Combined use of subclinical hydroxyurea and CHK1 inhibitor effectively controls melanoma and lung cancer progression, with reduced normal tissue toxicity compared to gemcitabine.
Animals
Antimetabolites, Antineoplastic
/ adverse effects
Antineoplastic Combined Chemotherapy Protocols
/ adverse effects
Cell Line, Tumor
Checkpoint Kinase 1
/ antagonists & inhibitors
Deoxycytidine
/ adverse effects
Disease Progression
Female
Humans
Hydroxyurea
/ adverse effects
Lung Neoplasms
/ drug therapy
Melanoma
/ drug therapy
Mice, Inbred BALB C
Mice, Nude
Protein Kinase Inhibitors
/ adverse effects
Gemcitabine
CHK1 inhibitor
hydroxyurea
macrophage infiltration
replication stress
Journal
Molecular oncology
ISSN: 1878-0261
Titre abrégé: Mol Oncol
Pays: United States
ID NLM: 101308230
Informations de publication
Date de publication:
07 2019
07 2019
Historique:
received:
23
11
2018
revised:
20
02
2019
accepted:
30
04
2019
pubmed:
3
5
2019
medline:
12
5
2020
entrez:
3
5
2019
Statut:
ppublish
Résumé
Drugs such as gemcitabine that increase replication stress are effective chemotherapeutics in a range of cancer settings. These drugs effectively block replication and promote DNA damage, triggering a cell cycle checkpoint response through the ATR-CHK1 pathway. Inhibiting this signalling pathway sensitises cells to killing by replication stress-inducing drugs. Here, we investigated the effect of low-level replication stress induced by low concentrations (> 0.2 mm) of the reversible ribonucleotide reductase inhibitor hydroxyurea (HU), which slows S-phase progression but has little effect on cell viability or proliferation. We demonstrate that HU effectively synergises with CHK1, but not ATR inhibition, in > 70% of melanoma and non-small-cell lung cancer cells assessed, resulting in apoptosis and complete loss of proliferative potential in vitro and in vivo. Normal fibroblasts and haemopoietic cells retain viability and proliferative potential following exposure to CHK1 inhibitor plus low doses of HU, but normal cells exposed to CHK1 inhibitor combined with submicromolar concentrations of gemcitabine exhibited complete loss of proliferative potential. The effects of gemcitabine on normal tissue correlate with irreversible ATR-CHK1 pathway activation, whereas low doses of HU reversibly activate CHK1 independently of ATR. The combined use of CHK1 inhibitor and subclinical HU also triggered an inflammatory response involving the recruitment of macrophages in vivo. These data indicate that combining CHK1 inhibitor with subclinical HU is superior to combination with gemcitabine, as it provides equal anticancer efficacy but with reduced normal tissue toxicity. These data suggest a significant proportion of melanoma and lung cancer patients could benefit from treatment with this drug combination.
Identifiants
pubmed: 31044505
doi: 10.1002/1878-0261.12497
pmc: PMC6599846
doi:
Substances chimiques
Antimetabolites, Antineoplastic
0
Protein Kinase Inhibitors
0
Deoxycytidine
0W860991D6
Checkpoint Kinase 1
EC 2.7.11.1
Hydroxyurea
X6Q56QN5QC
Gemcitabine
0
Types de publication
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1503-1518Informations de copyright
© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
Références
Mol Cell. 2005 Feb 4;17(3):393-403
pubmed: 15694340
Oncogene. 2013 Feb 7;32(6):788-96
pubmed: 22391562
PLoS One. 2012;7(8):e44021
pubmed: 22937147
Ann Oncol. 2018 May 1;29(5):1304-1311
pubmed: 29788155
Biotechniques. 2010 May;48(5):379-86
pubmed: 20569211
Nature. 2017 Sep 21;549(7672):394-398
pubmed: 28902841
J Clin Pharmacol. 2014 Sep;54(9):1016-22
pubmed: 24729271
Oncotarget. 2017 Jun 28;8(40):67754-67768
pubmed: 28978069
J Invest Dermatol. 2003 Nov;121(5):1150-9
pubmed: 14708619
J Biol Chem. 2009 Jul 3;284(27):18085-95
pubmed: 19416980
Cancer Res. 2013 Jun 15;73(12):3683-91
pubmed: 23548269
Clin Cancer Res. 2013 Aug 1;19(15):4046-57
pubmed: 23723299
Clin Cancer Res. 2018 Jun 15;24(12):2901-2912
pubmed: 29535131
Oncotarget. 2016 Jan 12;7(2):1380-94
pubmed: 26595527
Oncology. 2016;91(5):251-260
pubmed: 27598338
Mol Pharmacol. 2005 Dec;68(6):1636-44
pubmed: 16126823
Cancer Biol Ther. 2012 Sep;13(11):1072-81
pubmed: 22825331
Eur J Pharmacol. 2014 Oct 15;741:8-16
pubmed: 25084222
Clin Lymphoma Myeloma Leuk. 2013 Sep;13 Suppl 2:S300-4
pubmed: 24290215
PLoS One. 2012;7(12):e51733
pubmed: 23251614
Front Genet. 2015 Feb 27;6:70
pubmed: 25774168
Pharmacol Ther. 2014 Apr;142(1):1-10
pubmed: 24140082
J Cell Biol. 2010 Dec 27;191(7):1285-97
pubmed: 21173116
J Invest Dermatol. 2014 Jan;134(1):150-158
pubmed: 23842115
Cell. 2013 Nov 21;155(5):1088-103
pubmed: 24267891
Cell Rep. 2016 Feb 9;14(5):1114-1127
pubmed: 26804904
Nat Rev Cancer. 2015 May;15(5):276-89
pubmed: 25907220
Mol Cancer Ther. 2013 Nov;12(11):2285-95
pubmed: 24038068
BMC Bioinformatics. 2008 Nov 15;9:482
pubmed: 19014601
Cell Cycle. 2007 Jan 1;6(1):104-10
pubmed: 17245119
Nat Rev Drug Discov. 2015 Jun;14(6):405-23
pubmed: 25953507
Immunity. 2016 May 17;44(5):1177-89
pubmed: 27178469
J Leukoc Biol. 2009 Sep;86(3):573-6
pubmed: 19414536
Nucleic Acids Res. 2012 Nov;40(21):10780-94
pubmed: 22977173
Int J Cancer. 2015 Mar 15;136(6):1381-9
pubmed: 25098891
Mol Cancer Ther. 2018 Aug;17(8):1670-1682
pubmed: 29891488
Clin Cancer Res. 2017 May 15;23(10):2423-2432
pubmed: 27815358
Mol Cell. 2015 Sep 17;59(6):1011-24
pubmed: 26365377
BMC Cancer. 2013 Dec 21;13:604
pubmed: 24359526
J Clin Oncol. 2015 Mar 20;33(9):1060-6
pubmed: 25605849
DNA Repair (Amst). 2014 Jul;19:182-9
pubmed: 24767947
Nucleic Acids Res. 2015 Nov 16;43(20):9776-87
pubmed: 26271993
Oncotarget. 2016 Sep 20;7(38):61000-61020
pubmed: 27876705
Anticancer Drugs. 1994 Oct;5(5):573-8
pubmed: 7858290
Mol Cancer Ther. 2012 Feb;11(2):427-38
pubmed: 22203733
Clin Pharmacokinet. 1998 May;34(5):347-58
pubmed: 9592619