BX-795 inhibits neuroblastoma growth and enhances sensitivity towards chemotherapy
Rameswari Chilamakuri1, Danielle C Rouse1, Yang Yu2
1Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY, USA.
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.
Insights
High-risk neuroblastoma (NB) growth is driven by AKT signaling. Repurposed antiviral drug BX-795 inhibits this pathway, showing promise alone and in combination therapies for NB treatment.
Area of Science:
- Pediatric Oncology
- Cancer Cell Signaling
- Drug Repurposing
Background:
- High-risk neuroblastoma (NB) presents significant challenges in pediatric oncology, characterized by relapse, metastasis, drug resistance, and treatment toxicity.
- Increased expression of AKT1 and AKT2 genes correlates with advanced NB stage and predicts poor patient survival.
- The AKT signaling pathway is a critical oncogenic driver in NB and other cancers.
Purpose of the Study:
- To investigate the therapeutic potential of repurposing the antiviral inhibitor BX-795, which targets PDK1, an upstream activator of the AKT pathway, for high-risk neuroblastoma.
- To evaluate the efficacy of BX-795 as a monotherapy and in combination with existing chemotherapies for neuroblastoma.
Main Methods:
- Analysis of a 1235-patient primary NB dataset to correlate AKT1/AKT2 gene expression with clinical outcomes.
- In vitro assessment of BX-795's effects on NB cell proliferation, colony formation, apoptosis, and cell cycle progression.
- In vivo evaluation of BX-795 in a neuroblastoma spheroid tumor model and assessment of combination therapies with doxorubicin or crizotinib.
Main Results:
- BX-795 demonstrated potent, dose-dependent inhibition of NB cell proliferation and colony growth.
- BX-795 significantly induced apoptosis and arrested the cell cycle at mitosis in NB cells.
- Combination therapy of BX-795 with doxorubicin or crizotinib resulted in synergistic and significant inhibition of NB growth compared to monotherapy.
Conclusions:
- BX-795 effectively inhibits the AKT signaling pathway, leading to reduced neuroblastoma growth.
- The combination of BX-795 with current therapeutic agents represents a promising and clinically feasible strategy for treating high-risk neuroblastoma.
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