PDK1 is a potential therapeutic target against angiosarcoma cells.

Angiosarcoma is a rare and aggressive malignant neoplasm of endothelial cells. Recent studies have shown that the mTOR pathway is also aberrantly activated in cutaneous angiosarcoma. New therapeutic strategies are required because the prognosis of this disease is still poor. The aim of the present study was to determine the driver gene of angiosarcoma useful for the screening of small molecule inhibitors. We investigated the sensitivity of inhibitors for the PI3K/AKT/mTOR pathway in ISOS-1 and ISO-HAS cutaneous angiosarcoma cell lines. Flow cytometric analysis was conducted to evaluate cell-cycle progression and apoptosis. Western blot analyses were performed to elucidate the possible underlying mechanisms of growth inhibition. The colony formation assay was conducted to evaluate the clonogenic potential. We used the siRNA for PDK1 to examine the role of PDK1 on the growth of angiosarcoma cells. The PI3K inhibitor and mTOR inhibitor inhibited the growth of both cell lines in a dose-dependent manner. The PI3K inhibitor more effectively induced cell-cycle arrest at the G1 phase with the downregulated expression of cyclin D in ISOS-1 cells than the mTOR inhibitor. The PI3K inhibitor and mTOR inhibitor weakly but significantly induced G1 cell cycle arrest at the same degree in ISO-HAS cells. The expression of cyclin D was downregulated by the treatment with siRNA for PDK1, but not by the AKT inhibitor in ISOS-1 and ISO-HAS cells. The knock down of PDK1 with siRNA was more effective at reducing colony numbers than the mTOR inhibitor in ISOS-1 cells. These data showed that PDK1 played a pivotal role in the growth of angiosarcoma cells. Therefore, inhibition of PDK1, but not AKT, may be a more appropriate strategy than that of mTORC1 for the treatment of cutaneous angiosarcoma; the PDK1 inhibitor is promising as a therapeutic agent.

Wada M ，Horinaka M ，Yasuda S ，Masuzawa M ，Sakai T ，Katoh N ... -  《-》

Quinazoline based small molecule exerts potent tumour suppressive properties by inhibiting PI3K/Akt/FoxO3a signalling in experimental colon cancer.

Deregulation of PI3K signalling pathway is strongly involved in pathology of cancer and development of resistance in tumour cells. Here, we report that pharmacologically active vasicinone analogue, RLX (7, 8, 9, 10-Tetrahydroazepino [2, 1-b] quinazolin-12-(6H)-on), exhibited potent anticancer activities both in vitro and in vivo. In this study, RLX treatment displayed strong inhibition of proliferation against various cancer cell lines. However, colon cancer cells were found to be the most sensitive towards RLX mediated inhibition of proliferation. The result showed that RLX treatment followed strong concentration dependent inhibition of HCT-116 cell proliferation and colony formation. RLX treatment to HCT-116 was observed to be associated with down-regulation of p110α and p85 subunits of PI3K thereby decreasing the expression of subsequent downstream effector proteins. Interestingly, silencing of PI3K gene by siRNA in combination with RLX confirmed the anti-proliferation effect of RLX against HCT-116 cells and is mediated by the PI3K pathway. We also found that RLX induced sub-G1 arrest and mitochondrial potential loss followed by pFoxO3a(Thr32) nuclear-cytoplasmic translocation inhibition. Moreover, RLX treatment in in vivo models substantially resulted in a tumour growth inhibition. Overall, our findings reveal the functional role of the PI3K/Akt/FoxO3a pathway that gets deregulated in cancer and suggests its simultaneous targeting by RLX thereby further identifying the compound as a potent inhibitor of the PI3K/Akt/FoxO3a pathway under in vitro and tumour regression in vivo.

Qazi AK ，Hussain A ，Khan S ，Aga MA ，Behl A ，Ali S ，Singh SK ，Taneja SC ，Shah BA ，Saxena AK ，Mondhe DM ，Hamid A ... -  《-》

The PI3 kinase/mTOR blocker NVP-BEZ235 overrides resistance against irreversible ErbB inhibitors in breast cancer cells.

Brünner-Kubath C ，Shabbir W ，Saferding V ，Wagner R ，Singer CF ，Valent P ，Berger W ，Marian B ，Zielinski CC ，Grusch M ，Grunt TW ... -  《-》

PDK1 signaling toward PLK1-MYC activation confers oncogenic transformation, tumor-initiating cell activation, and resistance to mTOR-targeted therapy.

Tan J ，Li Z ，Lee PL ，Guan P ，Aau MY ，Lee ST ，Feng M ，Lim CZ ，Lee EY ，Wee ZN ，Lim YC ，Karuturi RK ，Yu Q ... -  《-》

Danusertib, a potent pan-Aurora kinase and ABL kinase inhibitor, induces cell cycle arrest and programmed cell death and inhibits epithelial to mesenchymal transition involving the PI3K/Akt/mTOR-mediated signaling pathway in human gastric cancer AGS and N

Yuan CX ，Zhou ZW ，Yang YX ，He ZX ，Zhang X ，Wang D ，Yang T ，Pan SY ，Chen XW ，Zhou SF ... -  《Drug Design Development and Therapy》