Preclinical studies of chaetoglobosin K and 4-phenyl-3-butenoic acid in tumorigenic cells

In cancer drug discovery, there is a continual need for new therapeutic agents for reasons such as acquired drug resistance, the identification of new molecular targets, and failure of drug candidates in clinical trials. The purpose of these studies was to investigate the biochemical mechanisms underlying the in vitro anti-tumor effects of the experimental compounds chaetoglobosin K (ChK) and 4-phenyl-3-butenoic acid (PBA) by analysis of their targeted cellular signaling pathways. These compounds have both been reported to suppress growth of ras-mutated epithelial cells in vitro through the modulation of signaling pathways often deregulated in human cancers.;PBA has been reported to modulate the p38 MAPK and .INK pathways and reverse the transformed phenotype of tumorigenic cells. In this report, we reveal that PBA increases histone acetylation in a manner similar to the HDAC inhibitor vorinostat in both ras-mutated epithelial cells and human lung carcinoma cells. Furthermore, we report that PBA has histone deacetylase (HDAC) enzyme inhibitory activity in vitro. It was also discovered that PBA inhibits the growth of ras-mutated epithelial cells by induction of a G1 phase cell cycle arrest. Additional studies attempted to determine whether the activation of p38 MAPK by PBA was related to the generation of reactive oxygen species (ROS).;Previous studies have reported that ChK decreases the activation of Akt in tumorigenic. In this report, we reveal that in addition to decreased Akt activation, ChK also concomitantly decreases the activation of JNK in both ras-mutated epithelial cells and human lung carcinoma cells. To further understand the mechanism by which ChK decreases the activation of the Akt and INK signaling pathways, upstream and downstream mediators of these pathways were monitored for changes in activation status or expression. Furthermore, it was determined that ChK did not inhibit the enzyme P13 kinase, an upstream activator of Akt, through the use of an in vitro enzyme assay. Additionally, these studies determined that mTOR is not involved in the mechanism in which Ala phosphorylation is decreased. Lastly, inhibition of the phosphatase PP2A did not affect ChK's ability to decrease Akt phosphorylation in ras-mutated epithelial cells.;Ultimately, these studies provide further insight on the biochemical mechanisms and targets by which PBA and ChK inhibit the proliferation of tumorigenic cells in vitro. This information is essential in assessing the safety and potential of these compounds for future in vivo and clinical studies and underscore the potential of these unique compounds as therapies that may be used in the treatment of human cancers.