zeylenone and Uterine-Cervical-Neoplasms

There is a strong rationale to therapeutically target the PI3K/Akt/mTOR and MAPK/ERK pathways in cervical carcinoma since they are highly deregulated in this disease. Previous study by our group have demonstrated that Zeylenone (Zey) exhibited strong suppressive activity on PI3K/AKT/mTOR and MAPK/ERK signaling, providing a foundation to investigate its antitumor activity in cervical carcinoma. Herein, the present study aimed to investigate suppressive effect of Zey on HeLa and CaSki cells, and further explore the underlying mechanisms. Cells were treated with Zey for indicated time, followed by measuring its effects on cell viability, colony formation, cell cycle, cell apoptosis, and signal pathways. In vivo antitumor activity of Zey was then assessed with nude xenografts. We found that Zey substantially suppressed cell proliferation, induced cell cycle arrest, and increased cell apoptosis, accompanied by increased production of ROS, decreased mitochondrial membrane potential, activated caspase apoptotic cascade, and attenuated PI3K/Akt/mTOR and MAPK/ERK pathways. Additionally, in vivo experiments showed that Zey exerted good antitumor efficacy against HeLa bearing mice models via decreasing levels of p-PI3K and p-ERK. Collectively, these data clearly demonstrated the antitumor activity of Zey in cervical carcinoma cells, which is most likely via the regulation of PI3K/Akt/mTOR and MAPK/ERK pathways.

Topics: Animals; Apoptosis; Caspases; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclohexanes; Cyclohexenes; Dioxanes; DNA, Neoplasm; Enzyme Activation; Female; Humans; MAP Kinase Signaling System; Mice, Inbred BALB C; Mitochondria; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; TOR Serine-Threonine Kinases; Tumor Stem Cell Assay; Uterine Cervical Neoplasms; Xenograft Model Antitumor Assays

Cervical carcinoma is a malignant tumor that poses a serious threat to women's health and survival. Approximately 10-25% of cervical cancers are adenocarcinomas (ACs). AC has high rates of recurrence and mortality, while there is no effective treatment for now. Zeylenone (Zey), which is isolated from an ethanol extract of the leaves of Uvaria grandiflora Roxb. of the family Annonaceae, has shown potent inhibitory activity against various tumor cells, including cervical carcinoma cells. To gain insight into the molecular mechanism underlying the effect of Zey on AC, we quantified protein expression changes in AC cells treated with Zey. We used stable isotope labeling with amino acids in cell culture (SILAC) in combination with high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) and bioinformatics analysis to compare protein expression profiles in HeLa cells before and after Zey treatment. Of 1805 differentially expressed proteins identified, 229 were screened as key protein molecules and classified into nine categories. Profiling of differentially-expressed proteins contributed to our understanding of the molecular mechanism by which Zey induces HeLa cell apoptosis. Using this method, candidate targets can be identified for developing new drugs against cervical carcinoma.

Topics: Amino Acids; Cyclohexanes; Dioxanes; Female; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Isotope Labeling; Neoplasm Proteins; Proteomics; Uterine Cervical Neoplasms