Tocilizumab potentiates cisplatin cytotoxicity and targets cancer stem cells in triple-negative breast cancer.

Autor: Alraouji NN; Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Al-Mohanna FH; Department of Comparative Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Ghebeh H; Stem Cell and Tissue Re-Engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia., Arafah M; Department of Pathology, College of Medicine, King Saud University, Riyadh, Saudi Arabia., Almeer R; Department of Zoology, College of Sciences, King Saud University, Riyadh, Saudi Arabia., Al-Tweigeri T; King Abdullah Centre for Oncology & Liver Diseases, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Aboussekhra A; Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Jazyk: angličtina
Zdroj: Molecular carcinogenesis [Mol Carcinog] 2020 Sep; Vol. 59 (9), pp. 1041-1051. Date of Electronic Publication: 2020 Jun 14.
DOI: 10.1002/mc.23234
Abstrakt: Triple-negative breast cancer (TNBC) is a very aggressive subtype with high recurrence rate and no molecular targets for therapies. This subtype is characterized by high expression/secretion of the proinvasive/metastatic interleukin-6 (IL-6) cytokine. In the present study, we have shown that tocilizumab inhibits the IL-6/STAT3 signaling and suppresses the cancer/inflammatory epigenetic IL-6/STAT3/NF-κB positive feedback loop. Furthermore, tocilizumab inhibited the proliferative and the migratory/invasiveness capacities as well as the epithelial-to-mesenchymal transition (EMT) process in TNBC cells. Importantly, tocilizumab suppressed the stemness-related characteristics of TNBC cells, through the inhibition of the Wnt/β-catenin breast cancer stem cell-related pathway. Additionally, we have shown that tocilizumab suppresses the paracrine activation of normal breast stromal fibroblasts to myofibroblats. Moreover, tocilizumab sensitized TNBC cells to the cytotoxic effect of cisplatin in vitro. Furthermore, pharmacological inhibition of IL-6 by tocilizumab had great inhibitory effect on tumor growth and the EMT process in humanized orthotopic breast tumors in mice. In addition, tocilizumab potentiated the proapoptotic effect of cisplatin in humanized breast tumors. Together, these findings indicate that tocilizumab can suppress the prometastatic capacity of TNBC cells and enhances the cytotoxic effect of cisplatin against these cells. Therefore, tocilizumab could be of great therapeutic value for these hard-to-treat TNBC patients.
(© 2020 Wiley Periodicals LLC.)
Databáze: MEDLINE
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