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RISS 인기검색어
- 검색키워드
- 저자 : Prasanna Rajagopalan (검색결과 2 건)
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A Novel, Potent, Small Molecule AKT Inhibitor Exhibits Efficacy against Lung Cancer Cells In Vitro
Saketh S. Dinavahi,Rajagopalan Prasanna,Sriram Dharmarajan,Yogeeswari Perumal,Srikant Viswanadha 대한암학회 2015 Cancer Research and Treatment Vol.47 No.4
Purpose Anomalies of Akt regulation, including overexpression in lung cancer, impart resistance toconventional chemotherapy and radiation, thereby implicating this kinase as a therapeuticintervention point. A novel scaffold of Akt inhibitors was developed through virtual screeningof chemical databases available at Birla Institute of Technology and Science, Pilani, Hyderabad,based on docking studies using Maestro. A benzothienopyrimidine derivative (BIA-6)was identified as a potential lead molecule that inhibited Akt1 enzyme activity with an IC50of 256 nM. Materials and MethodsBIA-6 was tested for in vitro Akt1 inhibition using a fluorescence resonance energy transferkit. Anti-proliferative activity was tested in NCI-H460, A549, NCI-H1975, and NCI-H2170cell lines. The effect of the compound on p-Akt (S473) was estimated. ResultsBIA-6 allosterically caused a dose dependent reduction of growth of cell lines with a halfmaximal growth inhibition (GI50) range of 0.49 !M to 6.6 !M. Cell cycle analysis indicatedthat BIA-6 caused a G1 phase arrest at < 100 nM but led to apoptosis at higher doses. BIA-6 also exhibited synergism with standard chemotherapeutic agents. ConclusionBIA-6 is a novel, allosteric Akt inhibitor with potent anti-cancer activity in lung cancer celllines, that effectively blocks the phosphoinositide-3 kinase/Akt pathway with a high marginselectivity towards normal cells.
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Ayed A. Dera,Prasanna Rajagopalan,Majed Al Fayi,Irfan Ahmed,Harish C. Chandramoorthy 대한약학회 2020 Archives of Pharmacal Research Vol.43 No.6
In this study, we report the combination ofindirubin-3-monoxime (I3M) and thymoquinone (Tq) tohave excellent therapeutic effi cacy in models of Lung cancer(LC). Preliminary screening was done with A549 cells. Cellcycle, apoptosis and NFκB phosphorylation were determinedby fl ow cytometry, while apoptotic proteins, Akt and mTORwere assessed by western blotting. Mouse xenograft modelwas used to assess the therapeutic effi cacy in-vivo . Synergisticreduction in cell viability was observed with I3M + Tqcombinations, which were non-toxic to normal HFL-1 cells. Cell cycle analysis indicated G 1 phase reduction with subsequentaccumulation of sub G 0 contents. Annexin V assayrevealed higher apoptotic cells with combinations comparedto individual treatments with a decrease in Bcl-2/Bax ratio. The combinations exhibited anti-metastasis activity in cellmigration in the scratch, scatter and tumour cell migration assays and eff ectively reduced the tumour growth in mouse xenograft model. Expression levels of p-AKT, p-mTOR,Caspase-3, p-53 and NFκB were signifi cantly reduced inthe combination treated mice compared to individual treatments. Results of current study demonstrate clear effi cacy ofI3M + Tq combinations in LC models mediated by suppressingAkt/mTOR/NFκB signalling. Further research is recommendedto transform these fi ndings into novel therapeuticcombinations against LC.
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