Combined inhibition of Ref-1 and STAT3 leads to synergistic tumour inhibition in multiple cancers using 3D and in vivo tumour co-culture models
| Autor: | Yan Tong, Michelle Grimard, Jack McGeown, Rachel A. Caston, Roberto Pili, Mark R. Kelley, Colton L. Starcher, Melissa L. Fishel, Fenil Shah, Karen E. Pollok, Teresa A. Zimmers, Joseph E. Rupert, Olivia Babb, Lee Armstrong, Adily N. Elmi, Edward A. Motea, Randall Wireman |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
STAT3 Transcription Factor Combination therapy Blotting Western Cancer‐associated fibroblasts STAT3 03 medical and health sciences Mice 0302 clinical medicine In vivo Pancreatic cancer Cell Line Tumor Nitriles medicine DNA-(Apurinic or Apyrimidinic Site) Lyase Tumor Microenvironment Animals Humans Viability assay Cytotoxicity Benzofurans Tumor microenvironment biology Chemistry Cell Biology Original Articles medicine.disease HCT116 Cells Immunohistochemistry Pancreatic Neoplasms 030104 developmental biology Pyrimidines Ruxolitinib 030220 oncology & carcinogenesis biology.protein Cancer research Molecular Medicine Cancer-Associated Fibroblasts Pyrazoles Original Article APE1/Ref‐1 Reactive Oxygen Species Naphthoquinones Napabucasin |
| Zdroj: | Journal of Cellular and Molecular Medicine |
| ISSN: | 1582-4934 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text