Restoring chemo‑sensitivity to temozolomide via targeted inhibition of poly (ADP‑ribose) polymerase‑1 by naringin in glioblastoma

Rao, Vanishree and Cheruku, Sri Pragnya and Manandhar, Suman and Vibhavari, RJA and Nandakumar, Krishnadas and Rao, Mallikarjuna C and Kumar, Nitesh (2021) Restoring chemo‑sensitivity to temozolomide via targeted inhibition of poly (ADP‑ribose) polymerase‑1 by naringin in glioblastoma. Chemical Papers, 75. pp. 4861-4871. ISSN 0366-6352

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Abstract

Inclining mortality with a constant plummet in the survival rates associated with glioblastoma still stands as an inveterate predicament. The only promising therapy with temozolomide (TMZ) is now side-lined due to escalated resistance mediated by Poly (ADP-ribose) Polymerase-1 (PARP-1). In the light of this, the very study was designed to evaluate the potential of an active phyto component named naringin, in inhibiting PARP-1, using in silico and in vitro methods. Under in silico settings, inhibitor bound crystal structure of PARP-1, i.e., 4UND was retrieved and molecular docking studies were performed against naringin using Schrodinger software. In vitro cytotoxicity and apoptotic detection assay were performed using C6 glioma cells. Docking studies revealed high afnity and low binding energy at the inhibition site with good stability. An increase in cytotoxicity to C6 cells was observed with TMZ and naringin combination when compared to TMZ alone. Isobologram plot confrmed the synergistic efect of the drug combination. A signifcant increase in the number of apoptotic cells with combination drugs, as evaluated by acridine orange and ethidium bromide staining reassured the reversal of resistance. In conclusion, chemosensitivity to TMZ was restored by successful inhibition of PARP-1 using naringin and the drug combination was hence proven efective in reversing TMZ resistance.

Item Type: Article
Uncontrolled Keywords: Glioblastoma ; Temozolomide ; Poly (ADP-ribose) polymerase-1 ; Naringin ; Chemoresistance.
Subjects: Pharmacy > MCOPS Manipal > Pharmacology
Depositing User: KMC Library
Date Deposited: 25 Nov 2021 08:47
Last Modified: 25 Nov 2021 08:47
URI: http://eprints.manipal.edu/id/eprint/157744

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