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Novel 1,4-dihydropyridine induces apoptosis in human cancer cells through overexpression of Sirtuin1

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1,4-Dihydropyridines (1,4-DHPs) are important as a class of heterocyclic compounds that exhibit wide range of biological actions. Many of its derivatives are already characterized as medicinally important drugs and used worldwide. In this study, we have screened some novel Hantzsch 1,4-DHP compounds using both in silico (QSAR and Pharmacophore) and in vitro (cytotoxic screening). 1,4-DHP showed selective cytotoxicity against five human cancerous cell lines; A375, A549, HeLa, HepG2 and SH-SY5Y but limited effect towards normal skin keratinocyte (HaCaT), lung fibroblast (WL-38) and healthy peripheral blood mononuclear cells. In A375 and HepG2 cells, one of the 1,4-DHP derivative (DHP-8) was found to inhibit cell proliferation, and simultaneously increased the apoptotic population as well as mitochondrial membrane depolarization. Furthermore, the mitochondrial signal was triggered with the activation of cleaved Caspase9, Caspase3 and PARP. The treatment with DHP-8 also increased the expression level of SIRT1, subsequently decreasing the level of pAKTser473 and survivin. Reduced pAKTser473 expression led to decrease the phosphorylated inactive form of GSK3βser9 and as a result, proteasomal degradation of Mcl-1 occurred in both the cell lines. Here, we suggest that the apoptotic effect of DHP-8 in A375 and HepG2 cells was mediated by AKT and survivin pathways through SIRT1 activation. The involvement of DHP-8 in SIRT1 activation was further verified by co-treatment of nicotinamide with DHP-8 in both A375 and HepG2 cells. Overall, this study emphasizes the possible potential and therapeutic role of DHP-8 in skin and liver cancer.

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Acknowledgements

The authors acknowledge infrastructural support from KU and other instrumental facilities at the Department of Biochemistry & Biophysics, KU funded by DST-FIST, DST-PURSE, UGC-SAP, Govt. of India. The computational work was performed at Bioinformatics Infrastructure Facility (BIF), KU funded by Department of Biotechnology (DBT-India).

Funding

The following authors acknowledge financial support with fellowships: DM - University Scholarship, K.U. (Grant Number M.S.No.Rev/1172 of 2016-17), RB - Research Assistant under BTISNet program at KU funded by Department of Biotechnology, Ministry of Science and Technology (DBT-India) (Grant Number BT/BI/25/001/2006), FS - funded by Council of Scientific and Industrial Research (Grant No. 09/096(0696)/2011-EMR-1).

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  1. Forid Saikh

    Present address: Kharagpur College, Kharagpur, West Bengal, 721305, India

Authors and Affiliations

  1. Department of Biochemistry and Biophysics, University of Kalyani, Nadia, Kalyani, West Bengal, 741235, India

    Debashri Manna, Rajabrata Bhuyan & Rita Ghosh

  2. Department of Chemistry, Organic Section, Jadavpur University, Kolkata, West Bengal, 700032, India

    Forid Saikh & Somnath Ghosh

  3. Department of Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata, West Bengal, 700016, India

    Jayasri Basak

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  1. Debashri Manna
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  2. Rajabrata Bhuyan
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  4. Somnath Ghosh
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  5. Jayasri Basak
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  6. Rita Ghosh
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Correspondence to Rita Ghosh.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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10495_2018_1483_MOESM1_ESM.docx

Fig. S1 a, b) A357 and HepG2 cells were treated with different concentrations of DHP-8 and NAM to analyse the induction of apoptosis by Annexin V-7AAD/ PE (Invitrogen) staining through FACS LSRFORTESSA. A typical snapshot of dual parameter dot plot of 7AAD and PE labelled AnnexinV fluorescence (X-axis) and PE (Y-axis) in logarithmic fluorescence intensity are shown. c, d) The bar diagram shows the p-AKT/ AKT ratio for the activation of AKT in A375 and HepG2 cells. All data were the Mean ± SD (n=3) and analyzed by one-way ANOVA. ‘*’ represents the significant difference between the untreated and DHP-8 treated cells (P* < 0.05). (DOCX 2013 KB)

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Manna, D., Bhuyan, R., Saikh, F. et al. Novel 1,4-dihydropyridine induces apoptosis in human cancer cells through overexpression of Sirtuin1. Apoptosis 23, 532–553 (2018). https://doi.org/10.1007/s10495-018-1483-6

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