Dual-targeted therapeutic strategy combining CSC–DC-based vaccine and cisplatin overcomes chemo-resistance in experimental mice model
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Background and purpose
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.
KeywordsCancer stem cells Dendritic cells Cisplatin Immunotherapy Multi-drug resistance Bcl-2
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.
Compliance with ethical standards
Conflict of interest
The authors declare no competing interests.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
For this type of study, formal consent is not required.
- 5.Sastry KS, Al-Muftah MA, Li P, Al-Kowari MK, Wang E, Ismail Chouchane A, Kizhakayil D, Kulik G, Marincola FM, Haoudi A, Chouchane L. Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells. Cell Death Differ. 2014;21(12):1936–49. https://doi.org/10.1038/cdd.2014.140.CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Salem ML, Eissa IR, Mohamed TM. Dendritic cells generated from naïve and tumor-bearing mice uniquely restores different leukocyte subpopulations in chemotherapy-treated tumor-bearing mice. Clin Cancer Investig J. 2016;5:1–10.Google Scholar
- 19.El-Ashmawy NE, El-Zamarany EA, Salem ML, Khedr EG, Ibrahim AO. A new strategy for enhancing antitumor immune response using dendritic cells loaded with chemo-resistant cancer stem-like cells in experimental mice model. Mol Immunol. 2019;111:106–17. https://doi.org/10.1016/j.molimm.2019.04.001(Epub 2019 Apr 30).CrossRefPubMedGoogle Scholar
- 24.Calcagno AM, Salcido CD, Gillet JP, Wu CP, Fostel JM, Mumau MD, Gottesman MM, Varticovski L, Ambudkar SV. Prolonged drug selection of breast cancer cells and enrichment of cancer stem cell characteristics. J Natl Cancer Inst. 2010;102(21):1637–52. https://doi.org/10.1093/jnci/djq361.CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Wan F, Zhang S, Xie R, Gao B, Campos B, Herold-Mende C, Lei T. The utility and limitations of neurosphere assay, CD133 immunophenotyping and side population assay in glioma stem cell research. Brain Pathol. 2010;20(5):877–89. https://doi.org/10.1111/j.1750-3639.2010.00379.x.CrossRefPubMedGoogle Scholar
- 35.Hu Y, Lu L, Xia Y, Chen X, Chang AE, Hollingsworth RE, Hurt E, Owen J, Moyer JS, Prince ME, Dai F, Bao Y, Wang Y, Whitfield J, Xia JC, Huang S, Wicha MS, Li Q. Therapeutic efficacy of cancer stem cell vaccines in the adjuvant setting. Cancer Res. 2016;76(16):4661–72. https://doi.org/10.1158/0008-5472.CAN-15-2664Epub 2016 Jun 20.CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Jiang T, Chen X, Zhou W, Fan G, Zhao P, Ren S, Zhou C, Zhang J. Immunotherapy with dendritic cells modified with tumor-associated antigen gene demonstrates enhanced antitumor effect against lung cancer. Transl Oncol. 2017;10(2):132–41. https://doi.org/10.1016/j.tranon.2016.12.002Epub 2017 Jan 25.CrossRefPubMedPubMedCentralGoogle Scholar
- 40.Tagliamonte M, Petrizzo A, Napolitano M, Luciano A, Rea D, Barbieri A, Arra C, Maiolino P, Tornesello M, Ciliberto G, Buonaguro FM, Buonaguro L. A novel multidrug metronomic chemotherapy significantly delays tumor growth in mice. J Transl Med. 2016;14:58. https://doi.org/10.1186/s12967-016-0812-1.CrossRefPubMedPubMedCentralGoogle Scholar