TY - JOUR
T1 - Thioridazine induces apoptosis by targeting the PI3K/Akt/mTOR pathway in cervical and endometrial cancer cells
AU - Kang, Sokbom
AU - Dong, Seung Myung
AU - Kim, Boh Ram
AU - Park, Mi Sun
AU - Trink, Barry
AU - Byun, Hyun Jung
AU - Rho, Seung Bae
N1 - Funding Information:
Acknowledgments This work was supported by a grant from the National Cancer Center, Korea (NCC-0910262-3). We thank Dr. S.A. Martinis (Department of Biochemistry, University of Illinois at Urbana-Champaign, IL), and Richard Yoo (University of Washington, Seattle, WA) for critical reading of the manuscript.
PY - 2012/9
Y1 - 2012/9
N2 - Recently, thioridazine (10-[2-(1-methyl-2-piperidyl) ethyl]-2- methylthiophenothiazine), a well-known anti-psychotic agent was found to have anti-cancer activity in cancer cells. However, the molecular mechanism of the agent in cellular signal pathways has not been well defined. Thioridazine significantly increased early- and late-stage apoptotic fraction in cervical and endometrial cancer cells, suggesting that suppression of cell growth by thioridazine was due to the induction of apoptosis. Cell cycle analysis indicated thioridazine induced the down-regulation of cyclin D1, cyclin A and CDK4, and the induction of p21 and p27, a cyclin-dependent kinase inhibitor. Additionally, we compared the influence of thioridazine with cisplatin used as a control, and similar patterns between the two drugs were observed in cervical and endometrial cancer cell lines. Furthermore, as expected, thioridazine successfully inhibited phosphorylation of Akt, phosphorylation of 4E-BP1 and phosphorylation of p70S6K, which is one of the best characterized targets of the mTOR complex cascade. These results suggest that thioridazine effectively suppresses tumor growth activity by targeting the PI3K/Akt/mTOR/p70S6K signaling pathway.
AB - Recently, thioridazine (10-[2-(1-methyl-2-piperidyl) ethyl]-2- methylthiophenothiazine), a well-known anti-psychotic agent was found to have anti-cancer activity in cancer cells. However, the molecular mechanism of the agent in cellular signal pathways has not been well defined. Thioridazine significantly increased early- and late-stage apoptotic fraction in cervical and endometrial cancer cells, suggesting that suppression of cell growth by thioridazine was due to the induction of apoptosis. Cell cycle analysis indicated thioridazine induced the down-regulation of cyclin D1, cyclin A and CDK4, and the induction of p21 and p27, a cyclin-dependent kinase inhibitor. Additionally, we compared the influence of thioridazine with cisplatin used as a control, and similar patterns between the two drugs were observed in cervical and endometrial cancer cell lines. Furthermore, as expected, thioridazine successfully inhibited phosphorylation of Akt, phosphorylation of 4E-BP1 and phosphorylation of p70S6K, which is one of the best characterized targets of the mTOR complex cascade. These results suggest that thioridazine effectively suppresses tumor growth activity by targeting the PI3K/Akt/mTOR/p70S6K signaling pathway.
KW - Anti-cancer activity
KW - Apoptosis
KW - Cervical tumorigenesis
KW - Thioridazine
KW - mTOR signaling
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U2 - 10.1007/s10495-012-0717-2
DO - 10.1007/s10495-012-0717-2
M3 - Article
C2 - 22460505
AN - SCOPUS:84865126692
SN - 1360-8185
VL - 17
SP - 989
EP - 997
JO - Apoptosis : an international journal on programmed cell death
JF - Apoptosis : an international journal on programmed cell death
IS - 9
ER -