Abstract
Background
Cisplatin has been extensively used in therapeutics for its broad-spectrum anticancer activity and frequently used for the treatment of solid tumors. However, it presents several side-effects and several cancers develop resistance. Combination therapy of cisplatin with poly (ADP-ribose) polymerase 1 (PARP1) inhibitors has been effective in increasing its efficacy at lower doses.
Methods and results
In this work, we have shown that the nitro-flavone derivative, 2-(4-Nitrophenyl)-4H-chromen-4-one (4NCO), can improve the sensitivity of cancer cells to cisplatin through inhibition of PARP1. The effect of 4NCO on cisplatin toxicity was studied through combination therapy in both exponential and density inhibited A375 melanoma cells. Combination index (CI) was determined from isobologram analysis. The mechanism of cell killing was assessed by lactate dehydrogenase (LDH) assay. Temporal nicotinamide adenine dinucleotide (NAD+) assay was done to show the inhibition of PARP1. We also performed in silico molecular modeling studies to know the binding mode of 4NCO to a modeled PARP1-DNA complex containing cisplatin-crosslinked adduct. The results from both in silico and in cellulo studies confirmed that PARP1 inhibition by 4NCO was most effective in sensitizing A375 melanoma cells to cisplatin. Isobologram analysis revealed that 4NCO reduced cell viability both in exponential and density inhibited A375 cells synergistically. The combination led to cell death through apoptosis.
Conclusion
The synthetic nitro-flavone derivative 4NCO effectively inhibited the important nuclear DNA repair enzyme PARP1 and therefore, could complement the DNA-damaging anticancer drug cisplatin in A375 cells and thus, could act as a potential adjuvant to cisplatin in melanoma therapy.





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Code availability
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Acknowledgements
The authors are grateful to Prof. S. Ghosh, Department of Chemistry, Jadavpur University for providing authentic samples of 4NCO for the work. The author, Anindita Mitra, acknowledges fellowship from Department of Science and Technology (DST-INSPIRE Grant: DST/INSPIRE Fellowship/2015/IF150061), Govt. of India. The authors also acknowledge the infrastructural facility at Department of Biotechnology (DBT) sponsored Bioinformatics Infrastructure Facility (BIF Centre), University of Kalyani for the work.
Funding
Department of Science & Technology—Promotion of University Research and Scientific Excellence II (DST-PURSE II), Govt. of India and University Grants Commission: Special Assistance Programme Departmental Research Support II (UGC-SAP DRS II), Govt. of India.
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Mitra, A., Ghosh, R. A375 melanoma cells are sensitized to cisplatin-induced toxicity by a synthetic nitro-flavone derivative 2-(4-Nitrophenyl)-4H-chromen-4-one through inhibition of PARP1. Mol Biol Rep 48, 5993–6005 (2021). https://doi.org/10.1007/s11033-021-06600-w
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DOI: https://doi.org/10.1007/s11033-021-06600-w