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Anti-neoplastic pharmacophore benzophenone-1 coumarin (BP-1C) targets JAK2 to induce apoptosis in lung cancer

Apoptosis volume 27, pages 49–69 (2022)Cite this article

Abstract

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.

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Data availability

All data generated or analysed during this study are included in this published article (and its Supplementary Information Files).

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Acknowledgements

Ankith Sherapura thankful to the Lady Tata Memorial Trust for JRS (2020–2021) and B.T. Prabhakar gratefully acknowledge the grant support by VGST (VGST/P-2/CISEE/GRD-231/2013–14) and SERB [EMR/2017/00088/ dated 3/01/2019]. Shaukath Ara Khanum thankfully acknowledges the financial support provided by VGST, Bangalore, under CISEE Program [Project Sanction Order No. VGST/CISEE/282/2012-13].

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Authors and Affiliations

  1. Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College, Kuvempu University, Shivamogga, Karnataka, 577203, India

    Ankith Sherapura, Vikas H. Malojirao, Prabhu Thirusangu, V. Vigneshwaran & B. T. Prabhakar

  2. Division for DNA Repair Research, Department of Neurosurgery, Centre for Neuroregeneration, Houston Methodist, Fannin Street, Houston, TX, USA

    Vikas H. Malojirao

  3. Department of Experimental Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA

    Prabhu Thirusangu

  4. School of System Biomedical Science and Department of Bioinformatics and Lifescience, Soongsil University, Seoul, South Korea

    B. S. Sharath

  5. Laboratory of Computational Modelling of Drugs, Higher Medical and Biological School, South Ural State University, Chaikovskogo 20A, Chelyabinsk, Russia, 454008

    Shivananda Kandagalla & Jurica Novak

  6. Department of Pharmacology and Centre for Lung and Vascular Biology, University of Illinois at Chicago, Chicago, 60612, USA

    V. Vigneshwaran

  7. Department of Chemistry, The National Institute of Engineering, Mysuru, Karnataka, 570008, India

    Lakshmi Ranganatha

  8. Department of Studies and Research in Biotechnology and Bioinformatics, Kuvempu University, Jnanasahyadri, Shankaraghatta, 577 451, India

    Y. L. Ramachandra

  9. Department of Radiation Oncology, Mangalore Institute of Oncology, Mangalore, Karnataka, 575 002, India

    Shrinath M. Baliga

  10. Department of Chemistry, Yuvaraja’s College (Autonomous), University of Mysore, Mysuru, Karnataka, 570 005, India

    Shaukath Ara Khanum

Authors
  1. Ankith Sherapura
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  2. Vikas H. Malojirao
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  3. Prabhu Thirusangu
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  4. B. S. Sharath
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  5. Shivananda Kandagalla
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  6. V. Vigneshwaran
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  7. Jurica Novak
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  8. Lakshmi Ranganatha
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  9. Y. L. Ramachandra
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  11. Shaukath Ara Khanum
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  12. B. T. Prabhakar
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Contributions

AS performed all the experiments, VHM, TP, VV assisted in experimental setup, and S.B.S, S.K, JN supported through in-silico approach, LR for synthesis of drug, SB, for scientific discussion and SAK and PBT designed the experiments, wrote the manuscript and monitored the entire investigation.

Corresponding authors

Correspondence to Shaukath Ara Khanum or B. T. Prabhakar.

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Sherapura, A., Malojirao, V.H., Thirusangu, P. et al. Anti-neoplastic pharmacophore benzophenone-1 coumarin (BP-1C) targets JAK2 to induce apoptosis in lung cancer. Apoptosis 27, 49–69 (2022). https://doi.org/10.1007/s10495-021-01699-5

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Keywords

  • Lung cancer
  • Coumarin
  • Benzophenone
  • JAK2/STAT3
  • Apoptosis