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Targeting ferroptosis for cancer therapy: exploring novel strategies from its mechanisms and role in cancers.

ABSTRACT: Ferroptosis is a novel form of non-apoptotic regulated cell death (RCD), with distinct characteristics and functions in physical conditions and multiple diseases such as cancers. Unlike apoptosis and autophagy, this new RCD is an iron-dependent cell death with features of lethal accumulation of reactive oxygen species (ROS) and over production of lipid peroxidation. Excessive iron from aberrant iron metabolisms or the maladjustment of the two main redox systems thiols and lipid peroxidation role as the major causes of ROS generation, and the redox-acrive ferrous (intracellular labile iron) is a crucial factor for the lipid peroxidation. Regulation of ferrroptosis also involves different pathways such as mevalonate pathway, P53 pathway and p62-Keap1-Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. Ferroptosis roles as a double-edged sword either suppressing or promoting tumor progression with the release of multiple signaling molecules in the tumor microenvironment. Emerging evidence suggests ferroptosis as a potential target for cancer therapy and ferroptosis inducers including small molecules and nanomaterials have been developed. The application of ferroptosis inducers also relates to overcoming drug resistance and preventing tumor metastasis, and may become a promising strategy combined with other anti-cancer therapies. Here, we summarize the ferroptosis characters from its underlying basis and role in cancer, followed by its possible applications in cancer therapies and challenges maintained.

SUBMITTER: Jiang M

PROVIDER: S-EPMC7481593 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Targeting ferroptosis for cancer therapy: exploring novel strategies from its mechanisms and role in cancers.

Jiang Minlin M Qiao Meng M Zhao Chuanliang C Deng Juan J Li Xuefei X Zhou Caicun C

Translational lung cancer research 20200801 4

Ferroptosis is a novel form of non-apoptotic regulated cell death (RCD), with distinct characteristics and functions in physical conditions and multiple diseases such as cancers. Unlike apoptosis and autophagy, this new RCD is an iron-dependent cell death with features of lethal accumulation of reactive oxygen species (ROS) and over production of lipid peroxidation. Excessive iron from aberrant iron metabolisms or the maladjustment of the two main redox systems thiols and lipid peroxidation role ...[more]

PMID: 32953528

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Project description:The majority of high-risk neuroblastomas can be divided into three distinct molecular subgroups defined by the presence of MYCN amplification, upstream TERT rearrangements or alternative lengthening of telomeres (ALT). The common defining feature of all three subgroups is altered telomere maintenance; MYCN amplification and upstream TERT rearrangements drive high levels of telomerase expression whereas ALT is a telomerase independent telomere maintenance mechanism. As all three telomere maintenance mechanisms are independently associated with poor outcomes, the development of strategies to selectively target either telomerase expressing or ALT cells holds great promise as a therapeutic approach that is applicable to the majority of children with aggressive disease.Here we summarise the biology of telomere maintenance and the molecular drivers of aggressive neuroblastoma before describing the most promising therapeutic strategies to target both telomerase expressing and ALT cancers. For telomerase-expressing neuroblastoma the most promising targeted agent to date is 6-thio-2'-deoxyguanosine, however clinical development of this agent is required. In osteosarcoma cell lines with ALT, selective sensitivity to ATR inhibition has been reported. However, we present data showing that in fact ALT neuroblastoma cells are more resistant to the clinical ATR inhibitor AZD6738 compared to other neuroblastoma subtypes. More recently a number of additional candidate compounds have been shown to show selectivity for ALT cancers, such as Tetra-Pt (bpy), a compound targeting the telomeric G-quadruplex and pifithrin-?, a putative p53 inhibitor. Further pre-clinical evaluation of these compounds in neuroblastoma models is warranted.In summary, telomere maintenance targeting strategies offer a significant opportunity to develop effective new therapies, applicable to a large proportion of children with high-risk neuroblastoma. In parallel to clinical development, more pre-clinical research specifically for neuroblastoma is urgently needed, if we are to improve survival for this common poor outcome tumour of childhood.

Dataset Information

Targeting ferroptosis for cancer therapy: exploring novel strategies from its mechanisms and role in cancers.

Publications

Targeting ferroptosis for cancer therapy: exploring novel strategies from its mechanisms and role in cancers.

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