cannogenin-thevetoside and Neoplasms

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Humans; Lipogenesis; Neoplasms; Oxidative Stress; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Protein Serine-Threonine Kinases; Ribulosephosphates; Signal Transduction

To investigate the cytotoxic effect of Peruvoside and mechanism of action in human cancers.. Cell viability was measured by MTT assay and the cell cycle arrest was identified by FACS. Real-time qPCR and western blotting studies were performed to identify important gene and protein expressions in the different pathways leading to apoptosis. Immunofluorescence was performed to understand protein localization and molecular docking studies were performed to identify protein-ligand interactions.. Peruvoside showed significant anti-proliferative activities against human breast, lung, and liver cancer cells in dose-dependent manner. The anti-cancer mechanism was further confirmed by DNA damage and cell cycle arrest at the G0/G1 phase. Dysregulation of Wnt/β-catenin signaling with Peruvoside treatment resulted in inhibition of cyclin D1 and c-Myc also observed in this study. Furthermore, we identified that Peruvoside can inhibit autophagy by PI3K/AKT/mTOR signaling and through downregulating MEK1. Moreover, Peruvoside has the ability to modulate the expressions of key proteins from the cell cycle, MAPK, NF-kB, and JAK-STAT signaling. In silico studies revealed that Peruvoside has the ability to interact with crucial proteins from different biochemical signaling pathways.. Our results demonstrated that Peruvoside has the ability to inhibit cancer cell proliferation by modulating the expression of various key proteins involved in cell cycle arrest, apoptosis, and autophagic cell death. Clinical data generated from the present study might provide a novel impetus for targeting several human cancers. Conclusively, our findings suggest that the Peruvoside possesses a broad spectrum of anticancer activity in breast, lung, and liver cancers, which provides an impetus for further investigation of the anticancer potentiality of this biomolecule.

Topics: Apoptosis; Autophagy; beta Catenin; Cardenolides; Cardiotonic Agents; Cell Cycle; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Mitogen-Activated Protein Kinases; Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; Wnt Proteins