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STAT3 inhibitory stattic enhances immunogenic cell death induced by chemotherapy in cancer cells

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Abstract

Background

Induction of immunogenic cell death (ICD) is considered a promising strategy for cancer immunotherapy. Stattic is an inhibitor of STAT3, which is found constitutively active in many cancers and plays a major role in cancer progression.

Objectives

In the present study, we proposed to evaluate whether stattic can enhance the effects of chemotherapy in the induction of ICD in cancer cells harboring hyperactive STAT3.

Methods

The growth inhibitory effects of stattic and chemo agents including doxorubicin (DOX) and oxaliplatin (OXP) were evaluated using MTT assay in B16F10 and CT26 cell lines. Flow cytometry was applied to study cell apoptosis and calreticulin (CRT) surface exposure. The levels of high mobility group box 1 (HGMB1), heat shock protein70 (HSP70) and interleukin-12 (IL-12) were measured using ELISA.

Results

Treatment of B16F10 and CT26 cells with stattic in combination with DOX resulted in synergistic antitumor effects with combination index being 0.82 and 0.87, respectively. Interestingly, we found a higher level of ICD markers including CRT expression as well as HMGB1 and HSP70 secretion in the cells received combination therapy of stattic and DOX as compared with monotherapies. Moreover, exposure of dendritic cells (DCs) to conditioned media (CM) from cancer cells treated with stattic and/or DOX resulted in secretion of IL-12, which is an indicator of DCs maturation and induction of Th1 response. OXP and stattic monotherapy induced ICD in CT26 cells and stimulated IL-12 secretion by DCs; however, we did not observe a significant increase in the level of ICD in CT26 cells and IL-12 secretion by DCs when CT26 cells were treated with stattic and OXP combination as compared with monotherapy groups.

Conclusion

These findings indicate that STAT3 inhibitory stattic can increase ICD induced by DOX.

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Acknowledgements

This study is part of a dissertation (No.128) by S.Jafari, submitted for Ph.D degree and supported financially by Biotechnology Research Center, Tabriz University of Medical Sciences.

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Authors and Affiliations

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

    Sevda Jafari & Ommoleila Molavi

  2. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

    Sevda Jafari, Mohammad Saied Hejazi & Ommoleila Molavi

  3. Faculty of Pharmacy and Pharmaceutical Science, University of Alberta, Edmonton, Canada

    Afsaneh Lavasanifar

  4. Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran

    Mohammad Saied Hejazi & Ommoleila Molavi

  5. Department of Pharmacology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

    Nasrin Maleki-Dizaji

  6. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Mehran Mesgari

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  1. Sevda Jafari
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Correspondence to Ommoleila Molavi.

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Jafari, S., Lavasanifar, A., Hejazi, M.S. et al. STAT3 inhibitory stattic enhances immunogenic cell death induced by chemotherapy in cancer cells. DARU J Pharm Sci 28, 159–169 (2020). https://doi.org/10.1007/s40199-020-00326-z

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  • DOI: https://doi.org/10.1007/s40199-020-00326-z

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