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Akt involvement in paclitaxel chemoresistance of human ovarian cancer cells

Cited 77 time in Web of Science Cited 79 time in Scopus
Authors
Kim, Su-Hyeong; Juhnn, Yong-Sung; Song, Yong-Sang
Issue Date
2007-04-04
Publisher
Wiley-Blackwell
Citation
Ann N Y Acad Sci. 2007 Jan;1095:82-9.
Keywords
Antineoplastic Agents, Phytogenic/*pharmacologyApoptosis/drug effectsCell Line, TumorDrug Resistance, Neoplasm/*physiologyFemaleHumansOvarian Neoplasms/drug therapy/*metabolism/pathologyPaclitaxel/*pharmacologyProto-Oncogene Proteins c-akt/*physiologySignal Transduction/drug effects
Abstract
Paclitaxel (taxol) is extensively used for chemotherapy of various cancers including ovarian cancer. Although paclitaxel induces apoptosis in cancer cells, its exact mechanism of action still remains to be determined. Akt mediates survival signals which preserve various cancer cells from apoptosis pathway. Thus, Akt is considered an exciting target for therapeutics. Here, we demonstrated that inhibition of Akt increases the efficacy of the paclitaxel-induced apoptosis in SKOV3 and PA-1 human ovarian cancer cells. The sensitivity to paclitaxel of SKOV3 and PA-1 cells was examined using the MTT assay. At a concentration of 30 nM, PA-1 cells were more sensitive to paclitaxel than SKOV3 cells. Apoptosis was accompanied by the release of cytochrome c into the cytoplasm and cleavage of poly (ADP-ribose) polymerase (PARP). To further elucidate the mechanism of apoptosis by paclitaxel, we compared the levels of phosphorylation of Akt between paclitaxel-resistant SKOV3 cells and paclitaxel-sensitive PA-1 cells. The higher level of phosphorylated Akt was shown in SKOV3 cells than in PA-1 cells. Interestingly, the treatment of paclitaxel decreased the amount of phosphorylated Akt in a time-dependent manner in both cell lines. Furthermore, inhibition of Akt by specific phosphatidyinositol-3-kinase (PI3K)-Akt inhibitors (Wortmannin, and LY294002) synergistically increased the efficacy of the paclitaxel-induced apoptosis in both cell lines. These results suggest that the addition of the Akt inhibitor may increase the therapeutic efficacy of paclitaxel for patients with ovarian cancer.
ISSN
0077-8923 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17404021

http://hdl.handle.net/10371/26538
DOI
https://doi.org/10.1196/annals.1397.012
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College of Medicine/School of Medicine (의과대학/대학원)Program in Cancer Biology (협동과정-종양생물학전공)Journal Papers (저널논문_협동과정-종양생물학전공)
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