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

Figure 3

Molecular findings, which support the theory that chloroquine and analogues exerts, at least in part, antineoplastic effects altering the phosphorylation status of EGFR/PI3K/Akt/mTOR/Atg and p53 pathways, inhibiting directly PI3K-Akt and mTOR kinases, obstructing catalytic subunits in the ATP-binding site or altering the recycling of tyrosine kinase receptors, besides impairing or interfering in lysosomal and autophagosome functions. mTOR phosphorylates the eukaryotic initiation factor 4E-binding protein (4E-BP) and the p70S6 kinase1 (S6K1). Therefore, if specific drug inhibitors against mTOR kinase are used, this should not only have altered proliferation but also the protein synthesis rate. Vesicular protein sorting 34 (Vps34) complex I has Atg14p as an additional factor, which participates in the formation of autophagosomes, while complex II has Vps38, which is required for vacuolar protein sorting. These catalytic complexes work as ubiquitin-like conjugation systems for phagophore elongation and recruitment of other proteins to the self-digesting process, as seen with Vps34, a phosphatidylinositol serine-threonine kinase, its binding partner Beclin-1 (Atg6) and the protein kinase p150 in mammals (Vps15). Assembly of this complex is crucial for autophagy and it recruits other proteins to the phagophore assembly site (PAS). Therefore, the phagophore elongates into a cup-shaped structure and begins to engulf cellular material, sequestering the material in a double-membraned autophagosome. Both chloroquine and hydroxychloroquine block autophagy in initial phases, causing accumulation of acidic vesicle cell markers and appear to deactivate upstream members of mitogen-activated protein kinase (MAPK) pathway, preventing phosphorylation and activation of extracellular signal-regulated kinases (ERK)1/2 by a paradoxical phosphorylation of Raf at specific residues, which possibly blocks ERK activation by Akt activity.