Anti-neoplastic pharmacophore benzophenone-1 coumarin (BP-1C) targets JAK2 to induce apoptosis in lung cancer
| Autor: | Shaukath Ara Khanum, B.T. Prabhakar, Shivananda Kandagalla, Ankith Sherapura, Vikas H. Malojirao, Shrinath M Baliga, Y L Ramachandra, Jurica Novak, V. Vigneshwaran, Prabhu Thirusangu, Lakshmi Ranganatha, B S Sharath |
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| Rok vydání: | 2021 |
| Předmět: |
Pharmacology
Cancer Research Programmed cell death biology Chemistry Biochemistry (medical) Clinical Biochemistry Pharmaceutical Science Cell Biology medicine.disease Hedgehog signaling pathway lung cancer coumarin benzophenone JAK2/STAT3 apoptosis Apoptosis medicine Cancer research biology.protein Adenocarcinoma Lung cancer STAT3 Protein kinase B Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Apoptosis. 27:49-69 |
| ISSN: | 1573-675X 1360-8185 |
| Popis: | Reigning of the abnormal gene activation associated with survival signalling in lung cancer leads to the anomalous growth and therapeutic failure. Targeting specific cell survival signalling like JAK2/STAT3 nexus has become a major focus of investigation to establish a target specific treatment. The 2-bromobenzoyl-4-methylphenoxy-acetyl hydra acetyl Coumarin (BP-1C), is new anti-neoplastic agent with apoptosis inducing capacity. The current study was aimed to develop antitumor phramacophore, BP-1C as JAK2 specific inhibitor against lung neoplastic progression. The study validates and identifies the molecular targets of BP-1C induced cell death. Cell based screening against multiple cancer cell lines identified, lung adenocarcinoma as its specific target through promotion of apoptosis. The BP-1C is able to induce, specific hall marks of apoptosis and there by conferring anti-neoplastic activity. Validation of its molecular mechanism, identified, BP-1C specifically targets JAK2Tyr1007/1008 phosphorylation, and inhibits its downstream STAT3Tyr705 signalling pathway to induce cell death. As a consequence, modulation in Akt/Src survival signal and altered expression of interwoven apoptotic genes were evident. The results were reproducible in an in-vivo LLC tumor model and in-ovo xenograft studies. The computational approaches viz, drug finger printing confers, BP-1C as novel class JAK2 inhibitor and molecular simulations studies assures its efficiency in binding with JAK2. Overall, BP-1C is a novel JAK2 inhibitor with experimental evidence and could be effectively developed into a promising drug for lung cancer treatment. |
| Databáze: | OpenAIRE |
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