casticin and Colonic-Neoplasms

We investigated the effect of casticin on apoptosis induced by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). We found that casticin potentiated TRAIL-induced apoptosis in human colon cancer cells. Casticin downregulated cell survival proteins including Bcl-xL, Bcl-2, survivin, XIAP and cFLIP, and induced death receptor 5 (DR5), but had no effect on DR4 and decoy receptors (DcR1 or DcR2). Deletion of DR5 by siRNA significantly reduced the apoptosis induced by TRAIL and casticin. In addition, casticin induced reactive oxygen species (ROS) generation in a dose-dependent manner. Collectively, the present study showed that casticin potentiates TRAIL-induced apoptosis through downregulation of cell survival proteins and induction of DR5 mediated by ROS.

Topics: Analysis of Variance; Apoptosis; Apoptosis Regulatory Proteins; bcl-X Protein; Colonic Neoplasms; Down-Regulation; Flavonoids; Gene Silencing; GPI-Linked Proteins; HCT116 Cells; HT29 Cells; Humans; Inhibitor of Apoptosis Proteins; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor, Member 10c; Survivin; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor Decoy Receptors; Up-Regulation; X-Linked Inhibitor of Apoptosis Protein

Bioassay-guided fractionation of the chloroform-soluble extract of the leaves of Vitex negundo led to the isolation of the known flavone vitexicarpin (1), which exhibited broad cytotoxicity in a human cancer cell line panel. In an attempt to increase the cytotoxic potency of 1, a series of acylation reactions was performed on this compound to obtain its methylated (2), acetylated (3), and six new acylated (4-9) derivatives. Compound 9, the previously unreported 5,3'-dihexanoyloxy-3,6,7,4'-tetramethoxyflavone, showed comparative cytotoxic potency to compound 1 and was selected for further evaluation. However, this compound was found to be inactive when evaluated in the in vivo hollow fiber assay with Lu1, KB, and LNCaP cells at the highest dose (40 mg/kg/body weight) tested, and in the in vivo P-388 leukemia model (135 mg/kg), using the ip administration route.

Topics: Acylation; Animals; Antineoplastic Agents, Phytogenic; Colonic Neoplasms; Disease Models, Animal; Drug Screening Assays, Antitumor; Flavonoids; Humans; Indonesia; Inhibitory Concentration 50; Leukemia P388; Lung Neoplasms; Male; Methylation; Mice; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Plant Leaves; Plants, Medicinal; Prostatic Neoplasms; Tumor Cells, Cultured; Vitex

A new labdane-type diterpene, vitexifolin A (1), a new clerodane-type diterpene, vitexifolin B (2), a new abeoabietane-type diterpene, vitexifolin C (3), and two new norlabdane-type diterpenes, vitexifolin D (4) and vitexifolin E (5), were isolated from the fruits of Vitex rotundifolia, along with a known halimane-type diterpene, vitetrifolin D (6), two known norlabdane-type diterpenes, trisnor-gamma-lactone (7) and iso-ambreinolide (8), and three known flavonoids, casticin (9), artemetin (10), and 5,3'-dihydroxy-6,7,4'-trimethoxyflavanone (11). Their chemical structures were determined on the basis of spectroscopic data. Casticin (9) exhibited considerable growth inhibitory activity against human lung cancer cells (PC-12) and human colon cancer cells (HCT116) using the MTT assay.

Topics: Animals; Antineoplastic Agents, Phytogenic; Chromatography, High Pressure Liquid; Cisplatin; Colonic Neoplasms; Diterpenes; Drug Screening Assays, Antitumor; Fruit; Humans; Lung Neoplasms; Molecular Conformation; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; PC12 Cells; Plants, Medicinal; Rats; Tumor Cells, Cultured; Verbenaceae