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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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Research Article

Doxorubicin-induced Immunogenic Cell Death Impairs Tumor Progression and Distant Metastasis in a 4T1 Breast Cancer Tumor Model

Author(s): Camila Magalhães Cardador, Thaís Bergmann de Castro, Raffael Júnio Araújo de Castro, Anamélia Lorenzetti Bocca, Luana Cristina Camargo, Thyago Arruda Pacheco, Luís Alexandre Muehlmann and João Paulo Figueiró Longo*

Volume 30, Issue 31, 2024

Published on: 22 July, 2024

Page: [2493 - 2504] Pages: 12

DOI: 10.2174/0113816128316870240610045550

Price: $65

Abstract

Introduction: Cancer is an individual disease and its formation and development are specific to each host. Conventional treatments are ineffective in complex cases, such as metastasis, and have severe adverse side effects. New strategies are needed to address the problem, and the use of immunogenic cell death (ICD) as a trigger or booster of the immune system through the exposure of damage-associated molecular patterns, along with tumor antigens, by cancerous cells is presented as an immunization approach in this work.

Methods: For this purpose, 4T1 cells were exposed to doxorubicin (DOX) for 24 hours and then, these cells undergoing ICD were subcutaneously administered to mice. The ICD induction by DOX on 4T1 was assessed by flow cytometry and image analysis. This immunization process was performed three times and after the last administration, the immunized mice were challenged with a subcutaneous xenograft of live cancer cells.

Results: The results demonstrate that the mice immunized with cells undergoing ICD after exposure to DOX presented no primary tumor or indications of distant metastatic lesion development.

Conclusion: In summary, our findings indicate that the immunization process utilizing ICD is indeed efficacious in managing this aggressive form of pre-clinical breast cancer.

