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Specific focus on "redox cancer therapy" by targeting drugs to redox homeostasis of the cancer cells is growing rapidly. Recent clinical studies showed that N-acetyl cysteine (NAC) treatment significantly decreased the metabolic heterogeneity and reduced Ki67 (a proliferation marker) with simultaneous enhancement in apoptosis of tumor cells in patients. However, it is not yet precisely known how thiol antioxidants enhance killing of cancer cells in a context dependent manner. To this end, we showed that a dietary compound, malabaricone C (mal C) generated copious amounts of reactive oxygen species (ROS) and also reduced GSH level in lung cancer cells. Paradoxically, although antioxidants supplementation reduced mal C-induced ROS, thiol-antioxidants (NAC/GSH) restored intracellular GSH level but enhanced DNA DSBs and apoptotic cell death induced by mal C. Our results unraveled two tightly coupled biochemical mechanisms attributing this sensitization process by thiol antioxidants. Firstly, thiol antioxidants enable the "catechol-quinone redox cycle" of mal C and ameliorate ROS generation and bio-molecular damage (DNA and protein). Secondly, thiol antioxidants cause rapid glutathionylation of transcription factors [p53, p65 (NF-κB) etc.], oxidized by mal C, and abrogates their nuclear sequestration and transcription of the anti-apoptotic genes. Furthermore, analyses of the mitochondrial fractions of p53 expressing and silenced cells revealed that cytoplasmic accumulation of glutathionylated p53 (p53-SSG) triggers a robust mitochondrial death process. Interestingly, mutation of redox sensitive cysteine residues at 124, 141 and 182 position in p53 significantly reduces mal C plus NAC mediated sensitization of cancer cells. The preclinical results, in two different tumor models in mice, provides further support our conclusion that NAC is able to sensitize mal C induced suppression of tumor growth in vivo., Competing Interests: Declaration of competing interest The authors have no conflict of interest to report., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Abstract: The nuclease activities of the malabaricones have been studied so as to establish a structure–activity correlation and deduce the mechanistic pathway of the process. The inactivity of malabaricone A and malabaricone D revealed that the resorcinol moiety, present in the malabaricones did not contribute to the nuclease activity. Amongst the test compounds, malabaricone C (mal C) containing a B-ring catechol moiety showed significantly better Cu(II)-dependent nuclease activity than the partially methylated catechol derivative, mal B and curcumin. Mal C was found to bind efficiently with Cu(II) and DNA to facilitate the DNA nicking via a site-specifically generated Cu(I)-peroxo complex. Consistent with its Cu(II)-dependent nuclease property, mal C showed better cytotoxicity (IC50 =5.26±1.20μM) than curcumin (IC50 =24.46±3.32μM) against the MCF-7 human breast cancer cell line. The mal C-induced killing of the MCF-7 cells followed an apoptotic pathway involving oxidative damage to the cellular DNA. [ABSTRACT FROM AUTHOR]