Figure 10.

Hypothesis of the mechanisms causing cancer cell death induced by emodin and physcion. The intracellular oxidative environment stimulates the conversion of the anthraquinones (emodin, R=H, and physcion, R=OCH₃) into their semiquinone forms, which may be causing both lipoperoxidation (LPO) and DNA damage and this last activating repair enzymes (e.g., PARP-1) and consequently increasing the ATP consumption. Anthraquinones could also be promoting an inhibition of metabolic processes important to cell survival and proliferation, via inhibition of AKT; this causes activation of FOXO factors, stimulation of cell cycle control, DNA repair, and activation of cell death pathways. The increased ATP consumption could also lead to AMPK activation, which inhibits anabolic pathways and activates catabolic processes. Taken together, the oxidative stress generated by the anthraquinones and the inhibition of AKT could both lead to loss of the metabolic profile favoring tumor survival and an imbalance in BAX and BCL-2 levels, resulting in induction of cell death via apoptosis and necrosis, independent of caspase-3 activation.