Combined inhibition of Ref-1 and STAT3 leads to synergistic tumour inhibition in multiple cancers using 3D and in vivo tumour co-culture models.
Animals
Benzofurans
/ pharmacology
Blotting, Western
Cell Line, Tumor
DNA-(Apurinic or Apyrimidinic Site) Lyase
/ genetics
HCT116 Cells
Humans
Immunohistochemistry
Mice
Naphthoquinones
/ pharmacology
Nitriles
Pancreatic Neoplasms
/ genetics
Pyrazoles
/ pharmacology
Pyrimidines
Reactive Oxygen Species
/ metabolism
STAT3 Transcription Factor
/ genetics
Tumor Microenvironment
/ drug effects
APE1/Ref-1
Cancer-associated fibroblasts
Napabucasin
Pancreatic cancer
Ruxolitinib
STAT3
tumor microenvironment
Journal
Journal of cellular and molecular medicine
ISSN: 1582-4934
Titre abrégé: J Cell Mol Med
Pays: England
ID NLM: 101083777
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
20
08
2020
revised:
19
10
2020
accepted:
09
11
2020
pubmed:
5
12
2020
medline:
12
10
2021
entrez:
4
12
2020
Statut:
ppublish
Résumé
With a plethora of molecularly targeted agents under investigation in cancer, a clear need exists to understand which pathways can be targeted simultaneously with multiple agents to elicit a maximal killing effect on the tumour. Combination therapy provides the most promise in difficult to treat cancers such as pancreatic. Ref-1 is a multifunctional protein with a role in redox signalling that activates transcription factors such as NF-κB, AP-1, HIF-1α and STAT3. Formerly, we have demonstrated that dual targeting of Ref-1 (redox factor-1) and STAT3 is synergistic and decreases cell viability in pancreatic cancer cells. Data presented here extensively expands upon this work and provides further insights into the relationship of STAT3 and Ref-1 in multiple cancer types. Using targeted small molecule inhibitors, Ref-1 redox signalling was blocked along with STAT3 activation, and tumour growth evaluated in the presence and absence of the relevant tumour microenvironment. Our study utilized qPCR, cytotoxicity and in vivo analysis of tumour and cancer-associated fibroblasts (CAF) response to determine the synergy of Ref-1 and STAT3 inhibitors. Overall, pancreatic tumours grown in the presence of CAFs were sensitized to the combination of STAT3 and Ref-1 inhibition in vivo. In vitro bladder and pancreatic cancer demonstrated the most synergistic responses. By disabling both of these important pathways, this combination therapy has the capacity to hinder crosstalk between the tumour and its microenvironment, leading to improved tumour response.
Identifiants
pubmed: 33274592
doi: 10.1111/jcmm.16132
pmc: PMC7812272
doi:
Substances chimiques
Benzofurans
0
Naphthoquinones
0
Nitriles
0
Pyrazoles
0
Pyrimidines
0
Reactive Oxygen Species
0
STAT3 Transcription Factor
0
napabucasin
0
ruxolitinib
82S8X8XX8H
APEX1 protein, human
EC 4.2.99.18
Apex1 protein, mouse
EC 4.2.99.18
DNA-(Apurinic or Apyrimidinic Site) Lyase
EC 4.2.99.18
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
784-800Subventions
Organisme : CSR NIH HHS
ID : R01NF180045
Pays : United States
Organisme : CSR NIH HHS
ID : R01CA138798
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA210489
Pays : United States
Organisme : CSR NIH HHS
ID : R01CA167291
Pays : United States
Organisme : U.S. Department of Defense
ID : W81XWH-19-1-0217
Organisme : CSR NIH HHS
ID : R01HL140961
Pays : United States
Organisme : CSR NIH HHS
ID : R01CA211098
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL143403
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA167291
Pays : United States
Organisme : CSR NIH HHS
ID : R01CA231267
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA221158
Pays : United States
Organisme : CSR NIH HHS
ID : R01CA205166
Pays : United States
Organisme : CSR NIH HHS
ID : U01HL143403
Pays : United States
Organisme : CSR NIH HHS
ID : R01CA167291-S1
Pays : United States
Organisme : CSR NIH HHS
ID : P30 CA082709
Pays : United States
Informations de copyright
© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
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