In:
Annals of the New York Academy of Sciences, Wiley, Vol. 1138, No. 1 ( 2008-09), p. 393-403
Abstract:
3′‐Phosphoinositide‐dependent kinase‐1 (PDK1) has been identified for its ability to phosphorylate and activate Akt. Accumulated studies have shown that the activation of the PDK1/Akt pathway plays a pivotal role in cell survival, proliferation, and tumorigenesis. Therefore, the PDK1/Akt pathway is believed to be a critical target for cancer intervention. In this paper, we report the discovery of a new function of phenothiazines, widely known as antipsychotics, inhibiting PDK1/Akt pathway. Upon epidermal growth factor (EGF) stimulation, phenothiazines specifically suppressed the kinase activity of PDK1 and the phosphorylation level of Akt. The inhibition of PDK1/Akt kinase resulted in suppression of EGF‐induced cell growth and induction of apoptosis in human ovary cancer cells. In particular, phenothiazines were highly selective for downstream targets of PDK1/Akt and did not inhibit the activation of phosphatidylinositol 3‐kinase (PI3K), EGFR, or extracellular signal‐regulated kinase 1/2 (ERK1/2). In particular, phenothiazines effectively suppressed tumor growth in nude mice of human cancer cells. Taken together, these findings provide strong evidence for novel function of phenothiazines, pharmacologically targeting PDK1/Akt for anticancer drug discovery.
Type of Medium:
Online Resource
ISSN:
0077-8923
,
1749-6632
DOI:
10.1196/nyas.2008.1138.issue-1
DOI:
10.1196/annals.1414.041
Language:
English
Publisher:
Wiley
Publication Date:
2008
detail.hit.zdb_id:
2834079-6
detail.hit.zdb_id:
211003-9
detail.hit.zdb_id:
2071584-5
SSG:
11
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