Akt involvement in paclitaxel chemoresistance of human ovarian cancer cells.
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.
Kim
Su-Hyeong
SH
Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 28 Yungun-dong, Chongno-gu, Seoul 110-744, Korea.
Juhnn
Yong-Sung
YS
Song
Yong-Sang
YS
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D051057:Proto-Oncogene Proteins c-akt; D017239:Paclitaxel