genistein and Neoplasms

Inhibitors of the ubiquitin-proteasome system (UPS) have been the object of research interests for many years because of their potential as anti-cancer agents. Research in this field is aimed at improving the specificity and safety of known proteasome inhibitors. Unfortunately, in vitro conditions do not reflect the processes taking place in the human body. Recent reports indicate that the components of human plasma affect the course of many signaling pathways, proteasome activity and the effectiveness of synthetic cytostatic drugs. Therefore, it is believed that the key issue is to determine the effects of components of the human diet, including effects of chemically active polyphenols on the ubiquitin-proteasome system activity in both physiological and pathological (cancerous) states. The following article summarizes the current knowledge on the direct and indirect synergistic and antagonistic effects between polyphenolic compounds present in the human diet and the efficiency of protein degradation via the UPS.

Topics: Animals; Diet; Humans; Neoplasms; Phenols; Polyphenols; Proteasome Endopeptidase Complex; Ubiquitin

DNA methylation is a mammalian epigenetic mark that is involved in defining where and when genes are expressed, both in normal cells and in the context of diseases. Like other epigenetic marks, it is reversible and can be modulated by chemical agents. Because it plays an important role in cancer by silencing certain genes, such as tumor suppressor genes, and by reactivating other regions, such as repeated elements, it is a promising therapeutic target. Two compounds are already approved to treat hematological cancers. Many efforts have been carried out to discover new molecules that are able to efficiently inhibit DNA methylation in cancer cells. We will briefly overview the foremost of these efforts by focusing on what we have learned to this point on non-nucleoside inhibitors and on what we consider to be the features of an ideal inhibitor.

Topics: Animals; Antineoplastic Agents; DNA Methylation; DNA Modification Methylases; Drug Discovery; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Models, Molecular; Molecular Targeted Therapy; Neoplasms; Nucleosides

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

Natural polyphenols are organic chemicals which contain phenol units in their structures. They show antitumor properties. However, a key problem is their short half-life and low bioavailability under in vivo conditions. Still, definitively demonstrating the human benefits of isolated polyphenolic compounds (alone or in combination) using modern scientific methodology has proved challenging. The most common discrepancy between experimental and clinical observations is the use of nonphysiologically relevant concentrations of polyphenols in mechanistic studies. Thus, it remains highly controversial how applicable underlying mechanisms are with bioavailable concentrations and biological half-life. The present Perspective analyses proposed antitumor mechanisms, in vivo reported antitumor effects, and possible mechanisms that may explain discrepancies between bioavailability and bioefficacy. Polyphenol metabolism and possible toxic side effects are also considered. Our main conclusion emphasizes that these natural molecules (and their chemical derivatives) indeed can be very useful, not only as cancer chemopreventive agents but also in oncotherapy.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Biological Availability; Drug Delivery Systems; Humans; Neoplasms; Phytochemicals; Polyphenols

A series of new flavanone derivatives of farrerol was synthesized by a convenient method. The in vitro anti-tumor activity of these compounds was evaluated against human Bel-7402, HL-60, BGC-823 and KB cell lines, the protein tyrosine kinase (PTK) inhibitor activity was also tested. Their cytoprotective activity was tested using hydrogen peroxide (H2O2)-induced injury in human umbilical vein endothelial cells. Their in vitro anti-atherosclerosis activity was tested on vascular smooth muscle cells by the MTT method using tetrandrine as a positive contrast drug. The structures of all compounds synthesized were confirmed by 1H, 13C NMR and ESI-MS. Most of the compounds exhibited good pharmacological activity and the preliminary structure-activity relationships were described.

Topics: Antineoplastic Agents; Atherosclerosis; Cell Line; Cell Line, Tumor; Cell Proliferation; Cytoprotection; Endothelial Cells; Flavanones; Humans; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neoplasms; Protein-Tyrosine Kinases; Structure-Activity Relationship

The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.

Topics: Animals; Cell Survival; Cells, Cultured; Mice; Molecular Structure; Neoplasms; Neurons; Pharmaceutical Preparations; Sensitivity and Specificity; Stem Cells