the inhibitor MK-571 and small interfering RNA in cell lines with intrinsic and acquired MRP1 overexpression (A549 and HL-60/ADR) and in cell lines stably transduced with MRP1 (MCF7/MRP1) increased intracellular drug accumulation and increased tumor cell sensitivity to geldanamycin analogues. CONCLUSIONS: These results suggest that elevated expression of MRP1, like the alternative efflux transporter MDR1 (ABCB1, P-glycoprotein), can significantly influence tumor cell sensitivity to geldanamycins as a potential chemoresistance factor.
Authors: Andy Y Shih; Delinda A Johnson; Gloria Wong; Andrew D Kraft; Lei Jiang; Heidi Erb; Jeffrey A Johnson; Timothy H Murphy Journal: J Neurosci Date: 2003-04-15 Impact factor: 6.167
Authors: Charles S Morrow; Christina Peklak-Scott; Bimjhana Bishwokarma; Timothy E Kute; Pamela K Smitherman; Alan J Townsend Journal: Mol Pharmacol Date: 2006-01-24 Impact factor: 4.436
Authors: Wensheng Lang; Gary W Caldwell; Jian Li; Gregory C Leo; William J Jones; John A Masucci Journal: Drug Metab Dispos Date: 2006-09-29 Impact factor: 3.922
Authors: Victoria Smith; Edward A Sausville; Richard F Camalier; Heinz-Herbert Fiebig; Angelika M Burger Journal: Cancer Chemother Pharmacol Date: 2005-04-20 Impact factor: 3.333
Authors: J N Weinstein; T G Myers; P M O'Connor; S H Friend; A J Fornace; K W Kohn; T Fojo; S E Bates; L V Rubinstein; N L Anderson; J K Buolamwini; W W van Osdol; A P Monks; D A Scudiero; E A Sausville; D W Zaharevitz; B Bunow; V N Viswanadhan; G S Johnson; R E Wittes; K D Paull Journal: Science Date: 1997-01-17 Impact factor: 47.728
Authors: P Skehan; R Storeng; D Scudiero; A Monks; J McMahon; D Vistica; J T Warren; H Bokesch; S Kenney; M R Boyd Journal: J Natl Cancer Inst Date: 1990-07-04 Impact factor: 13.506
Authors: Chitra F Manohar; James A Bray; Helen R Salwen; Janice Madafiglio; Andy Cheng; Claudia Flemming; Glenn M Marshall; Murray D Norris; Michelle Haber; Susan L Cohn Journal: Oncogene Date: 2004-01-22 Impact factor: 9.867
Authors: M Kaliszczak; H Patel; S H B Kroll; L Carroll; G Smith; S Delaney; D A Heathcote; A Bondke; M J Fuchter; R C Coombes; A G M Barrett; S Ali; E O Aboagye Journal: Br J Cancer Date: 2013-09-26 Impact factor: 7.640