VS-5584, a PI3K/mTOR dual inhibitor, exerts antitumor effects on neuroblastomas in vitro and in vivo

• Published in: Journal of pediatric surgery Vol. 56; no. 8; pp. 1441 - 1448
• Main Authors: Chen, Yun, Tsai, Huang-Wen, Tsai, Ya-Hui, Tseng, Sheng-Hong
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.08.2021
• Subjects: Antitumor effects; Neuroblastoma; PI3K/mTOR dual inhibitor; VS-5584; VS-5584; Neuroblastoma; PI3K/mTOR dual inhibitor; Antitumor effects
• ISSN: 0022-3468; 1531-5037
• DOI: 10.1016/j.jpedsurg.2020.10.033

•VS-5584 is an orally administered PI3K/mTOR dual inhibitor.•VS-5584 inhibits proliferation, inducing G0/G1 cell cycle arrest in neuroblastomas.•VS-5584 blocks the PI3K/mTOR pathway in neuroblastoma cells.•VS-5584 exerts antitumor effects on neuroblastomas both in vitro and in vivo. The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is closely related to oncogenesis. PI3K/mTOR inhibitors are considered capable of counteracting the feedback mechanisms within the pathway. In this study, we investigated the antitumor effects of VS-5584, an orally administered PI3K/mTOR dual inhibitor, on neuroblastomas. The effects of VS-5584 on proliferation, cell cycle distribution, and related signaling molecules were examined in neuroblastoma cells using the (3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide)-based colorimetric assay, flow cytometry, and western blotting, respectively. Nude mice were subcutaneously inoculated with human neuroblastoma cells, followed by VS-5584 treatment for two weeks. Tumor growth was tracked and tumor tissues were subjected to immunohistochemical investigations. In neuroblastoma cells, VS-5584 significantly inhibited proliferation and induced G0/G1 cell cycle arrest. Additionally, VS-5584 decreased the expression of phospho-S6 kinase 1 (p-S6K1), p-retinoblastoma protein, p-cyclin-dependent kinase 2, and cyclin E1, and increased the expression of p21 and p27 in neuroblastoma cells. In mice, VS-5584 significantly suppressed tumor growth in neuroblastomas and downregulated the expression of p-mTOR and p-S6K1 in tumor tissues. VS-5584 blocks the PI3K/mTOR pathway, induces a G0/G1 cell cycle arrest, and exerts antitumor effects on neuroblastomas both in vitro and in vivo.