4-methylesculetin and Neoplasms

Coumarins are fused benzene and pyrone ring systems which prompt biological investigation to assess their potential therapeutic significance. It possesses immeasurable anticancer potential with minimum side effects depending on the substitutions on the basic nucleus. Coumarins have a tremendous ability to regulate diverse range of cellular pathways that can be explored for selective anticancer activity. This is the first standalone review that emphasis on the assorted retrosynthetic approaches, important targets for molecularly targeted cancer therapy and structure activity relationship studies that highlight the chemical groups responsible for evoking the anticancer potential of coumarin derivatives reported from 2011 to 2014.

Topics: Antineoplastic Agents; Cell Proliferation; Coumarins; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Neoplasms; Protein Kinase Inhibitors; Protein Kinases; Structure-Activity Relationship

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