Combined inhibition of Ref‐1 and STAT3 leads to synergistic tumour inhibition in multiple cancers using 3D and in vivo tumour co‐culture models
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Dec 03, 2020
- Source ID
- 10.1111/jcmm.16132
Entities
People
- Adily N. Elmi
- Colton L. Starcher
- Edward A. Motea
- Fenil Shah
- Jack Mcgeown
- Joseph Rupert
- Karen E. Pollok
- Lee Armstrong
- Mark R. Kelley
- Melissa Fishel
- Michelle Grimard
- Olivia Babb
- Rachel A. Caston
- Randall Wireman
- Roberto Pili
- Teresa A. Zimmers
- Yan Tong
Organizations
- Center for Scientific Review
- Indiana University
- United States Department of Defense