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Blockade of TGF-βR improves the efficacy of doxorubicin by modulating the tumor cell motility and affecting the immune cells in a melanoma model

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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.

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Data availability

The data supporting the findings of this study are provided as supplementary files.

Change history

  • 19 September 2021

    The affiliation 4 contained mistake where two “s” have been missed in “System” and “Poisoning” words. This has been updated and correctly captured as "Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran".

Abbreviations

TGF-β:

Transforming growth factor-β

EMT:

Epithelial to mesenchymal transition

Tregs:

Regulatory T cells

APCs:

Antigen-presenting cells

TGF-βR:

Receptor of TGF-β

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

MDSCs:

Myeloid-derived suppressor cells

ALK-5:

Activin receptor-like kinase-5

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Funding

No funding information is available for this study.

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Authors and Affiliations

  1. Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Alireza Mardomi & Mahsa Panahi

  2. Nanobiotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran

    Alireza Mardomi & Ali Salimi

  3. Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran

    Marzieh Ghollasi

  4. Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran

    Mohsen Korani

  5. Department of Hematology and Blood Bank, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Mohammad Parsa-Kondelaji

  6. Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

    Mehdi Sabzichi

Authors
  1. Alireza Mardomi
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  2. Marzieh Ghollasi
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  3. Mohsen Korani
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  4. Mahsa Panahi
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  5. Mohammad Parsa-Kondelaji
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  6. Mehdi Sabzichi
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  7. Ali Salimi
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Contributions

AM: conceptualization and practical experiments; MG and MK: data analysis and manuscript drafting; MP, MS, and MPK: collaboration in cell culture and animal model studies; AS: study design, management, and critical revision of the manuscript. All data were generated in-house and no paper mill was used.

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Correspondence to Ali Salimi.

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This study was conducted under ethical approvals from the local ethics committee (registration code: IR. BMSU.REC.1399.98000536) and in accordance with the NIH Guide to Laboratory Animal Care.

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Mardomi, A., Ghollasi, M., Korani, M. et al. Blockade of TGF-βR improves the efficacy of doxorubicin by modulating the tumor cell motility and affecting the immune cells in a melanoma model. Naunyn-Schmiedeberg's Arch Pharmacol 394, 2309–2322 (2021). https://doi.org/10.1007/s00210-021-02134-x

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  • DOI: https://doi.org/10.1007/s00210-021-02134-x

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