Figure 2.

General scheme of the mechanism of action of temozolomide. TMZ (temozolomide) can induce different events. On one hand, it methylates DNA forming N7-methylguanine (N7-meG) and N3-methyladenine (N3-meA), and less frequently, O6-methylguanine. DNA methylation induces the DNA mismatch repair (MMR) system that cannot remove the O6MG, creating futile cycles of mismatch and repair and generating DNA single- and double-strand breaks. Finally, stalled replication forks appear, and the cell cycle is blocked. All these events induce cell death through the activation of apoptosis, senescence, and mitotic catastrophe. On the other hand, TMZ can induce endoplasmic reticulum stress with consequent mitochondrial membrane depolarization and release of reactive oxygen species (ROS) in the cytoplasm. ROS release is associated with the induction of CMA activity, which in turn concurs to cell death.