Oridonin induces apoptosis via PI3K/Akt pathway in cervical carcinoma HeLa cell line

• Published in: Acta pharmacologica Sinica Vol. 28; no. 11; pp. 1819 - 1826
• Main Authors: Hu, Hong-zhen, Yang, Yue-bo, Xu, Xiang-dong, Shen, Hong-wei, Shu, Yi-min, Ren, Zi, Li, Xiao-mao, Shen, Hui-ming, Zeng, Hai-tao
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.11.2007
• Subjects: Apoptosis - drug effects; Caspases - metabolism; Collagen Type XI - metabolism; Cytochromes c - metabolism; Diterpenes, Kaurane - pharmacology; Down-Regulation - drug effects; Female; HeLa Cells; Humans; In Vitro Techniques; Membrane Potential, Mitochondrial - drug effects; Mitochondria - metabolism; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphorylation; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Signal Transduction - drug effects; Uterine Cervical Neoplasms - drug therapy; Uterine Cervical Neoplasms - pathology; 子宫癌; 细胞凋亡; 肿瘤学
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1111/j.1745-7254.2007.00667.x

Aim： To investigate the apoptosis-inducing effect of oridonin, a diterpenoid isolated from Rabdosia rubescens, in the human cervical carcinoma HeLa cell line. Methods： A morphological analysis, nuclear condensation, and fragmentation of chromatin were monitored using Hoechst 33342 staining. Cell viability was assessed using the 3-（4, 5-dimethylthiazol-（2）-yl）-2, 5-diphenyl tetrazolium bromide （MTT） assay. Cell apoptosis and the apoptosis-related activation in the HeLa cell line were evaluated by flow cytometry and Western blotting. Results： Oridonin suppressed the proliferation of the HeLa cell line in a dose- and time-dependent fashion. Oridonin treatment downregulated the activation of protein kinase B （Akt）, the expression of forkhead box class O （FOXO） transcription factor, and glycogen synthase kinase 3 （GSK3）. Oridonin also induced the release of cytochrome c accompanied by the activation of caspase-3 and poly-adenosine diphosphate-ribose polymerase cleavage. In addition, Z-D（OMe）-E（OMe）-V-D（OMe）- FMK （z-DEVD-fmk）, an inhibitor of caspases, prevented caspase-3 activation and abrogated oridonin-induced cell death. Finally, oridonin treatment of the HeLa cell line downregulated the expression of the inhibitor of the apoptosis protein. Conclusion： Our results showed that oridonin-induced apoptosis involved several molecular pathways. Oridonin may suppress constitutively activated targets of phosphatidylinositol 3-kinase （Akt, FOXO, and GSK3） in the HeLa cell line, inhibiting the proliferation and induction of caspase-dependent apoptosis.