Fig. 6

Multiple effects of HMA on colon cancer cell metabolism. HMA inhibits NHEs, thus lowering intracellular pH, enters the cell and induces mechanical stress and metabolic perturbations, which, in turn, stimulate ROS production, causing damage to mitochondria and DNA. DNA damage is then recognized by PARP-1 (poly(ADP-ribose) polymerase-1) that reacts to the dangerous situation by synthesizing high amounts of PAR (poly(ADP-ribose). PAR can act here as a signalling death molecule for mitochondrial AIF (apoptosis inducing factor) , which is then released from damaged mitochondria and, promotes cell death through the parthanatos process. After this cascade of events, autophagy is futile and its stall contributes to cell death; moreover, a pathway of death dependent on the necroptosis factor RIPK3 becomes activated. In addition to these factors/processes, other still unknown mechanisms (denoted as “???”) could be involved in HMA toxicity