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Indirubin-3-monoxime and thymoquinone exhibit synergistic efficacy as therapeutic combination in in-vitro and in-vivo models of Lung cancer

Archives of Pharmacal Research 2020년 43권 6호 p.655 ~ 665
 ( Dera Ayed A. ) - King Khalid University College of Applied Medical Sciences Department of Clinical Laboratory Sciences

 ( Rajagopalan Prasanna ) - King Khalid University College of Applied Medical Sciences Department of Clinical Laboratory Sciences
 ( Al Fayi Majed ) - King Khalid University College of Applied Medical Sciences Department of Clinical Laboratory Sciences
 ( Ahmed Irfan ) - King Khalid University College of Applied Medical Sciences Department of Clinical Laboratory Sciences
 ( Chandramoorthy Harish C. ) - King Khalid University College of Medicine Department of Microbiology and Clinical Parasitology

Abstract


In this study, we report the combination of indirubin-3-monoxime (I3M) and thymoquinone (Tq) to have excellent therapeutic efficacy in models of Lung cancer (LC). Preliminary screening was done with A549 cells. Cell cycle, apoptosis and NFκB phosphorylation were determined by flow cytometry, while apoptotic proteins, Akt and mTOR were assessed by western blotting. Mouse xenograft model was used to assess the therapeutic efficacy in-vivo. Synergistic reduction in cell viability was observed with I3M?+?Tq combinations, which were non-toxic to normal HFL-1 cells. Cell cycle analysis indicated G1 phase reduction with subsequent accumulation of sub G0 contents. Annexin V assay revealed higher apoptotic cells with combinations compared to individual treatments with a decrease in Bcl-2/Bax ratio. The combinations exhibited anti-metastasis activity in cell migration in the scratch, scatter and tumour cell migration assays and effectively reduced the tumour growth in mouse xenograft model. Expression levels of p-AKT, p-mTOR, Caspase-3, p-53 and NFκB were significantly reduced in the combination treated mice compared to individual treatments. Results of current study demonstrate clear efficacy of I3M?+?Tq combinations in LC models mediated by suppressing Akt/mTOR/NFκB signalling. Further research is recommended to transform these findings into novel therapeutic combinations against LC.

키워드

A549; Akt; Apoptosis; Indirubin; Lung cancer; mTOR; Nfκb; Synergism; Thymoquinone
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