Biological Mechanisms to Reduce Radioresistance and Increase the Efficacy of Radiotherapy: State of the Art

Abstract

Cancer treatment with ionizing radiation (IR) is a well-established and effective clinical method to fight different types of tumors and is a palliative treatment to cure metastatic stages. Approximately half of all cancer patients undergo radiotherapy (RT) according to clinical protocols that employ two types of ionizing radiation: sparsely IR (i.e., X-rays) and densely IR (i.e., protons). Most cancer cells irradiated with therapeutic doses exhibit radio-induced cytotoxicity in terms of cell proliferation arrest and cell death by apoptosis. Nevertheless, despite the more tailored advances in RT protocols in the last few years, several tumors show a relatively high percentage of RT failure and tumor relapse due to their radioresistance. To counteract this extremely complex phenomenon and improve clinical protocols, several factors associated with radioresistance, of both a molecular and cellular nature, must be considered. Tumor genetics/epigenetics, tumor microenvironment, tumor metabolism, and the presence of non-malignant cells (i.e., fibroblast-associated cancer cells, macrophage-associated cancer cells, tumor-infiltrating lymphocytes, endothelial cells, cancer stem cells) are the main factors important in determining the tumor response to IR. Here, we attempt to provide an overview of how such factors can be taken advantage of in clinical strategies targeting radioresistant tumors.

A Compact Neutron Generator for the Niort® Treatment of Severe Solid Cancers

“…Published evidences support the hypothesis that saturation of the repair system leads to increasing genomic instability that may contribute to inactivate tumour cells as the dose per fraction is increased beyond the dose range normally studied in vitro. 38,39 Furthermore, some trials indicated that the DNA of cancer cells repairs more slowly and produces also more DNA breaks (single and double) than normal cells, also because various proteins involved in cell death and DNA damage mechanisms decrease the radioresistance of the fast-doubling cancer cells, while increase the radioresistance of slow doubling normal cells. 40 For what concerns the cells radiosensitivity, even whether the underpinning radio-biological mechanisms are not still fully understood, there exists an increasing amount of data at the biochemical level concerning the IR effects due to accelerator-produced charged particles (as protons and heavy ions), but few data concerning the effects due to high-LET beams of fast neutrons.…”

Targeting GSTP1-dependent ferroptosis in lung cancer radiotherapy: Existing evidence and future directions

“…Meanwhile, radiation is able to significantly increase the staining of C11-BODIPY, lipid peroxidation markers MDA and 4-HNE in cancer cells and tumor samples, indicating that radiation induces lipid peroxidation (Lei et al, 2020a;Zhang et al, 2021a;Zhou et al, 2022). Similarly, irradiated cells exhibit increased expression of the ferroptosis marker gene prostaglandin endoperoxide synthase 2 (PTGS2) (Busato et al, 2022;Yang et al, 2022). Furthermore, Seiji Torii et al shows that knockdown of Arachidonate 15-Lipoxygenase (ALOX15) decreases erastin-induced and RSL3-induced cellular ferroptosis, on the contrary exogenous overexpression of ALOX15 enhances the effects of these compounds.…”

LIF Inhibits Proliferation of Esophageal Squamous Carcinoma Cells by Radiation Mediated Through JAK-STAT Signaling Pathway

“…Currently, the X-rays used for radiotherapy of EC are low LET rays and cause damage to double-stranded DNA. Biological effects on tumor tissue are limited by factors such as cell cycle and hypoxia, which are unfavorable factors for the treatment of EC 4 . A high-LET carbon ion causes highly complex DNA lesions that include double-strand breaks.…”