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Re-examining HSPC1 inhibitors
Authors
A Cercek
A Citri
+63 more
A Sharma
AN Tse
B Chen
B Lamottke
BS Blagg
CW Ang
D Hanahan
D Hanahan
D Kennedy
Dale Vimalachandran
DB Solit
DH Choi
DR Ciocca
DS Hong
EB Garon
EL Davenport
F Lamoureux
F Rappa
F Wang
FU1 Hartl
HH Kampinga
HJ Kim
HM Kantarjian
I Grivicich
J Ge
JL Holmes
John H. H. Williams
JR Hecht
K Zitzmann
KH Lee
KT Flaherty
L Mayor-López
L Neckers
LR Kelland
LV Sequist
M Tatokoro
M Tsuruta
MA Socinski
MV Powers
N Azoitei
N Gaspar
N Gaspar
N Niewidok
Nina Claire Dempsey-Hibbert
NP Shah
P Csermely
Paul A. Sutton
R Nazarian
S He
S Modi
S Modi
SH1 McLaughlin
Sheah Lin Lee
T Okui
T Okui
T Wendel
Terence David Wardle
U Banerji
W Guo
W Liu
Y Kanazawa
YS Kim
Z Milicevic
Publication date
1 January 2017
Publisher
'Springer Science and Business Media LLC'
Doi
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on
PubMed
Abstract
© 2017, The Author(s). 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
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info:doi/10.1007%2Fs12192-017-...
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