Cargando…
Endogenous Akt Activity Promotes Virus Entry and Predicts Efficacy of Novel Chimeric Orthopoxvirus in Triple-Negative Breast Cancer
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high recurrence rate and poor prognosis. Here, we describe a novel, chimeric orthopoxvirus (CF33) that efficiently kills TNBC. Cytotoxicity was assayed in vitro in four TNBC cell lines. Viral replication was examined...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026447/ https://www.ncbi.nlm.nih.gov/pubmed/29988465 http://dx.doi.org/10.1016/j.omto.2018.04.001 |
_version_ | 1783336444682567680 |
---|---|
author | Choi, Audrey H. O’Leary, Michael P. Lu, Jianming Kim, Sang-In Fong, Yuman Chen, Nanhai G. |
author_facet | Choi, Audrey H. O’Leary, Michael P. Lu, Jianming Kim, Sang-In Fong, Yuman Chen, Nanhai G. |
author_sort | Choi, Audrey H. |
collection | PubMed |
description | Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high recurrence rate and poor prognosis. Here, we describe a novel, chimeric orthopoxvirus (CF33) that efficiently kills TNBC. Cytotoxicity was assayed in vitro in four TNBC cell lines. Viral replication was examined through standard plaque assay. Two orthotopic TNBC xenograft models were generated in athymic nude mice and were injected with CF33 intratumorally. CF33 was effective in vitro with potent cytotoxicity and efficient intracellular replication observed in TNBC lines with phosphatidylinositol 3-kinase (PI3K)/Akt pathway mutations that resulted in endogenous phospho-Akt (p-Akt) activity (BT549, Hs578T, and MDA-MB-468). Relative resistance to CF33 by wild-type PI3K/Akt pathway cell line MDA-MB-231 was overcome using higher MOI. The virus was effective in vivo with significant tumor size reduction in both xenograft models. Mechanistically, CF33 appears to share similar properties to vaccinia virus with respect to Akt-mediated and low-pH-mediated viral entry. In summary, CF33 demonstrated potent antitumoral effect in vitro and in vivo, with the most potent effect predicted by the presence of endogenous Akt activity in the TNBC cell line. Further investigation of its mechanism of action as well as genetic modifications to enhance its natural viral tropism are warranted for preclinical development. |
format | Online Article Text |
id | pubmed-6026447 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-60264472018-07-09 Endogenous Akt Activity Promotes Virus Entry and Predicts Efficacy of Novel Chimeric Orthopoxvirus in Triple-Negative Breast Cancer Choi, Audrey H. O’Leary, Michael P. Lu, Jianming Kim, Sang-In Fong, Yuman Chen, Nanhai G. Mol Ther Oncolytics Article Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high recurrence rate and poor prognosis. Here, we describe a novel, chimeric orthopoxvirus (CF33) that efficiently kills TNBC. Cytotoxicity was assayed in vitro in four TNBC cell lines. Viral replication was examined through standard plaque assay. Two orthotopic TNBC xenograft models were generated in athymic nude mice and were injected with CF33 intratumorally. CF33 was effective in vitro with potent cytotoxicity and efficient intracellular replication observed in TNBC lines with phosphatidylinositol 3-kinase (PI3K)/Akt pathway mutations that resulted in endogenous phospho-Akt (p-Akt) activity (BT549, Hs578T, and MDA-MB-468). Relative resistance to CF33 by wild-type PI3K/Akt pathway cell line MDA-MB-231 was overcome using higher MOI. The virus was effective in vivo with significant tumor size reduction in both xenograft models. Mechanistically, CF33 appears to share similar properties to vaccinia virus with respect to Akt-mediated and low-pH-mediated viral entry. In summary, CF33 demonstrated potent antitumoral effect in vitro and in vivo, with the most potent effect predicted by the presence of endogenous Akt activity in the TNBC cell line. Further investigation of its mechanism of action as well as genetic modifications to enhance its natural viral tropism are warranted for preclinical development. American Society of Gene & Cell Therapy 2018-04-05 /pmc/articles/PMC6026447/ /pubmed/29988465 http://dx.doi.org/10.1016/j.omto.2018.04.001 Text en © 2018 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Choi, Audrey H. O’Leary, Michael P. Lu, Jianming Kim, Sang-In Fong, Yuman Chen, Nanhai G. Endogenous Akt Activity Promotes Virus Entry and Predicts Efficacy of Novel Chimeric Orthopoxvirus in Triple-Negative Breast Cancer |
title | Endogenous Akt Activity Promotes Virus Entry and Predicts Efficacy of Novel Chimeric Orthopoxvirus in Triple-Negative Breast Cancer |
title_full | Endogenous Akt Activity Promotes Virus Entry and Predicts Efficacy of Novel Chimeric Orthopoxvirus in Triple-Negative Breast Cancer |
title_fullStr | Endogenous Akt Activity Promotes Virus Entry and Predicts Efficacy of Novel Chimeric Orthopoxvirus in Triple-Negative Breast Cancer |
title_full_unstemmed | Endogenous Akt Activity Promotes Virus Entry and Predicts Efficacy of Novel Chimeric Orthopoxvirus in Triple-Negative Breast Cancer |
title_short | Endogenous Akt Activity Promotes Virus Entry and Predicts Efficacy of Novel Chimeric Orthopoxvirus in Triple-Negative Breast Cancer |
title_sort | endogenous akt activity promotes virus entry and predicts efficacy of novel chimeric orthopoxvirus in triple-negative breast cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026447/ https://www.ncbi.nlm.nih.gov/pubmed/29988465 http://dx.doi.org/10.1016/j.omto.2018.04.001 |
work_keys_str_mv | AT choiaudreyh endogenousaktactivitypromotesvirusentryandpredictsefficacyofnovelchimericorthopoxvirusintriplenegativebreastcancer AT olearymichaelp endogenousaktactivitypromotesvirusentryandpredictsefficacyofnovelchimericorthopoxvirusintriplenegativebreastcancer AT lujianming endogenousaktactivitypromotesvirusentryandpredictsefficacyofnovelchimericorthopoxvirusintriplenegativebreastcancer AT kimsangin endogenousaktactivitypromotesvirusentryandpredictsefficacyofnovelchimericorthopoxvirusintriplenegativebreastcancer AT fongyuman endogenousaktactivitypromotesvirusentryandpredictsefficacyofnovelchimericorthopoxvirusintriplenegativebreastcancer AT chennanhaig endogenousaktactivitypromotesvirusentryandpredictsefficacyofnovelchimericorthopoxvirusintriplenegativebreastcancer |