Sensitisation of cancer cells to radiotherapy by serine and glycine starvation

Abstract

BACKGROUND: Cellular metabolism is an integral component of cellular adaptation to stress, playing a pivotal role in the resistance of cancer cells to various treatment modalities, including radiotherapy. In response to radiotherapy, cancer cells engage antioxidant and DNA repair mechanisms which mitigate and remove DNA damage, facilitating cancer cell survival. Given the reliance of these resistance mechanisms on amino acid metabolism, we hypothesised that controlling the exogenous availability of the non-essential amino acids serine and glycine would radiosensitise cancer cells. METHODS: We exposed colorectal, breast and pancreatic cancer cell lines/organoids to radiation in vitro and in vivo in the presence and absence of exogenous serine and glycine. We performed phenotypic assays for DNA damage, cell cycle, ROS levels and cell death, combined with a high-resolution untargeted LCMS metabolomics and RNA-Seq. RESULTS: Serine and glycine restriction sensitised a range of cancer cell lines, patient-derived organoids and syngeneic mouse tumour models to radiotherapy. Comprehensive metabolomic and transcriptomic analysis of central carbon metabolism revealed that amino acid restriction impacted not only antioxidant response and nucleotide synthesis but had a marked inhibitory effect on the TCA cycle. CONCLUSION: Dietary restriction of serine and glycine is a viable radio-sensitisation strategy in cancer.

Rewiring of cortical glucose metabolism fuels human brain cancer growth

“…Blocking IMPDH may still have therapeutic benefit in glioma with a favorable therapeutic ratio because of the preference for gliomas to salvage hypoxanthine. Restricting dietary serine could help slow GBM growth and potentially augment the efficacy of standard of care GBM treatments 51 , though the efficacy of this approach could be limited by local production of serine in the GBM microenvironment 52 .The patient-to-patient heterogeneity in environmental serine dependence we observed suggests that isotope tracing could be used a precision medicine technique to determine which patients are mostly likely to benefit from dietary serine restriction.…”

Glycine homeostasis requires reverse SHMT flux

“…Consistent with endogenous serine and glycine metabolism remaining largely unaltered in response to diets lacking these amino acids, even the levels of serine and glycine stay the same except after eating, when they are lower due to lack of dietary influx. These observations are particularly important as serine and glycine-free diets have anticancer activity in mice and are currently being tested in humans (NCT05183295) 11,30,31,[40][41][42][43] . Our data suggest that the impact of these diets, at least in mice, is limited to the fed state.…”

Hypoxia-Responsive Aggregation of Gold Nanoparticles for Near-Infrared-II Photoacoustic Imaging-Guided Enhanced Radiotherapy

“…We studied the assembly process of nanomaterials in tumor response to NTR enzymes by NIR-II PA imaging. NPs (200 μL, 2 mg mL −1 ) dispersed in PBS solution were injected through the tail vein, and the PA imaging (PA 1200 nm ) signal changes over time (6,12,18,24,36, and 48 h) were recorded. As shown in Figure 5a, the PA signal increased gradually after 6 h and peaked after 24 h within the hypoxic staining images of the heart, liver, spleen, lung, and kidney of mice treated with PBS and AuNNP@PAA/NIC + X-ray (scale bar: 100 μm).…”

“…In clinical practice, RT is used in different phases of treatment for 60–70% of patients with malignant tumors . Unfortunately, the therapeutic use of RT in cancer treatment is severely constrained by radioresistance brought on by intratumoral hypoxia and the toxicity of high-dose radiation for surrounding healthy tissues. − It is well known that hypoxia is one of the defining characteristics of most solid tumors and an important cause of cancer progression and poor prognosis. − During RT, the hypoxic environment reduces the production of ROS and cytotoxic substances. , In addition, reducing substances, including sulfhydryl-containing molecules within the tumor, can significantly reduce the ionizing damage to the genomic DNA of cancer cells caused by ionizing radiation. − To address these issues, a variety of radiosensitizers that attempt to increase the radiation sensitivity of cancer cells have been developed and used in clinical settings, including sodium glycidazole and nimozole. − However, due to the low bioavailability in the body, large doses of sensitizers are required to achieve satisfactory radiosensitization effects, leading to serious negative impacts on healthy tissues, organs, and the central nervous system. High-atomic-number (high-Z) metals have received a lot of interest in the field of radiosensitization because they can greatly enhance the attenuation of X-rays and facilitate the deposition of radiation energy within the tumor. − To date, many nanoplatforms containing high-Z elements for radiosensitization have been successfully developed. − However, most of the current nanomedicines are unable to penetrate tumors and cannot reach cancer cells located far from the tumor-associated blood vessels, especially in the hypoxic area.…”