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...

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Autores principales:	Rameswari Chilamakuri, Danielle C. Rouse, Yang Yu, Abbas S. Kabir, Aaron Muth, Jianhua Yang, Jeffery M. Lipton, Saurabh Agarwal
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	PDK1 BX-795 Neuroblastoma Pediatric cancer AKT pathway Drug repurposing Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/876fff3a8ac947789e0b637412ec2d83
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spelling	oai:doaj.org-article:876fff3a8ac947789e0b637412ec2d832021-11-24T04:27:44ZBX-795 inhibits neuroblastoma growth and enhances sensitivity towards chemotherapy1936-523310.1016/j.tranon.2021.101272https://doaj.org/article/876fff3a8ac947789e0b637412ec2d832022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S1936523321002631https://doaj.org/toc/1936-5233High-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.Rameswari ChilamakuriDanielle C. RouseYang YuAbbas S. KabirAaron MuthJianhua YangJeffery M. LiptonSaurabh AgarwalElsevierarticlePDK1BX-795NeuroblastomaPediatric cancerAKT pathwayDrug repurposingNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENTranslational Oncology, Vol 15, Iss 1, Pp 101272- (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	PDK1 BX-795 Neuroblastoma Pediatric cancer AKT pathway Drug repurposing Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	PDK1 BX-795 Neuroblastoma Pediatric cancer AKT pathway Drug repurposing Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Rameswari Chilamakuri Danielle C. Rouse Yang Yu Abbas S. Kabir Aaron Muth Jianhua Yang Jeffery M. Lipton Saurabh Agarwal BX-795 inhibits neuroblastoma growth and enhances sensitivity towards chemotherapy
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	article
author	Rameswari Chilamakuri Danielle C. Rouse Yang Yu Abbas S. Kabir Aaron Muth Jianhua Yang Jeffery M. Lipton Saurabh Agarwal
author_facet	Rameswari Chilamakuri Danielle C. Rouse Yang Yu Abbas S. Kabir Aaron Muth Jianhua Yang Jeffery M. Lipton Saurabh Agarwal
author_sort	Rameswari Chilamakuri
title	BX-795 inhibits neuroblastoma growth and enhances sensitivity towards chemotherapy
title_short	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_sort	bx-795 inhibits neuroblastoma growth and enhances sensitivity towards chemotherapy
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/876fff3a8ac947789e0b637412ec2d83
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BX-795 inhibits neuroblastoma growth and enhances sensitivity towards chemotherapy

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