« Previous Next »
[1]
Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011; 144(5): 646-74.
[2]
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100(1): 57-60.
[3]
Hanahan D. Hallmarks of cancer: New dimensions. Cancer Discov 2022; 12(1): 31-46.
[http://dx.doi.org/10.1158/2159-8290.CD-21-1059] [PMID: 35022204]
[4]
Rodrigues MC, Morais JAV, Ganassin R, et al. An overview on immunogenic cell death in cancer biology and therapy. Pharmaceutics 2022; 14(8): 1564.
[http://dx.doi.org/10.3390/pharmaceutics14081564] [PMID: 36015189]
[5]
Steeg PS. Targeting metastasis. Nat Rev Cancer 2016; 16(4): 201-18.
[http://dx.doi.org/10.1038/nrc.2016.25] [PMID: 27009393]
[6]
Nardin S, Mora E, Varughese FM, et al. Breast cancer survivorship, quality of life, and late toxicities. Front Oncol 2020; 10: 864.
[http://dx.doi.org/10.3389/fonc.2020.00864] [PMID: 32612947]
[7]
Rodrigues MC, de Sousa Júnior WT, Mundim T, et al. Induction of immunogenic cell death by photodynamic therapy mediated by aluminum-phthalocyanine in nanoemulsion. Pharmaceutics 2022; 14(1): 196.
[http://dx.doi.org/10.3390/pharmaceutics14010196] [PMID: 35057091]
[8]
Garg AD, Dudek-Peric AM, Romano E, Agostinis P. Immunogenic cell death. Int J Dev Biol 2015; 59(1-2-3): 131-40.
[http://dx.doi.org/10.1387/ijdb.150061pa]
[9]
Krysko DV, Garg AD, Kaczmarek A, Krysko O, Agostinis P, Vandenabeele P. Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer 2012; 12(12): 860-75.
[http://dx.doi.org/10.1038/nrc3380] [PMID: 23151605]
[10]
de Lima LI, Faria RS, Franco MS, et al. Combined paclitaxel-doxorubicin liposomal results in positive prognosis with infiltrating lymphocytes in lung metastasis. Nanomedicine 2020; 15(28): 2753-70.
[http://dx.doi.org/10.2217/nnm-2020-0201] [PMID: 33179587]
[11]
Vasconcelos MJA. The induction of immunogenic cell death by photodynamic therapy in B16F10 cells in vitro is affected by the concentration of the photosensitizer. Photodiagn Photodyn Ther 2021; 102392.
[12]
Longo J, Muehlmann L, Almeida-Santos M, Azevedo R. Preventing metastasis by targeting lymphatic vessels with photodynamic therapy based on nanostructured photosensitizers. J Nanomed Nanotechnol 2015; 6(5): 1.
[13]
Lu J, Liu X, Liao YP, et al. Breast cancer chemo-immunotherapy through liposomal delivery of an immunogenic cell death stimulus plus interference in the IDO-1 pathway. ACS Nano 2018; 12(11): 11041-61.
[http://dx.doi.org/10.1021/acsnano.8b05189] [PMID: 30481959]
[14]
Ren X, Wang N, Zhou Y, et al. An injectable hydrogel using an immunomodulating gelator for amplified tumor immunotherapy by blocking the arginase pathway. Acta Biomater 2021; 124: 179-90.
[http://dx.doi.org/10.1016/j.actbio.2021.01.041] [PMID: 33524560]
[15]
Rodrigues MC, Vieira LG, Horst FH, et al. Photodynamic therapy mediated by aluminium-phthalocyanine nanoemulsion eliminates primary tumors and pulmonary metastases in a murine 4T1 breast adenocarcinoma model. J Photochem Photobiol B 2020; 204: 111808.
[http://dx.doi.org/10.1016/j.jphotobiol.2020.111808] [PMID: 32006892]
[16]
dos Santos Câmara AL, Nagel G, Tschiche HR, et al. Acid-sensitive lipidated doxorubicin prodrug entrapped in nanoemulsion impairs lung tumor metastasis in a breast cancer model. Nanomedicine 2017; 12(15): 1751-65.
[http://dx.doi.org/10.2217/nnm-2017-0091] [PMID: 28703043]
[17]
da Rocha MCO, da Silva PB, Radicchi MA, et al. Docetaxel-loaded solid lipid nanoparticles prevent tumor growth and lung metastasis of 4T1 murine mammary carcinoma cells. J Nanobiotechnol 2020; 18(1): 43.
[http://dx.doi.org/10.1186/s12951-020-00604-7] [PMID: 32164731]
[18]
Tseng JC, Kung AL. In vivo imaging of inflammatory phagocytes. Chem Biol 2012; 19(9): 1199-209.
[http://dx.doi.org/10.1016/j.chembiol.2012.08.007] [PMID: 22999887]
[19]
