Abstract
AbstractHead and neck squamous cell carcinoma (HNSCC) is a common malignancy that develops in or around the throat, larynx, nose, sinuses and mouth, and is mostly treated with a combination of chemo- and radiotherapy (RT). The main goal of RT is to kill enough of the cancer cell population, whilst preserving the surrounding normal and healthy tissue. The mechanisms by which conventional photon RT achieves this have been extensively studied over several decades, but little is known about the cell death pathways that are activated in response to RT of increasing linear energy transfer (LET), including proton beam therapy and heavy ions. Here, we provide an up-to-date review on the observed radiobiological effects of low- versus high-LET RT in HNSCC cell models, particularly in the context of specific cell death mechanisms, including apoptosis, necrosis, autophagy, senescence and mitotic death. We also detail some of the current therapeutic strategies targeting cell death pathways that have been investigated to enhance the radiosensitivity of HNSCC cells in response to RT, including those that may present with clinical opportunities for eventual patient benefit.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the eighth most common cancer in the UK, with more than 12 000 new cases every year and a one-year survival rate as low as 20% in the hypopharyngeal cancer subtype (Ref. 1)
proton beam therapy (PBT) displays increases in linear energy transfer (LET) at the Bragg peak and beyond the distal edge, which creates ionisation events and damage that is in closer proximity, such as the induction of complex DNA damage (CDD) containing multiple DNA lesions (Ref. 6)
This increase in CDD represents a challenge to the cellular DNA repair machinery and can contribute to the therapeutic effect of PBT, and more so of heavy ions that are of significantly higher LET
Summary
Head and neck squamous cell carcinoma (HNSCC) is the eighth most common cancer in the UK, with more than 12 000 new cases every year and a one-year survival rate as low as 20% in the hypopharyngeal cancer subtype (Ref. 1). Independently from the source and type of IR used, the main goal of RT is to cause sufficient damage to macromolecules DNA, and to lipids, proteins and many metabolites and to promote cancer cell death while preserving the surrounding healthy tissue The latter is where targeted dose delivery and energy deposition by PBT have a significant advantage over conventional photon irradiation. When the pro-apoptotic signal overcomes the anti-apoptotic one, mitochondrial proteins are released into the cytoplasm (e.g. cytochrome C and diablo IAP-binding mitochondrial protein) and this triggers initiator caspase 9 activation (Ref. 26) Both the intrinsic and extrinsic pathways of apoptosis proceed with the activation of effector caspases (caspases [3, 6] and 7), which in turn catalyse the specific cleavage of many key cellular proteins. Mitotic death can be triggered by either exogenous or endogenous sources, which cause several cell dysfunctions, such as altered DNA replication and
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