Potential Inhibition of PDK1/Akt Signaling by Phenothiazines Suppresses Cancer Cell Proliferation and Survival

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.

Cytostatic in vitro Effects of DTCM-Glutarimide on Bladder Carcinoma Cells

“…Combinations of caspasedependent and -independent mechanisms of cell death have been reported by others after PDK1 inhibition. While phenothiazines induced apoptosis in human ovary cancer cells (Choi et al, 2008), the PDK1 inhibitor OSU03012 induced mitochondrial dependent apoptosis of medulloblastoma cells (Baryawno et al, 2010), but was also reported to induce autophagy through accumulation of reactive oxygen species in hepatocellular carcinoma (Sargeant et al, 2007). In the present study, cytometric analysis after AO staining failed to detect increased autophagy in cells treated with DTCM-g. Also, we were unable to detect any necrosis after treating cells with this drug, suggesting that reduced cell numbers may result of impaired proliferation rather than cell death.…”

“…Sato et al, (2002) proved potent anti-tumor activity of the PDK1 inhibitor UCN-01 in murine colon adenocarcinoma NL-17 cells. Also, the inhibition of PDK1 by phenothiazines resulted in suppression of EGF-induced cell growth in ovary cancer cells and inhibited growth in other several cancer cell lines, including melanoma (SK-MEL-28), colon (HT29, Colo205, SW480, HCT116) and breast cancer (MCF7) (Choi et al, 2008). Likewise, the inhibitor OSU03012 had profound effects on medulloblastoma (Baryawno et al, 2010) and neuroblastoma survival in vitro and in vivo (Segerstrom et al, 2011).…”

Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia

“…These effects of PPZ were linked by biochemical, cell biological, and genetic studies to activation of PP2A, a tumor-suppressive protein phosphatase. The ability of PPZ to activate PP2A thus represents the likely mechanism for the previously unexplained ability of phenothiazines to downregulate PI3K/AKT signaling and may explain the recurrent identification of these compounds in unbiased screens for agents with antineoplastic activity (18)(19)(20)(21)(49)(50)(51)(52)(53).…”

“…The antipsychotic effects of phenothiazines correlate with their ability to block dopamine receptors, but a broad array of other activities have been described, including antitumor effects. The basis for the antiproliferative activities of phenothiazines are uncertain and have been variously attributed to a number of mechanisms, including inhibition of PKC (17), calmodulin (18), PI3K/AKT signaling (18)(19)(20)(21), and cancer stem cell activity (22).…”

Alterações na expressão de genes para citocinas, fatores de crescimento e seus receptores estão associadas com as neoplasias epiteliais ovarianas

“…Alterações na expressão gênica e neoplasias ovarianas las de câncer de cólon ativados pela via MAPK resulta em significativa inibição do crescimento celular e no aumento das taxas de apoptose. Além disso, Choi et al (2008) 47 demonstraram que a inibição da PDK1 resulta na supressão do crescimento celular induzido por EGF e na promoção de apoptose em células humanas de câncer de ovário, concluindo que inibidores da PDK1 poderiam ser eficazes no tratamento desse tipo de câncer.…”