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Dual-targeted therapeutic strategy combining CSC–DC-based vaccine and cisplatin overcomes chemo-resistance in experimental mice model

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Abstract

Background and purpose

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Emerging evidence suggests that one of the main reasons of chemotherapy treatment failure is the development of multi-drug resistance (MDR) associated with cancer stem cells (CSCs). Our aim is to identify a therapeutic strategy based on MDR-reversing agents.

Materials and methods

CSC-enriched Ehrlich carcinoma (EC) cell cultures were prepared by drug-resistant selection method using different concentrations of cisplatin (CIS). Cell cultures following drug exposure were analyzed by flow cytometry for CSC surface markers CD44+/CD24−. We isolated murine bone marrow-derived dendritic cells (DCs) and then used them to prepare CSC–DC vaccine by pulsation with CSC-enriched lysate. DCs were examined by flow cytometry for phenotypic markers. Solid Ehrlich carcinoma bearing mice were injected with the CSC–DC vaccine in conjunction with repeated low doses of CIS. Tumor growth inhibition was evaluated and tumor tissues were excised and analyzed by real-time PCR to determine the relative gene expression levels of MDR and Bcl-2. Histopathological features of tumor tissues excised were examined.

Results and conclusion

Co-treatment with CSC–DC and CIS resulted in a significant tumor growth inhibition. Furthermore, the greatest response of downregulation of MDR and Bcl-2 relative gene expression were achieved in the same group. In parallel, the histopathological observations demonstrated enhanced apoptosis and absence of mitotic figures in tumor tissues of the co-treatment group. Dual targeting of resistant cancer cells using CSC–DC vaccine along with cisplatin represents a promising therapeutic strategy that could suppress tumor growth, circumvent MDR, and increase the efficacy of conventional chemotherapies.

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Acknowledgements

The authors are grateful to Dr. Noha El-Anwar, Lecturer of Pathology, Faculty of Medicine, Tanta University, Egypt for her assistance in the histopathological examination of the tumor sections.

Author information

Authors and Affiliations

  1. Biochemistry Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt

    N. E. El-Ashmawy, E. G. Khedr & A. O. Ibrahim

  2. Zoology Department, Faculty of Science, Tanta University, Tanta, Egypt

    M. L. Salem

  3. Center of Excellence in Cancer Research, Tanta University, Tanta, Egypt

    M. L. Salem

  4. Clinical Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt

    E. A. El-Zamarany

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  1. N. E. El-Ashmawy
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  2. M. L. Salem
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  3. E. G. Khedr
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  5. A. O. Ibrahim
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Correspondence to A. O. Ibrahim.

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El-Ashmawy, N.E., Salem, M.L., Khedr, E.G. et al. Dual-targeted therapeutic strategy combining CSC–DC-based vaccine and cisplatin overcomes chemo-resistance in experimental mice model. Clin Transl Oncol 22, 1155–1165 (2020). https://doi.org/10.1007/s12094-019-02242-4

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