Epoxyazadiradione exhibit activities in head and neck squamous cell carcinoma by targeting multiple pathways
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Epoxyazadiradione exhibit activities in head and neck squamous cell carcinoma by targeting multiple pathways Vipin Rai1 · Sushil Kumar Aggarwal2 · Sumit Singh Verma1 · Nikee Awasthee1 · Anupam Dhasmana3,7 · Sadhna Aggarwal4 · Satya N. Das4,8 · Mangalam S. Nair5 · Sanjay Yadav6 · Subash C. Gupta1 Accepted: 30 August 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract The head and neck squamous cell carcinoma (HNSCC) constitute about 90% of all head and neck cancers. HNSCC falls in the top 10 cancers in men globally. Epoxyazadiradione (EPA) and Azadiradione (AZA) are the limonoids derived from the medicinal plant Azadirachta indica (popularly known as Neem). Whether or not the limonoids exhibit activities against HNSCC and the associated mechanism remains elusive. Herein, we demonstrate that EPA exhibits stronger activity in HNSCC in comparison to AZA. The limonoids obeyed the Lipinski’s rule of 5. EPA exhibited activities in a variety of HNSCC lines like suppression of the proliferation and the induction of apoptosis. The limonoid suppressed the level of proteins associated with anti-apoptosis (survivin, Bcl-2, Bcl-xL), proliferation (cyclin D1), and invasion (MMP-9). Further, the expression of proapoptotic Bax and caspase-9 cleavage was induced by the limonoid. Exposure of EPA induced reactive oxygen species (ROS) generation in the FaDu cells. N-acetyl-L-cysteine (ROS scavenger) abrogated the down-regulation of tumorigenic proteins caused by EPA exposure. EPA induced NOX-5 while suppressing the expression of programmed death-ligand 1 (PD-L1). Further, hydrogen peroxide induced NF-κB-p65 nuclear translocation and EPA inhibited the translocation. Finally, EPA modulated the expression of lncRNAs in HNSCC lines. Overall, these results have shown that EPA exhibit activities against HNSCC by targeting multiple cancer related signalling molecules. Currently, we are evaluating the efficacy of this molecule in mice models. Keywords Carcinogenesis · Head and neck squamous cell carcinoma · Limonoid · Long non-coding RNA · Reactive oxygen species
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10495-020-01633-1) contains supplementary material, which is available to authorized users. * Subash C. Gupta [email protected] 1
Head and neck cancer (HNC) is one of the ten common cancers globally. More than 650,000 cases are identified worldwide, out of which 330,000 dies of the disease annually [1]. HNC is a heterogeneous tumour at various anatomic sites 5
Division of Organic Chemistry, CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram, India
Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
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Department of Otorhinolaryngology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221 005, India
Department of Biochemistry, All India Institute of Medical Sciences, Raebareli 229405, India
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Department of Bioscie
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