Aminoquinolines as Translational Models for Drug Repurposing: Anticancer Adjuvant Properties and Toxicokinetic-Related Features

Figure 2

Pathways involved in general cytotoxicity and activation of apoptosis by 4-aminoquinolines. The transportation of both drugs is completely via passive diffusion (i.e., no transporters are involved). Bak and Bax are p53-induced proapoptotic members that constitute the apoptotic pore complex for the release of mitochondrial cytochrome c, leading to mitochondrial depolarization, activation of caspase-3, cleaving of poly-(ADP-ribose)-polymerase 1 (PARP-1), and nuclear DNA fragmentation. Aminoquinoline-dependent DNA damage activates p53 and its downstream gene p21, resulting in cell cycle arrest after a post-translational p53 activation by phosphorylation of the ataxia telangiectasia-mutated (ATM) protein, leading to ATM-dependent phosphorylation of p53 checkpoint protein kinase. Moreover, chloroquine, quinacrine, and amodiaquine trigger p53 stabilization in TP53-specific reporter human cancer cells and block the p53 ubiquitination properties of human double minute 2 (Hdm2) molecules, which in turn prevents p53 proteasome degradation. Stimulation of histone acetyltransferase (HAC) and inhibition of histone deacetylase (HDAC) are part of the rationale pattern of arresting growth. Chloroquine is linked to the activation of p53, inhibition of NF-κB (factor nuclear kappa B) and uveal autoantigen with coiled-coil domains and ankyrin repeats (UACA), which promotes secretion of prostate apoptosis response-4 (Par-4) and expression of glucose regulated protein 78 (GRP78) receptor on the cancer cell surface, and consequent apoptosis.