Antitumor efficacy induced by a B16F10 tumor cell vaccine treated with mitoxantrone alone or in combination with reserpine and verapamil in mice

He,Xiangfeng; Wang,Jing; Dou,Jun; Yu,Fangliu; Cai,Kai; Li,Xiaoli; Zhang,Hongyi; Gu,Ning

doi:10.3892/etm.2011.283

Antitumor efficacy induced by a B16F10 tumor cell vaccine treated with mitoxantrone alone or in combination with reserpine and verapamil in mice

Authors:
- Xiangfeng He
- Jing Wang
- Jun Dou
- Fangliu Yu
- Kai Cai
- Xiaoli Li
- Hongyi Zhang
- Ning Gu
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Affiliations: Department of Pathogenic Biology and Immunology, Medical School, Southeast University, Nanjing 210009, P.R. China, Department of Gynecology and Obstetrics, Zhongda Hospital, Nanjing, P.R. China, School of Biological Science and Medical Engineering, Southeast University, Nanjing, P.R. China
Published online on: June 14, 2011 https://doi.org/10.3892/etm.2011.283
Pages: 911-916

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Abstract

An apoptotic tumor cell serves as a potential potent trigger for the initiation of naturally occurring tumor immunity. In the present study, a B16F10 tumor cell vaccine treated with mitoxantrone (MIT) was developed, and its antitumor effect on mice was evaluated. The results indicated that the B16F10 tumor cell vaccine treated with MIT alone or in combination with reserpine (RP) and verapamil (VP) for 12 h triggered apoptosis, and that the expression of CD80, the MHC Ⅱ class molecule, NKG2D and its ligand were significantly increased compared to the expression levels in the control group. The tumor vaccine immunogenicity was significantly enhanced in the vaccinated mice, resulting in augmented cytotoxicity of splenocytes and NK cells as well as the splenocyte proliferative response compared to the control group mice. Notably, the mice vaccinated with the B16F10 tumor cell vaccine treated with MIT, RP and VP did not generate tumors only after 60 days into the observation, but the mice also generated a powerful immune prophylactic efficiency against the B16F10 tumor cell challenge. These findings demonstrated the safety and efficacy of the B16F10 tumor cell vaccine treated with MIT alone or in combination with RP and VP in the murine model, and suggest that an apoptotic tumor cell vaccine modeled on naturally occurring tumor immune responses in vivo may provide a safe and immunogenic tumor vaccine for potential applications in humans.

