RESUMEN
Radiotherapy is a leading treatment for various types of cancer. However, exposure to high-dose ionizing radiation causes acute gastrointestinal injury and gastrointestinal syndrome. This has significant implications for human health, and therefore, radioprotection is a major area of research. Radiation induces the loss of intestinal stem cells; hence, the protection of stem cells expressing LGR5 (a marker of intestinal epithelial stem cells) is a key strategy for the prevention of radiation-induced injury. In this study, we identified valproic acid (VPA) as a potent radioprotector using an intestinal organoid culture system. VPA treatment increased the number of LGR5+ stem cells and organoid regeneration after irradiation. N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT, an inhibitor of NOTCH signaling) blocked the radioprotective effects of VPA, indicating that NOTCH signaling is a likely mechanism underlying the observed effects of VPA. In addition, VPA acted as a radiosensitizer via the inhibition of histone deacetylase (HDAC) in a colorectal cancer organoid. These results demonstrate that VPA exerts strong protective effects on LGR5+ stem cells via NOTCH signaling and that the inhibition of NOTCH signaling reduces these protective effects, providing a basis for the improved management of radiation injury.
Asunto(s)
Neoplasias/radioterapia , Organoides/efectos de los fármacos , Sustancias Protectoras/farmacología , Traumatismos por Radiación/tratamiento farmacológico , Ácido Valproico/farmacología , Animales , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores Notch/metabolismoRESUMEN
Enhancing the radioresponsiveness of colorectal cancer (CRC) is essential for local control and prognosis. However, consequent damage to surrounding healthy cells can lead to treatment failure. We hypothesized that shortchain fatty acids (SCFAs) could act as radiosensitizers for cancer cells, allowing the administration of a lower and safer dose of radiation. To test this hypothesis, the responses of threedimensionalcultured organoids, derived from CRC patients, to radiotherapy, as well as the effects of combined radiotherapy with the SCFAs butyrate, propionate and acetate as candidate radiosensitizers, were evaluated via reverse transcriptionquantitative polymerase chain reaction, immunohistochemistry and organoid viability assay. Of the three SCFAs tested, only butyrate suppressed the proliferation of the organoids. Moreover, butyrate significantly enhanced radiationinduced cell death and enhanced treatment effects compared with administration of radiation alone. The radiationbutyrate combination reduced the proportion of Ki67 (proliferation marker)positive cells and decreased the number of S phase cells via FOXO3A. Meanwhile, 3/8 CRC organoids were found to be nonresponsive to butyrate with lower expression levels of FOXO3A compared with the responsive cases. Notably, butyrate did not increase radiationinduced cell death and improved regeneration capacity after irradiation in normal organoids. These results suggest that butyrate could enhance the efficacy of radiotherapy while protecting the normal mucosa, thus highlighting a potential strategy for minimizing the associated toxicity of radiotherapy.