Gamma irradiation promotes chemo-sensitization potential of gallic acid through attenuation of autophagic flux to trigger apoptosis in an NRF2 inactivation signalling pathway

Srimanta Patra; Chandra Sekhar Bhol; Debasna Pritimanjari Panigrahi; Prakash Priyadarshi Praharaj; Biswajita Pradhan; Mrutyunjay Jena; Sujit Kumar Bhutia

doi:10.1016/j.freeradbiomed.2020.06.022

Gamma irradiation promotes chemo-sensitization potential of gallic acid through attenuation of autophagic flux to trigger apoptosis in an NRF2 inactivation signalling pathway

Free Radic Biol Med. 2020 Nov 20:160:111-124. doi: 10.1016/j.freeradbiomed.2020.06.022. Epub 2020 Aug 2.

Authors

Srimanta Patra¹, Chandra Sekhar Bhol¹, Debasna Pritimanjari Panigrahi¹, Prakash Priyadarshi Praharaj¹, Biswajita Pradhan², Mrutyunjay Jena², Sujit Kumar Bhutia³

Affiliations

¹ Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, India.
² PG Department of Botany, Berhampur University, Berhampur, 760007, India.
³ Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, India. Electronic address: sujitb@nitrkl.ac.in.

PMID: 32755671
DOI: 10.1016/j.freeradbiomed.2020.06.022

Abstract

Ionizing radiation has the potential to cause structural modification or change in electrochemical properties in parent lead pharmacophores that exhibit enhanced bioactivity. Gallic acid (GA), a triphenolic compound has displayed potent anticancer drug potency due to its withstanding antioxidant propensity. This study uncovered the comparative efficacy of gamma-irradiated gallic acid (GAIR) in the modulation of an antioxidant system for regulation apoptosis and autophagy. GAIR exhibited remarkable anti-proliferative efficacy as shown by MTT, clonogenic survival, and scratch assay. In addition to this, GAIR promoted intrinsic apoptosis through mitochondrial superoxide generation. GAIR decreased the activity of antioxidant enzymes by downregulating nuclear factor erythroid 2-related factor 2 (NRF2) and its downstream effector molecules NAD(P)H Quinone Dehydrogenase 1 (NQO1) and gamma-glutamylcysteine synthetase (GCLC). Simultaneously, GAIR attenuated autophagosome-lysosome fusion without altering the lysosomal activity. Inhibition of autophagic flux resulted in the accumulation of lipid droplets (LDs) such as hexadecanoic acid and oleic acid that fuelled superoxide generation leading to apoptosis. In the meantime, under oxidative upset, conversion of LDs to free fatty acids reduced leading to inhibition of ATP generation that subsequently provoked apoptosis. The effects of autophagy inhibition by GAIR on the therapeutic efficacy of chemotherapeutic drugs was studied and the co-treatment markedly decreased the cell viability and increased apoptosis. Further, GAIR exhibited potent antitumor activity in Dalton's Lymphoma-tumor bearing mice through modulation of apoptosis and autophagy without toxic activity. In conclusion, change in electrochemical properties by gamma radiation enhances the anticancer efficacy of gallic acid through superoxide mediated apoptosis fuelled by inhibition of lipophagy in an NRF2 dependent signaling pathway.

Keywords: Apoptosis; Autophagy; Gallic acid; Gamma-irradiation; Superoxide.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis*
Autophagy*
Gallic Acid* / pharmacology
Mice
NF-E2-Related Factor 2* / genetics
NF-E2-Related Factor 2* / metabolism
Reactive Oxygen Species
Signal Transduction

Substances

NF-E2-Related Factor 2
Reactive Oxygen Species
Gallic Acid