scutellarein and Neoplasms

Flavones have antioxidant, anti-proliferative, anti-tumor, anti-microbial, estrogenic, acetyl cholinesterase, anti-inflammatory activities and are also used in cancer, cardiovascular disease, neurodegenerative disorders, etc. Also, flavonoids are found to have an effect on several mammalian enzymes like protein kinases that regulate multiple cell signaling pathways and alterations in multiple cellular signaling pathways are frequently found in many diseases. Flavones have been an indispensable anchor for the development of new therapeutic agents. The majority of metabolic diseases are speculated to originate from oxidative stress, and it is therefore significant that recent studies have shown the positive effect of flavones on diseases related to oxidative stress. Due to the wide range of biological activities of flavones, their structure-activity relationships have generated interest among medicinal chemists. The outstanding development of flavones derivatives in diverse diseases in very short span of time proves its magnitude for medicinal chemistry research. The present review gives detail about the structural requirement of flavone derivatives for various pharmacological activities. This information may provide an opportunity to scientists of medicinal chemistry discipline to design selective, optimize as well as poly-functional flavone derivatives for the treatment of multi-factorial diseases.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Cardiovascular Diseases; Chemistry, Pharmaceutical; Flavones; Humans; Neoplasms; Neurodegenerative Diseases; Protein Kinase Inhibitors; Protein Kinases; Structure-Activity Relationship

To explore antitumor agents with potent efficacy and low toxicity, scutellarein derivatives with benzoic acid mustard (10a-c, 11a-c and 13a-c) were designed and synthesized. The antiproliferative activities of the target derivatives against A549, MCF-7 and Bel-7402 cancer cell lines were tested. Compound 10a showed the strongest potency with an IC

Topics: Antineoplastic Agents; Apigenin; Apoptosis; Apoptosis Regulatory Proteins; Benzoic Acid; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Neoplasms; Signal Transduction

The ubiquitin-proteasome pathway plays an important role in regulating apoptosis and the cell cycle. Recently, proteasome inhibitors have been shown to have antitumor effects and have been used in anticancer therapy for several cancers such as multiple myeloma. Although some flavones, such as apigenin, chrysin and luteolin, have a specific role in the inhibition of proteasome activity and induced apoptosis in some reports, these findings did not address all flavone types. To further investigate the proteasome-inhibitory mechanism of flavonoids, we examined the inhibitory activity of 5,6,7-trihydroxyflavone, baicalein and 5,6,7,4'-tetrahydroxyflavone, scutellarein on extracted proteasomes from mice and cancer cells. Unlike the other flavones, baicalein and scutellarein did not inhibit proteasome activity or accumulate levels of ubiquitinated proteins. These results indicate that flavones with hydroxy groups at positions 5, 6 and 7 of the A-ring lack the anti-proteasome function.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Apigenin; Apoptosis; Flavanones; Flavones; HCT116 Cells; Humans; Jurkat Cells; Molecular Structure; Neoplasms; Phytotherapy; Plant Extracts; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Rabbits; Structure-Activity Relationship

Bezielle is a botanical extract that has selective anti-tumor activity, and has shown a promising efficacy in the early phases of clinical testing. Bezielle inhibits mitochondrial respiration and induces reactive oxygen species (ROS) in mitochondria of tumor cells but not in non-transformed cells. The generation of high ROS in tumor cells leads to heavy DNA damage and hyper-activation of PARP, followed by the inhibition of glycolysis. Bezielle therefore belongs to a group of drugs that target tumor cell mitochondria, but its cytotoxicity involves inhibition of both cellular energy producing pathways. We found that the cytotoxic activity of the Bezielle extract in vitro co-purified with a defined fraction containing multiple flavonoids. We have isolated several of these Bezielle flavonoids, and examined their possible roles in the selective anti-tumor cytotoxicity of Bezielle. Our results support the hypothesis that a major Scutellaria flavonoid, scutellarein, possesses many if not all of the biologically relevant properties of the total extract. Like Bezielle, scutellarein induced increasing levels of ROS of mitochondrial origin, progressive DNA damage, protein oxidation, depletion of reduced glutathione and ATP, and suppression of both OXPHOS and glycolysis. Like Bezielle, scutellarein was selectively cytotoxic towards cancer cells. Carthamidin, a flavonone found in Bezielle, also induced DNA damage and oxidative cell death. Two well known plant flavonoids, apigenin and luteolin, had limited and not selective cytotoxicity that did not depend on their pro-oxidant activities. We also provide evidence that the cytotoxicity of scutellarein was increased when other Bezielle flavonoids, not necessarily highly cytotoxic or selective on their own, were present. This indicates that the activity of total Bezielle extract might depend on a combination of several different compounds present within it.

Topics: Antineoplastic Agents; Apigenin; Cell Line; Cell Line, Tumor; Cell Survival; Comet Assay; DNA Damage; Energy Metabolism; Flavonoids; Glutathione; Humans; Membrane Potential, Mitochondrial; Mitochondria; Molecular Structure; Neoplasms; Oxidation-Reduction; Plant Extracts; Reactive Oxygen Species; Scutellaria; Time Factors