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Targeting non-apoptotic cell death in cancer treatment by nanomaterials: Recent advances and future outlook

https://doi.org/10.1016/j.nano.2020.102243Get rights and content

Abstract

Many tumors develop resistance to most of the apoptosis-based cancer therapies. In this sense targeting non-apoptotic forms of cell death including necroptosis, autophagy and ferroptosis may have therapeutic benefits in apoptosis-defective cancer cells. Nanomaterials have shown great advantages in cancer treatment owing to their unique characteristics. Besides, the capability of nanomaterials to induce different forms of cell death has gained widespread attention in cancer treatment. Reports in this field reflect the therapeutic potential of necroptotic cell death induced by nanomaterials in cancer. Also, autophagic cell death induced by nanomaterials alone and as a part of chemo-, radio- and photothermal therapy holds great promise as anticancer therapeutic option. Besides, ferroptosis induction by iron-based nanomaterials in drug delivery, immunotherapy, hyperthermia and imaging systems shows promising results in malignancies. Hence, this review is devoted to the latest efforts and the challenges in this field of research and its clinical merits.

Section snippets

Necroptosis in cancer

Necroptosis is defined as a novel cell death that has some distinguishing characteristics in comparison with other cell death types.20 Pharmacological inhibition and genetic deletion of caspases are known as the main reasons of necroptosis occurrence that upon cellular incapability to trigger apoptosis are able to act as a “backup” form of PCD.21 Although necroptosis contribution in infection and inflammation is well recognized, the evidence of a physiological role in development is not known.20

Autophagic cell death

Autophagy is an intracellular bulk degradation mechanism that delivers vesicles containing misfolded macromolecules and organelles called autophagosomes to lysosomes in order to get removed.59 Autophagy is a double-edged sword in controlling cellular fate, while restricted autophagy is fundamentally a pro-survival mechanism that provides cells with alternative nutrient resources. Under stressful conditions, extensive autophagy will result in irreversible cellular damage and ultimately cell

Ferroptosis in cancer

Ferroptosis is another type of PCD which is independent from caspase and RIP1 pathway, but depends on iron-mediated ROS accumulation and plays a key role in many of the physiological and pathological contexts in cells.140,141 The main regulator of ferroptosis is glutathione peroxidase 4 (GPX4), which defends cells from lipid peroxidation.140,141 Contrary to the other forms of PCD, no nuclear shrinkage or plasma membrane rupture is detected in ferroptosis, while it is associated with

Conclusion and perspective

Anomalies in PCD pathways are associated with tumor initiation and progression alongside resistance to anticancer therapies. The PCD network can provide a variety of potential targets which enable altering the key signaling pathways in PCD by manipulating the gene and protein effectors in the global PCD network and thus can favor the cancer therapy. Owing to the intrinsic apoptosis resistance occurring in many cancer cells, targeting the non-apoptotic routes of PCD hold great promise in cancer

Funding

This study was not funded.

Declaration of competing interest

The authors inform no conflicts of interest.

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    Both authors contributed equally to present study.

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