ellagic-acid and Neoplasms

Human cells possess tightly controlled mechanisms to rescue DNA replication following DNA damage caused by environmental and endogenous carcinogens using a set of low-fidelity translesion synthesis (TLS) DNA polymerases. These polymerases can copy over replication blocking DNA lesions while temporarily leaving them unrepaired, preventing cell death at the expense of increasing mutation rates and contributing to the onset and progression of cancer. In addition, TLS has been implicated as a major cellular mechanism promoting acquired resistance to genotoxic chemotherapy. Owing to its central role in mutagenesis and cell survival after DNA damage, inhibition of the TLS pathway has emerged as a potential target for the development of anticancer agents. This review will recap our current understanding of the structure and regulation of DNA polymerase complexes that mediate TLS and describe how this knowledge is beginning to translate into the development of small molecule TLS inhibitors.

Topics: Animals; Antineoplastic Agents; Cell Survival; DNA Damage; DNA-Directed DNA Polymerase; Dose-Response Relationship, Drug; Humans; Molecular Structure; Neoplasms; Small Molecule Libraries; 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

A comprehensive herbal medicine information system for cancer (CHMIS-C) has been developed. The current version of the database integrates information on more than 200 anticancer herbal recipes that have been used for the treatment of different types of cancer in clinic, 900 individual ingredients, and 8500 small organic molecules isolated from herbal medicines. Furthermore, subsidiary databases of literature references and molecular targets have been constructed. A number of web-based searching tools have been developed and integrated into the information system for efficient data mining. The compounds in the database have been linked to the corresponding entries in the National Cancer Institute's database, and to a database of drugs approved by the U.S. Food and Drug Administration. This paper provides a description of the individual subsidiary databases, integration of the entire database, and data mining tools. We demonstrate that this comprehensive information system may be used as an effective informatics tool for anticancer drug discovery.

Topics: Antineoplastic Agents, Phytogenic; Databases, Factual; Internet; National Institutes of Health (U.S.); Neoplasms; Phytotherapy; Plant Preparations; United States; United States Food and Drug Administration