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BX-795 inhibits neuroblastoma growth and enhances sensitivity towards chemotherapy
High-risk neuroblastoma (NB) represents a major clinical challenge in pediatric oncology due to relapse of metastatic, drug-resistant disease, and treatment-related toxicities. An analysis of 1235 primary NB patient dataset revealed significant increase in AKT1 and AKT2 gene expression with cancer s...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Neoplasia Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8626612/ https://www.ncbi.nlm.nih.gov/pubmed/34823094 http://dx.doi.org/10.1016/j.tranon.2021.101272 |
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author | Chilamakuri, Rameswari Rouse, Danielle C. Yu, Yang Kabir, Abbas S. Muth, Aaron Yang, Jianhua Lipton, Jeffery M. Agarwal, Saurabh |
author_facet | Chilamakuri, Rameswari Rouse, Danielle C. Yu, Yang Kabir, Abbas S. Muth, Aaron Yang, Jianhua Lipton, Jeffery M. Agarwal, Saurabh |
author_sort | Chilamakuri, Rameswari |
collection | PubMed |
description | High-risk neuroblastoma (NB) represents a major clinical challenge in pediatric oncology due to relapse of metastatic, drug-resistant disease, and treatment-related toxicities. An analysis of 1235 primary NB patient dataset revealed significant increase in AKT1 and AKT2 gene expression with cancer stage progression. Additionally, Both AKT1 and AKT2 expression inversely correlate with poor overall survival of NB patients. AKT1 and AKT2 genes code for AKT that drive a major oncogenic cell signaling pathway known in many cancers, including NB. To inhibit AKT pathway, we repurposed an antiviral inhibitor BX-795 that inhibits PDK1, an upstream activator of AKT. BX-795 potently inhibits NB cell proliferation and colony growth in a dose-dependent manner. BX-795 significantly enhances apoptosis and blocks cell cycle progression at mitosis phase in NB. Additionally, BX-795 potently inhibits tumor formation and growth in a NB spheroid tumor model. We further tested dual therapeutic approaches by combining BX-795 with either doxorubicin or crizotinib and found synergistic and significant inhibition of NB growth, in contrast to either drug alone. Overall, our data demonstrate that BX-795 inhibits AKT pathway to inhibit NB growth, and combining BX-795 with current therapies is an effective and clinically tractable therapeutic approach for NB. |
format | Online Article Text |
id | pubmed-8626612 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Neoplasia Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-86266122021-12-03 BX-795 inhibits neuroblastoma growth and enhances sensitivity towards chemotherapy Chilamakuri, Rameswari Rouse, Danielle C. Yu, Yang Kabir, Abbas S. Muth, Aaron Yang, Jianhua Lipton, Jeffery M. Agarwal, Saurabh Transl Oncol Original Research High-risk neuroblastoma (NB) represents a major clinical challenge in pediatric oncology due to relapse of metastatic, drug-resistant disease, and treatment-related toxicities. An analysis of 1235 primary NB patient dataset revealed significant increase in AKT1 and AKT2 gene expression with cancer stage progression. Additionally, Both AKT1 and AKT2 expression inversely correlate with poor overall survival of NB patients. AKT1 and AKT2 genes code for AKT that drive a major oncogenic cell signaling pathway known in many cancers, including NB. To inhibit AKT pathway, we repurposed an antiviral inhibitor BX-795 that inhibits PDK1, an upstream activator of AKT. BX-795 potently inhibits NB cell proliferation and colony growth in a dose-dependent manner. BX-795 significantly enhances apoptosis and blocks cell cycle progression at mitosis phase in NB. Additionally, BX-795 potently inhibits tumor formation and growth in a NB spheroid tumor model. We further tested dual therapeutic approaches by combining BX-795 with either doxorubicin or crizotinib and found synergistic and significant inhibition of NB growth, in contrast to either drug alone. Overall, our data demonstrate that BX-795 inhibits AKT pathway to inhibit NB growth, and combining BX-795 with current therapies is an effective and clinically tractable therapeutic approach for NB. Neoplasia Press 2021-11-22 /pmc/articles/PMC8626612/ /pubmed/34823094 http://dx.doi.org/10.1016/j.tranon.2021.101272 Text en © 2021 The Authors https://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 | Original Research Chilamakuri, Rameswari Rouse, Danielle C. Yu, Yang Kabir, Abbas S. Muth, Aaron Yang, Jianhua Lipton, Jeffery M. Agarwal, Saurabh BX-795 inhibits neuroblastoma growth and enhances sensitivity towards chemotherapy |
title | BX-795 inhibits neuroblastoma growth and enhances sensitivity towards chemotherapy |
title_full | BX-795 inhibits neuroblastoma growth and enhances sensitivity towards chemotherapy |
title_fullStr | BX-795 inhibits neuroblastoma growth and enhances sensitivity towards chemotherapy |
title_full_unstemmed | BX-795 inhibits neuroblastoma growth and enhances sensitivity towards chemotherapy |
title_short | BX-795 inhibits neuroblastoma growth and enhances sensitivity towards chemotherapy |
title_sort | bx-795 inhibits neuroblastoma growth and enhances sensitivity towards chemotherapy |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8626612/ https://www.ncbi.nlm.nih.gov/pubmed/34823094 http://dx.doi.org/10.1016/j.tranon.2021.101272 |
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