title: Re-examining HSPC1 inhibitors.
abstract: HSPC1 is a critical protein in cancer development and progression, including colorectal cancer (CRC). However, clinical trial data reporting the effectiveness of HSPC1 inhibitors on several cancer types has not been as successful as predicted. Furthermore, some N-terminal inhibitors appear to be much more successful than others despite similar underlying mechanisms. This study involved the application of three N-terminal HSPC1 inhibitors, 17-DMAG, NVP-AUY922 and NVP-HSP990 on CRC cells. The effects on client protein levels over time were examined. HSPC1 inhibitors were also applied in combination with chemotherapeutic agents commonly used in CRC treatment (5-fluorouracil, oxaliplatin and irinotecan). As HSPA1A and HSPB1 have anti-apoptotic activity, gene-silencing techniques were employed to investigate the significance of these proteins in HSPC1 inhibitor and chemotherapeutic agent resistance. When comparing the action of the three HSPC1 inhibitors, there are distinct differences in the time course of important client protein degradation events. The differences between HSPC1 inhibitors were also reflected in combination treatment-17-DMAG was more effective compared with NVP-AUY922 in potentiating the cytotoxic effects of 5-fluorouracil, oxaliplatin and irinotecan. This study concludes that there are distinct differences between N-terminal HSPC1 inhibitors, despite their common mode of action. Although treatment with each of the inhibitors results in significant induction of the anti-apoptotic proteins HSPA1A and HSPB1, sensitivity to HSPC1 inhibitors is not improved by gene silencing of HSPA1A or HSPB1. HSPC1 inhibitors potentiate the cytotoxic effects of chemotherapeutic agents in CRC, and this approach is readily available to enter clinical trials. From a translational point of view, there may be great variability in sensitivity to the inhibitors between individual patients.
authors.affiliation: Chester Centre for Stress Research, Institute of Medicine, University of Chester, Bache Hall, CH2 1BR, Chester, UK. lee.sheahlin@gmail.com.|University Hospital Southampton, Tremona Road, SO16 6YD, Southampton, UK. lee.sheahlin@gmail.com.
authors.forename: Sheah Lin
authors.identifier: 0000-0001-8793-9384
authors.initials: SL
authors.lastname: Lee
authors.affiliation: Chester Centre for Stress Research, Institute of Medicine, University of Chester, Bache Hall, CH2 1BR, Chester, UK.|Centre for Biomedicine Research, Manchester Metropolitan University, Chester Street, M1 5GD, Manchester, UK.
authors.forename: Nina Claire
authors.initials: NC
authors.lastname: Dempsey-Hibbert
authors.affiliation: Countess of Chester Hospital, Liverpool Rd, CH2 1UL, Chester, UK.
authors.forename: Dale
authors.initials: D
authors.lastname: Vimalachandran
authors.affiliation: Countess of Chester Hospital, Liverpool Rd, CH2 1UL, Chester, UK.
authors.forename: Terence David
authors.initials: TD
authors.lastname: Wardle
authors.affiliation: Countess of Chester Hospital, Liverpool Rd, CH2 1UL, Chester, UK.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Sutton
authors.affiliation: Chester Centre for Stress Research, Institute of Medicine, University of Chester, Bache Hall, CH2 1BR, Chester, UK.
authors.forename: John H H
authors.initials: JH
authors.lastname: Williams
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000737:chemistry / Q000633:toxicity*; D053148:Caspase 3 / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019073:HT29 Cells; D006360:Heat-Shock Proteins; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry / Q000633:toxicity*; D047029:Lactams, Macrocyclic / Q000737:chemistry / Q000633:toxicity*; D018832:Molecular Chaperones; D011728:Pyridones / Q000737:chemistry / Q000633:toxicity*; D011743:Pyrimidines / Q000737:chemistry / Q000633:toxicity*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012118:Resorcinols / Q000737:chemistry / Q000633:toxicity*
chemical_list: C570862:2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido(4,3-d)pyrimidin-5(6H)-one; C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D016227:Benzoquinones; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; C112969:HSP90AA1 protein, human; C490786:HSPA1A protein, human; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D007555:Isoxazoles; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones; D011728:Pyridones; D011743:Pyrimidines; D034741:RNA, Small Interfering; D012118:Resorcinols; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D053148:Caspase 3
keywords: Chemoresistance; Chemotherapy; Colorectal cancer; Heat shock proteins; Novel target; Tumour evolvability