cardamonin and Colonic-Neoplasms

Cardamonin (CAD) is a member of the aromatic ketones family that is closely related to anti-bacterial, anti-inflammatory and anti-cancer effects. Nevertheless, the physiological function of cardamonin in chronic colitis and colon cancer has not been well verified. We found that cardamonin treatment alleviates intestinal disease, including recurring colitis and colitis-associated tumorigenesis, along with the reduced secretion of IL-1β and TNF-α. Further, cardamonin inhibits cell viability and inflammation factors of colorectal cancer cells in vitro. In tumor cells, the inhibitory effect of cardamonin on cell proliferation is closely related to decreased phosphorylation of signal transducers and activators of transcription (STAT) signals. This study reveals the crucial role of cardamonin in sustaining gastrointestinal homeostasis and offers a new strategy for colon cancer therapy.

Topics: Animals; Carcinogenesis; Cell Survival; Chalcones; Colitis; Colon; Colonic Neoplasms; Dextran Sulfate; Disease Models, Animal; HT29 Cells; Humans; Inflammation; Interleukin-1beta; Neoplasm Recurrence, Local; NF-kappa B; Signal Transduction; STAT Transcription Factors; Tumor Necrosis Factor-alpha

Aberrant accumulation of intracellular β-catenin and subsequent activation of β-catenin response transcription (CRT) in intestinal epithelial cells is a frequent early event during the development of colon cancer. Here we show that cardamonin, a chalcone isolated from Aplinia katsumadai Hayata, inhibited CRT in SW480 colon cancer cells that carry inactivating mutation in the adenomatous polyposis coli (APC) gene. Cardamonin also down-regulated intracellular β-catenin levels in SW480 cells without affecting its mRNA levels. Interestingly, pharmacological inhibition of the proteasome prevented the cardamonin-induced down-regulation of β-catenin. In addition, cardamonin suppressed the expression of cyclin D1 and c-myc, which are known β-catenin/T cell factor (TCF)-dependent genes. Moreover, cardamonin inhibited the growth of various colon cancer cells and induced G2/M cell cycle arrest in SW480 colon cancer cells. These findings indicate that cardamonin is a potential chemotherapeutic agent against colon cancer.

Topics: Antineoplastic Agents; beta Catenin; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chalcones; Colonic Neoplasms; Down-Regulation; Humans

TNF-related apoptosis-inducing ligand (TRAIL) is currently in clinical trials as a treatment for cancer, but development of resistance is a major drawback. Thus agents that can overcome resistance to TRAIL are urgently needed. Cardamonin (2',4'-dihydroxy-6'-methoxychalcone) has been shown to affect cell growth by modulating various cell signalling pathways. Hence, we investigated the effect of cardamonin on the actions of TRAIL.. The effect of cardamonin on TRAIL was measured by plasma membrane integrity, phosphatidylserine exposure, mitochondrial activity, and activation of caspase-8, caspase-9, and caspase-3 in human colon cancer cells.. Cardamonin potentiated TRAIL-induced apoptosis and this correlated with up-regulation of both the TRAIL death receptor (DR) 4, 5 at mRNA and protein levels. TRAIL-decoy receptor DcR1 was down-regulated by cardamonin. Induction of DRs by cardamonin occurred in a variety of cell types. Gene silencing of the DRs by small interfering RNA (siRNA) abolished the effect of cardamonin on TRAIL-induced apoptosis, suggesting that sensitization was mediated through the DR. Induction of the DR by cardamonin was p53-independent but required CCAAT/enhancer binding protein homologous protein (CHOP); cardamonin induced CHOP, and its silencing by siRNA eliminated the induction of DR5. Cardamonin increased the production of reactive oxygen species (ROS) and quenching ROS abolished its induction of receptors and enhancement of TRAIL-induced apoptosis. Cardamonin also decreased the expression of various cell survival proteins.. Cardamonin potentiates TRAIL-induced apoptosis through ROS-CHOP-mediated up-regulation of DRs, decreased expression of decoy receptor and cell survival proteins. Thus, cardamonin has the potential to make TRAIL more effective as an anticancer therapy.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Cell Line, Tumor; Chalcones; Colonic Neoplasms; Down-Regulation; Humans; Reactive Oxygen Species; Receptors, Death Domain; TNF-Related Apoptosis-Inducing Ligand; Transcription Factor CHOP; Up-Regulation