VS-5584 Inhibits Human Osteosarcoma Cells Growth by Induction of G1- phase Arrest through Regulating PI3K/mTOR and MAPK Pathways

Curr Cancer Drug Targets. 2020;20(8):616-623. doi: 10.2174/1568009620666200414150353.


Background: Activation of the PI3K/mTOR signaling pathway plays a key role in the progression of human osteosarcoma. Studies have confirmed that VS-5584 was a novel inhibitor of the PI3K/mTOR pathway, and displayed potential anticancer activity.

Objective: To explore the anticancer effect and underlying mechanism of VS-5584 against the growth of human osteosarcoma cells.

Methods: U2OS and MG-63 human osteosarcoma cells were cultured and the cytotoxicity, cell apoptosis in VS-5584-treated cells were explored by the CCK8 assay, flow cytometric analysis and western blot. Cell migration and tube formation were also employed to examine the anticancer potential.

Results: The results showed that VS-5584 treatment dose-dependently inhibited the growth of U2OS and MG-63 cells by induction of G1-phase arrest through regulating p21, p27, Cyclin B1 and Cdc2. Further investigation revealed that VS-5584 treatment effectively inhibited the PI3K/mTOR signaling pathway and triggered MAPK phosphorylation. Moreover, VS-5584 treatment dramatically suppressed cell migration and tube formation of HUVECs, followed by the down-regulation of HIF-1α and VEGF.

Conclusion: Our findings validated that VS-5584 may be a promising anticancer agent with potential application in the chemotherapy and chemoprevention of human osteosarcoma.

Keywords: G1-phase arrest; MAPK; PI3K/mTOR; VS-5584; cytotoxicity; osteosarcoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Bone Neoplasms / drug therapy
  • Bone Neoplasms / genetics
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology
  • Cell Proliferation
  • G1 Phase Cell Cycle Checkpoints / drug effects*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • MAP Kinase Signaling System / drug effects*
  • Morpholines / pharmacology*
  • Osteosarcoma / drug therapy*
  • Osteosarcoma / genetics
  • Osteosarcoma / metabolism
  • Osteosarcoma / pathology
  • Phosphatidylinositol 3-Kinase / chemistry*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Purines / pharmacology*
  • Tumor Cells, Cultured


  • Biomarkers, Tumor
  • Morpholines
  • Purines
  • VS-5584
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt