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  Many studies have revealed that EGFR is functionally dysregulated in various

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تاريخ التسجيل : 26/01/2015

مُساهمةموضوع: Many studies have revealed that EGFR is functionally dysregulated in various   الأربعاء نوفمبر 18, 2015 7:04 pm

The phosphatidyl inositol 3 kinase Aktmammalian target of rapamycin pathway has been INNO-406 構造 identified as a pivotal key regulator. mTOR has an impact on various cellular functions, including cell growth, proliferation and cell survival. Two mTOR inhibitors, temsiroli mus and everolimus, have been approved by the FDA to treat advanced RCC due to prolonged progression free survival. However, targeted therapy is not curative in metastatic RCC and drug response is limited. Recently, it has been shown that chronic mTOR inhibition evokes undesired feed back mechanisms in RCC cells, which may lead to re sistance development. Undesirable feedback has also been demonstrated in prostate cancer cells after chronic exposure to everolimus, indicating molecular alterations tied to acquired resistance.

Agents tar geting such feedback loops and cross talk with other pathways involved in acquired resistance to mTOR inhibition Lapatinib 溶解度 are, therefore, urgently required. Studies and clinical trials have demonstrated that histone dea cetylase inhibitors in combination with other therapies, including targeted therapies, induce syner gistic or additive anti tumor effects. It has also been reported that during chronic application of evero limus, combination with the HDAC inhibitor valproic acid contributes to sustained anti tumor activity. Additionally, HDAC inhibitors have been shown to re sensitize tumor cells to cytotoxic drug treatment. Hence, HDAC inhibition might prove promis ing in reversing everolimus resistance in RCC. To fol low up on a pilot study employing everolimus resistant RCC Caki 1 cells.

resistance dependent functional and molecular aberrations were investigated in the same cell LY2109761 TGF-beta/Smad 阻害剤 line. Further investigation was designed to determine whether Cakires cell growth could be influenced by the HDAC inhibitor VPA, whereby the growth behav ior of Cakires compared to VPA treated Cakires cells was evaluated. It is shown that everolimus resistance contrib utes to a significant increase in the IC50, an elevated per centage of G2M phase cells and distinct up regulation of the cell cycle activating proteins cdk2 and cyclin A. VPA counteracted everolimus resistance by significantly inhibit ing tumor growth and reducing cdk2 and cyclin A. Thus, VPA might represent a new promising treatment option for RCC patients with acquired everolimus resistance.

Results Exposure to everolimus induced resistance in RCC cells 24 h exposure to ascending concentrations of everolimus induced a dose dependent significant reduc tion in the number of Cakipar cells compared to the un treated control with an IC50 of 0. 78 0. 23 nM. Everolimus resistance was ev idenced by a significant shift of the IC50 to 10. 47 3. 14 nM. Resistance towards everolimus significantly enhanced the G2M phase Evaluation of cell cycle progression revealed significant alterations after acquired everolimus resistance. The G2 M phase percentage was increased in unsynchronized Cakires cells, compared to Cakipar, and was accompanied by a decrease in the S phase. Synchronization of the cells led to a similar shift, additionally reducing the percentage of G0G1 phase cells in Cakires.
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Many studies have revealed that EGFR is functionally dysregulated in various
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