vs-5584 and Bone-Neoplasms

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.. To explore the anticancer effect and underlying mechanism of VS-5584 against the growth of human osteosarcoma cells.. 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.. 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.. Our findings validated that VS-5584 may be a promising anticancer agent with potential application in the chemotherapy and chemoprevention of human osteosarcoma.

Topics: Apoptosis; Biomarkers, Tumor; Bone Neoplasms; Cell Proliferation; G1 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Humans; MAP Kinase Signaling System; Morpholines; Osteosarcoma; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Purines; Tumor Cells, Cultured

Osteosarcoma is a highly invasive primary malignant bone tumor. PI3K/mTOR pathway plays a key role in tumor progression, and inhibition of PI3K/mTOR pathway represents a novel strategy in therapy of osteosarcoma. CCT128930 and VS5584 are both inhibitors of PI3K/mTOR, but the anticancer mechanism of CCT128930 or/and VS5584 against human osteosarcoma cells remains unclear. Herein, U2OS and MG63 human osteosarcoma cells were cultured, and the anticancer effects of CCT128930 alone and the combined effect of CCT128930 and VS5584 against human osteosarcoma cells were explored. The results showed that CCT128930 as PI3K/mTOR inhibitor effectively inhibited p-p70 and p-AKT expression and dose-dependently inhibited U2OS cells and MG63 human osteosarcoma cells growth. Further studies found that CCT128930 triggered significant G-1 phase arrest and apoptosis, as convinced by the dysfunction of p27, Cyclin B1, Cyclin D1 and Cdc2, and PARP cleavage and caspase-3 activation. Moreover, CCT128930 treatment obviously enhanced VS5584-induced growth inhibition and apoptosis in human osteosarcoma cells, followed by enhanced PARP cleavage and caspase-3 activation. Taken together, CCT128930 alone or combined treatment with CCT128930 and VS5584 both effectively inhibited human osteosarcoma cells growth by induction of G1-phase arrest and apoptosis through regulating PI3K/mTOR and MAPKs pathways.

Topics: Antineoplastic Agents; Apoptosis; Bone Neoplasms; Caspase 3; Cell Cycle Checkpoints; Cell Line, Tumor; Drug Synergism; G1 Phase; Humans; Morpholines; Osteosarcoma; Phosphatidylinositol 3-Kinases; Purines; Pyrimidines; Pyrroles; TOR Serine-Threonine Kinases