Targeting autophagy using metallic nanoparticles: a promising strategy for cancer treatment

Abstract

Despite the extensive genetic and phenotypic variations present in the different tumors, they frequently share common metabolic alterations, such as autophagy. Autophagy is a self-degradative process in response to stresses by which damaged macromolecules and organelles are targeted by autophagic vesicles to lysosomes and then eliminated. It is known that autophagy dysfunctions can promote tumorigenesis and cancer development, but, interestingly, its overstimulation by cytotoxic drugs may also induce cell death and chemosensitivity. For this reason, the possibility to modulate autophagy may represent a valid therapeutic approach to treat different types of cancers and a variety of clinical trials, using autophagy modulators, are currently employed. On the other hand, recent progress in nanotechnology offers plenty of tools to fight cancer with innovative and efficient therapeutic agents by overcoming obstacles usually encountered with traditional drugs. Interestingly, nanomaterials can modulate autophagy and have been exploited as therapeutic agents against cancer. In this article, we summarize the most recent advances in the application of metallic nanostructures as potent modulators of autophagy process through multiple mechanisms, stressing their therapeutic implications in cancer diseases. For this reason, we believe that autophagy modulation with nanoparticle-based strategies would acquire clinical relevance in the near future, as a complementary therapy for the treatment of cancers and other diseases.

Keywords: Autophagy; Cancer therapy; Nanomaterials; Nanomedicine.

Fig. 1

Mechanism of macroautophagy. Cellular stresses induce AMPK signaling that inhibits the anti-autophagic mTOR complex (mTORC1 and mTORC2). Consequently, Beclin-1, ULK1, and Vps34 mediate phagophore formation and autophagy initiation. Recruitment of LC-3 II into the growing phagophore is dependent on ATG5–ATG12 interaction which favors the binding of LC3B-II on both internal and external surfaces of autophagosomes, where it plays a role in both fusion of membranes with lysosomes and in selecting cargo for lysosomal degradation. Depending on the nature of the stimulus and by cellular context, autophagy acts as a pro-survival mechanism by maintaining vital cellular activities, or drives cell death-type-II, thus acting as tumor suppressor event

Fig. 2

The dual role of autophagy in cancer. A variety of cellular stresses, including (1) nutrient deprivation, (2) oxidative stress, (3) hypoxia and (4) chemotherapy, can result in the induction of a protective autophagy leading tumor progression and chemoresistance. However, the same stresses can also induce and autophagy with tumor suppressor role. Indeed, cancer cells having an uncontrolled extensive autophagy can also undergo cell death-type II, likely due to excessive degradation of cellular constituents and organelles. Importantly, the inhibition of protective autophagy leads to apoptotic and necrotic cell death. In contrast, the inhibition of autophagy cell death (for instance by oncogenic mutant p53 isoforms) may lead to tumorigenesis through mTOR signaling and ROS

Fig. 3

Passive and active targeting of nanoparticles in cancer treatment. Passive tumor targeting is achieved by extravasation of nanoparticles through increased permeability of the tumor vasculature (EPR effect). Active tumor targeting (left inset) can be achieved by functionalization of nanoparticles with targeting ligands that promote cell-specific recognition and binding. Once internalized, the nanoparticles can express their cytotoxic potential by releasing the drug and/or another compound

Fig. 4

Cytosolic delivery of drug-loaded metallic nanoparticles via receptor-mediated endocytosis and its effect on autophagy and mitophagy modulation. The metallic nanoparticles, once internalization via receptor-mediated endocytosis, release the drugs or other compounds loaded, thus exerting a cytotoxic effect against cancer cells. The release occurs as a consequence of some cellular environmental stimuli, such as changes in pH and redox status by evoking changes in the nanocarrier structure. The toxic effect is exerted in various manners by inducing mitochondrial damage, and autophagy and mitophagy processes that culminate with apoptotic and autophagic cell death