Santos DS, Morais JAV, Vanderlei ÍAC, et al. Oral delivery of fish oil in oil-in-water nanoemulsion: Development, colloidal stability and modulatory effect on in vivo inflammatory induction in mice. Biomed Pharmacother 2021; 133: 110980.
[http://dx.doi.org/10.1016/j.biopha.2020.110980] [PMID: 33249282]
[20]
Silva GS, Silva DA, Guilhelmelli F, et al. Zymosan enhances in vitro phagocyte function and the immune response of mice infected with Paracoccidioides brasiliensis. Med Mycol 2021; 59(8): 749-62.
[http://dx.doi.org/10.1093/mmy/myaa117] [PMID: 33550415]
[21]
Cardoso-Miguel MRD, Bürgel PH, de Castro RJA, et al. Dectin-2 is critical for phagocyte function and resistance to Paracoccidioides brasiliensis in mice. Med Mycol 2023; 61(11): myad117.
[http://dx.doi.org/10.1093/mmy/myad117] [PMID: 37960963]
[22]
Kaiser J. Taking a shot at cancer. Science 2022; 376(6589): 126-9.
[http://dx.doi.org/10.1126/science.abq3738] [PMID: 35389791]
[23]
Longo JPF, Muehlmann LA. Application of nanomedicine in immunotherapy: Recent advances and prospects. Pharmaceutics 2023; 15(7): 1910.
[http://dx.doi.org/10.3390/pharmaceutics15071910] [PMID: 37514096]
[24]
Yu R, Zhao F, Xu Z, Zhang G, Du B, Shu Q. Current status and future of cancer vaccines: A bibliographic study. Heliyon 2024; 10(2): e24404.
[http://dx.doi.org/10.1016/j.heliyon.2024.e24404] [PMID: 38293405]
[25]
Sayour E, Mendez-Gomez H, Mitchell D. Cancer vaccine immunotherapy with RNA-loaded liposomes. Int J Mol Sci 2018; 19(10): 2890.
[http://dx.doi.org/10.3390/ijms19102890] [PMID: 30249040]
[26]
Cardador CM, Muehlmann LA, Coelho CM, et al. Nucleotides entrapped in liposome nanovesicles as tools for therapeutic and diagnostic use in biomedical applications. Pharmaceutics 2023; 15(3): 873.
[http://dx.doi.org/10.3390/pharmaceutics15030873] [PMID: 36986734]
[27]
Capici S, Ammoni LC, Meli N, et al. Personalised therapies for metastatic triple-negative breast cancer: When target is not everything. Cancers 2022; 14(15): 3729.
[http://dx.doi.org/10.3390/cancers14153729] [PMID: 35954393]
[28]
Miranda-Vilela AL, Grisolia CK, Longo JPF, et al. Oil rich in carotenoids instead of vitamins C and E as a better option to reduce doxorubicin-induced damage to normal cells of Ehrlich tumor-bearing mice: Hematological, toxicological and histopathological evaluations. J Nutr Biochem 2014; 25(11): 1161-76.
[http://dx.doi.org/10.1016/j.jnutbio.2014.06.005] [PMID: 25127291]
[29]
Gustafson DL, Rastatter JC, Colombo T, Long ME. Doxorubicin pharmacokinetics: Macromolecule binding, metabolism, and excretion in the context of a physiologic model. J Pharm Sci 2002; 91(6): 1488-501.
[http://dx.doi.org/10.1002/jps.10161] [PMID: 12115848]
[30]
Longo JPF, Muehlmann LA, Miranda-Vilela AL, et al. Prevention of distant lung metastasis after photodynamic therapy application in a breast cancer tumor model. J Biomed Nanotechnol 2016; 12(4): 689-99.
[http://dx.doi.org/10.1166/jbn.2016.2208] [PMID: 27301195]
[31]
de Andrade LR, Tedesco AC, Primo FL, et al. Tumor cell death in orthotopic breast cancer model by NanoALA: A novel perspective on photodynamic therapy in oncology. Nanomedicine 2020; 15(10): 1019-36.
[http://dx.doi.org/10.2217/nnm-2019-0458] [PMID: 32264766]
[32]
Pulaski BA, Ostrand-Rosenberg S. Mouse 4T1 breast tumor model. Curr Protoc Immunol 2000; 39(1): 1-16.
[33]
Coelho JM, Camargo NS, Ganassin R, et al. Oily core/amphiphilic polymer shell nanocapsules change the intracellular fate of doxorubicin in breast cancer cells. J Mater Chem B Mater Biol Med 2019; 7(41): 6390-8.
[http://dx.doi.org/10.1039/C9TB00587K] [PMID: 31642844]
[34]
Ganassin R, Merker C, Rodrigues MC, et al. Nanocapsules for the co-delivery of selol and doxorubicin to breast adenocarcinoma 4T1 cells in vitro. Artif Cells Nanomed Biotechnol 2018; 46(8): 2002-12.
[PMID: 29179603]
[35]
