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.