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1.	Saito H, Frleta D, Dubsky P and Palucka AK: Dendritic cell-based vaccination against cancer. Hematol Oncol Clin North Am. 20:689–710. 2006. View Article : Google Scholar : PubMed/NCBI
2.	Dou J, Chu LL, Zhao FS, et al: Study of immunotherapy of murine myeloma by an IL-21-based tumor vaccine in Balb/c mice. Cancer Biol Ther. 6:1871–1879. 2007. View Article : Google Scholar : PubMed/NCBI
3.	Chunyu C, Han Yu, Yushan R and Yanlin W: Mitoxantrone-mediated apoptotic B16-F1 cells induce specific anti-tumor immune response. Cell Mol Immunol. 6:469–475. 2009. View Article : Google Scholar : PubMed/NCBI
4.	Obeid M, Tesniere A, Ghiringhelli F, et al: Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 13:54–61. 2007. View Article : Google Scholar : PubMed/NCBI
5.	Mimeault M, Hauke R, Mehta PP, et al: Recent advances in cancer stem/progenitor cell research: therapeutic implications for overcoming resistance to the most aggressive cancers. J Cell Mol Med. 11:981–1011. 2007. View Article : Google Scholar : PubMed/NCBI
6.	An Y and Ongkeko WM: ABCG2: the key to chemoresistance in cancer stem cells? Expert Opin Drug Metab Toxicol. 5:1529–1542. 2009. View Article : Google Scholar : PubMed/NCBI
7.	Schinkel AH and Jonker JW: Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Advanced Drug Delivery Rev. 55:3–29. 2003. View Article : Google Scholar : PubMed/NCBI
8.	Van Veen HW, Venema K, Bolhuis H, et al: Multidrug resistance mediated by a bacterial homolog of the human multidrug transporter MDR1. Proc Natl Acad Sci USA. 93:10668–10672. 1996.PubMed/NCBI
9.	Droi S, Eytan GD and Assaraf YG: Potentiation of anticancer-drug cytotoxicity by multidrug-resistance chemosensitizers involves alterations in membrane fluidity leading to increased membrane permeability. Eur J Biochem. 228:1020–1029. 1995. View Article : Google Scholar
10.	Spengler G, Viveiros M, Martins M, et al: Demonstration of the activity of P-glycoprotein by a semi-automated fluorometric method. Anticancer Res. 29:2173–2177. 2009.PubMed/NCBI
11.	Fengshu Z, Jun D, XiangFeng H, et al: Enhancing therapy of B16F10 melanoma efficacy through tumor vaccine expressing GPI-anchored IL-21 and secreting GM-CSF in mouse model. Vaccine. 28:2846–2852. 2010. View Article : Google Scholar : PubMed/NCBI
12.	Hyesung K, Hyemi P, Jungsun P, et al: Dendritic cell vaccine in addition to FOLFIRI regimen improve antitumor effects through the inhibition of immunosuppressive cells in murine colorectal cancer model. Vaccine. 28:7787–7796. 2010. View Article : Google Scholar
13.	Groh V, Steinle A, Spies T, et al: Recognition of stress-induced MHC molecules by intestinal epithelial gammadelta T cells. Science. 279:1737–1740. 1998. View Article : Google Scholar : PubMed/NCBI
14.	Jun D, Yongfang W, Jing W, et al: Antitumor efficacy induced by human ovarian cancer cells secreting IL-21 alone or combination with GM-CSF cytokines in nude mice model. Immunobiology. 214:483–492. 2009. View Article : Google Scholar : PubMed/NCBI
15.	Jun D, Quan T, Fengshu Z, et al: Comparison of immune responses induced in mice by vaccination with DNA vaccine constructs expressing mycobacterial antigen 85A & interleukin-21 and Bacillus Galmette-Guérin. Immunol Invest. 37:113–127. 2008.PubMed/NCBI
16.	Dou J, Wen P, Hu W, et al: Identifying tumor stem-like cells in mouse melanoma cell lines by analyzing the characteristics of side population cells. Cell Biol Int. 33:807–815. 2009. View Article : Google Scholar : PubMed/NCBI
17.	Karla PK, Earla R, Boddu SH, et al: Molecular expression and functional evidence of a drug efflux pump (BCRP) in human corneal epithelial cells. Curr Eye Res. 34:1–9. 2009. View Article : Google Scholar : PubMed/NCBI
18.	Yuan JH, He ZM, Yu YH, et al: Expression establishment and functional analysis of breast cancer resistance protein with doxycycline induced tet regulating system in mouse fibroblast cell line PA317. Ai Zheng. 23:1127–1133. 2004.
19.	Lecoeur H, Février M, Garcia S, Rivière Y and Gougeon ML: A novel flow cytometric assay for quantitation and multiparametric characterization of cell-mediated cytotoxicity. J Immunol Methods. 253:177–187. 2001. View Article : Google Scholar : PubMed/NCBI
20.	Fengshu Z, Jun D, Wang J, et al: Investigation on the anti-tumor efficacy by expression of GPI-anchored mIL-21 on the surface of B16F10 cells in C57BL/6 mice. Immunobiology. 215:89–100. 2010. View Article : Google Scholar : PubMed/NCBI
21.	Goodell MA, Brose K, Paradis G, et al: Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med. 183:1797–1806. 1996. View Article : Google Scholar : PubMed/NCBI
22.	Jun D and Ning G: Emerging strategies for the identification and targeting of cancer stem cells. Tumor Bio. 31:243–253. 2010. View Article : Google Scholar : PubMed/NCBI
23.	Frank MO, Kaufman J, Tian S, et al: Harnessing naturally occurring tumor immunity: a clinical vaccine trial in prostate cancer. PLoS One. 5:e123672010. View Article : Google Scholar : PubMed/NCBI
24.	Taniguchi K, Nishiura H, Ota Y, et al: Roles of the ribosomal protein S19 dimer and chemically induced apoptotic cells as a tumor vaccine in syngeneic mouse transplantation models. J Immunother. 34:16–27. 2011. View Article : Google Scholar
25.	Banchereau J and Steinman R: Dendritic cells and the control of immunity. Nature. 392:245–152. 1998. View Article : Google Scholar
26.	Gardai SJ, McPhillips KA, Frasch SC, et al: Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell. 123:321–334. 2005. View Article : Google Scholar
27.	Hu W, Wang J, Dou J, et al: Augmenting therapy of ovarian cancer efficacy by secreting IL-21 human umbilical cord blood stem cells in nude mice. Cell Transplant. Nov 5–2010.(E-pub ahead of print).
28.	Panaretakis T, Joza N, Modjtahedi N, et al: The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death. Cell Death Differ. 15:1499–1509. 2008. View Article : Google Scholar : PubMed/NCBI
29.	Davide B, Stefano G, Giovanna C, et al: Post-apoptotic tumors are more palatable to dendritic cells and enhance their antigen cross-presentation activity. Vaccine. 26:6422–6432. 2008. View Article : Google Scholar : PubMed/NCBI
30.	Palucka AK, Ueno H, Fay JW, et al: Taming cancer by inducing immunity via dendritic cells. Immunol Rev. 220:129–150. 2007. View Article : Google Scholar : PubMed/NCBI