Mussi SV, Silva RC, Oliveira MC, Lucci CM, Azevedo RB, Ferreira LAM. New approach to improve encapsulation and antitumor activity of doxorubicin loaded in solid lipid nanoparticles. Eur J Pharm Sci 2013; 48(1-2): 282-90.
[http://dx.doi.org/10.1016/j.ejps.2012.10.025] [PMID: 23178339]
[36]
Obeid M, Tesniere A, Ghiringhelli F, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 2007; 13(1): 54-61.
[http://dx.doi.org/10.1038/nm1523] [PMID: 17187072]
[37]
Pan H, Liu P, Zhao L, Pan Y, Mao M, Kroemer G, Eds. Immunogenic cell stress and death in the treatment of cancer. Seminars in Cell & Developmental Biology. Elsevier 2024.
[38]
Radicchi MA, de Oliveira JV, Mendes ACP, et al. Lipid nanoemulsion passive tumor accumulation dependence on tumor stage and anatomical location: A new mathematical model for in vivo imaging biodistribution studies. J Mater Chem B Mater Biol Med 2018; 6(44): 7306-16.
[http://dx.doi.org/10.1039/C8TB01577E] [PMID: 32254640]
[39]
Seong J, Kim K. Activation of cellular players in adaptive immunity via exogenous delivery of tumor cell lysates. Pharmaceutics 2022; 14(7): 1358.
[http://dx.doi.org/10.3390/pharmaceutics14071358] [PMID: 35890254]
[40]
de Oliveira JV, Oliveira da Rocha MC, de Sousa-Junior AA, Rodrigues MC, Farias GR, da Silva PB. Tumor vascular heterogeneity and the impact of subtumoral nanoemulsion biodistribution. Nanomedicine 2023; 17(27): 2073-88.
[41]
Ilkovitch D, Lopez DM. The liver is a site for tumor-induced myeloid-derived suppressor cell accumulation and immunosuppression. Cancer Res 2009; 69(13): 5514-21.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-4625] [PMID: 19549903]
[42]
Alizadeh D, Trad M, Hanke NT, et al. Doxorubicin eliminates myeloid-derived suppressor cells and enhances the efficacy of adoptive T-cell transfer in breast cancer. Cancer Res 2014; 74(1): 104-18.
[http://dx.doi.org/10.1158/0008-5472.CAN-13-1545] [PMID: 24197130]
[43]
Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin–cyclophosphamide chemotherapy. Cancer Immunol Immunother 2009; 58(1): 49-59.
[http://dx.doi.org/10.1007/s00262-008-0523-4] [PMID: 18446337]
[44]
Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009; 9(3): 162-74.
[http://dx.doi.org/10.1038/nri2506] [PMID: 19197294]
[45]
Lees JG, White D, Keating BA, et al. Oxaliplatin-induced haematological toxicity and splenomegaly in mice. PLoS One 2020; 15(9): e0238164.
[http://dx.doi.org/10.1371/journal.pone.0238164] [PMID: 32877416]
[46]
Parretta E, Cassese G, Barba P, Santoni A, Guardiola J, Di Rosa F. CD8 cell division maintaining cytotoxic memory occurs predominantly in the bone marrow. J Immunol 2005; 174(12): 7654-64.
[http://dx.doi.org/10.4049/jimmunol.174.12.7654] [PMID: 15944266]
[47]
Kim HJ, Cantor H. CD4 T-cell subsets and tumor immunity: The helpful and the not-so-helpful. Cancer Immunol Res 2014; 2(2): 91-8.
[http://dx.doi.org/10.1158/2326-6066.CIR-13-0216] [PMID: 24778273]
[48]
Oh DY, Fong L. Cytotoxic CD4+ T cells in cancer: Expanding the immune effector toolbox. Immunity 2021; 54(12): 2701-11.
[http://dx.doi.org/10.1016/j.immuni.2021.11.015] [PMID: 34910940]
[49]
Wang H, Najibi AJ, Sobral MC, et al. Biomaterial-based scaffold for in situ chemo-immunotherapy to treat poorly immunogenic tumors. Nat Commun 2020; 11(1): 5696.
[http://dx.doi.org/10.1038/s41467-020-19540-z] [PMID: 33173046]
[50]
Weigelt B, Peterse JL, van’t Veer LJ. Breast cancer metastasis: Markers and models. Nat Rev Cancer 2005; 5(8): 591-602.
[http://dx.doi.org/10.1038/nrc1670] [PMID: 16056258]
[51]
Longo JPF, de Melo LND, Mijan MC, et al. Photodynamic therapy mediated by liposomal chloroaluminum-phthalocyanine induces necrosis in oral cancer cells. J Biomater Tissue Eng 2013; 3(1): 148-56.
[http://dx.doi.org/10.1166/jbt.2013.1070]

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