1. Academic Validation
  2. BX-795 inhibits neuroblastoma growth and enhances sensitivity towards chemotherapy

BX-795 inhibits neuroblastoma growth and enhances sensitivity towards chemotherapy

  • Transl Oncol. 2022 Jan;15(1):101272. doi: 10.1016/j.tranon.2021.101272.
Rameswari Chilamakuri 1 Danielle C Rouse 1 Yang Yu 2 Abbas S Kabir 1 Aaron Muth 1 Jianhua Yang 2 Jeffery M Lipton 3 Saurabh Agarwal 4
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY, USA.
  • 2 Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
  • 3 Institute of Molecular Medicine, Feinstein Institutes for Medical Research, New York, NY, USA.
  • 4 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY, USA. Electronic address: agarwals@stjohns.edu.
Abstract

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.

Keywords

AKT pathway; BX-795; Drug repurposing; Drug synergy; Neuroblastoma; PDK1; Pediatric cancer.

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