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The IL6/JAK2/STAT3 axis dysregulation and the related downstream pathways are a major contributor to the progression of non-small-cell lung carcinoma (NSCLC) and mainly affect apoptosis. Furthermore, tubulin inhibitors are potential chemotherapeutic agents against NSCLC. In this study, we have provided new molecular insights into the antiproliferative activity of six 3β-acetoxy-5α-androstane heterocycle compounds against NSCLC. The cell line A549, which represents a good model of NSCLC, was used to evaluate the antitumour activity of tested androstane derivatives, and non-cancerous gingival mesenchymal stem cell line (GMSC) were used to assess the specificity and toxicity of the tested compounds. Further on, molecular docking predictions were used to determine the molecular targets for the most promising cytotoxic compound. To assess apoptosis and cell cycle progression in treated A549 cells, flow cytometry was used. RT-qPCR and ELISA analyses were used to gain deep insights into cellular and molecular mechanisms. Results revealed that compound 4 has potential cytotoxicity on A549 cells, with lower IC₅₀ value (27.36 μM). Moreover, in silico, compound 4 showed a good binding affinity to JAK2 and tubulin-colchicine soblidotin molecular targets. This was further confirmed on the molecular level. Compound 4 has also led to apoptosis and increased fragmentation of DNA, and mitochondrial dysfunction. Our findings have provided good evidence that compound 4 may be a dual inhibitor of IL6/JAK2/STAT3 and tubulin formation in lung cancer. These findings support further molecular exploration of this androstane derivative as promising anti-lung cancer agent. Communicated by Ramaswamy H. Sarma

The IL6/JAK2/STAT3 axis dysregulation and the related downstream pathways are a major contributor to the progression of non-small-cell lung carcinoma (NSCLC) and mainly affect apoptosis. Furthermore, tubulin inhibitors are potential chemotherapeutic agents against NSCLC. In this study, we have provided new molecular insights into the antiproliferative activity of six 3β-acetoxy-5α-androstane heterocycle compounds against NSCLC. The cell line A549, which represents a good model of NSCLC, was used to evaluate the antitumour activity of tested androstane derivatives, and non-cancerous gingival mesenchymal stem cell line (GMSC) were used to assess the specificity and toxicity of the tested compounds. Further on, molecular docking predictions were used to determine the molecular targets for the most promising cytotoxic compound. To assess apoptosis and cell cycle progression in treated A549 cells, flow cytometry was used. RT-qPCR and ELISA analyses were used to gain deep insights into cellular and molecular mechanisms. Results revealed that compound 4 has potential cytotoxicity on A549 cells, with lower IC₅₀ value (27.36 μM). Moreover, in silico, compound 4 showed a good binding affinity to JAK2 and tubulin-colchicine soblidotin molecular targets. This was further confirmed on the molecular level. Compound 4 has also led to apoptosis and increased fragmentation of DNA, and mitochondrial dysfunction. Our findings have provided good evidence that compound 4 may be a dual inhibitor of IL6/JAK2/STAT3 and tubulin formation in lung cancer. These findings support further molecular exploration of this androstane derivative as promising anti-lung cancer agent. Communicated by Ramaswamy H. Sarma