Blockade of TGF-βR improves the efficacy of doxorubicin by modulating the tumor cell motility and affecting the immune cells in a melanoma model
- 9 September 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Naunyn-Schmiedebergs Archiv für experimentelle Pathologie und Pharmakologie
- Vol. 394 (11), 2309-2322
- https://doi.org/10.1007/s00210-021-02134-x
Abstract
TGF-β contributes to drug resistance and the invasiveness of tumor cells and weakens the anti-tumor immune responses. The present study aimed at examining the efficacy of the combination of SB431542, as a specific inhibitor of TGF-βR, and doxorubicin in controlling the melanoma tumor in mice. The impact of the combination of the doxorubicin and SB431542 on the cell growth, apoptosis, migration, and invasiveness of B16-F10 cells was examined. Besides, the B16-F10 tumor was induced in C57BL/6 mice, and the effects of the mentioned treatment on the tumor volume, survival, and the exhaustion state of T cells were evaluated. Although the combination of doxorubicin and SB431542 did not exhibit synergism in the inhibition of cell growth and apoptosis induction, it efficiently prohibited the migration and the epithelial to mesenchymal transition of B16-F10 cells, and the combination of doxorubicin and SB431542 caused an increase in mRNA levels of E-cadherin and, on the other hand, led to a decline in the expression of Vimentin. Tumor volume and the survival of tumor-bearing mice were efficiently controlled by the combination therapy. This treatment also eventuated in a decrease in the percentage of PD-L1+, TCD4+, and TCD8+ cells as indicators of exhausted T cells within the spleens of tumor-bearing mice. Blockade of TGF-βR also propelled the RAW 264.7 cells towards an anti-tumor M1 macrophage phenotype. The inhibition of TGF-βR demonstrated a potential to increase the efficacy of doxorubicin chemotherapy by the means of affecting cellular motility and restoring the anti-tumor immune responses.Keywords
Funding Information
- Mazandaran University of Medical Sciences (MAZUMS.SRC.16/97)
This publication has 57 references indexed in Scilit:
- TGF-β-induced epithelial-mesenchymal transition: A link between cancer and inflammationSeminars in Cancer Biology, 2012
- Probing the Dynamics of Doxorubicin-DNA Intercalation during the Initial Activation of Apoptosis by Fluorescence Lifetime Imaging Microscopy (FLIM)PLOS ONE, 2012
- Regulatory T cell: a protection for tumour cellsJournal of Cellular and Molecular Medicine, 2012
- Regulation of EMT by TGFβ in cancerFEBS Letters, 2012
- Mechanisms and management of doxorubicin cardiotoxicityHerz, 2011
- TGF-β and immune cells: an important regulatory axis in the tumor microenvironment and progressionTrends in Immunology, 2010
- Chronic inflammation, the tumor microenvironment and carcinogenesisCell Cycle, 2009
- Resistance to Chemotherapy in Cancer: A Complex and Integrated Cellular ResponsePharmacology, 2008
- TGF-β activates Erk MAP kinase signalling through direct phosphorylation of ShcAThe EMBO Journal, 2007
- Comparison of Uveal Melanoma Growth Rates With Mitotic Index and MortalityAmerican Journal of Ophthalmology, 1985