A chemical screen for medulloblastoma identifies quercetin as a putative radiosensitizer

Abstract

Treatment of medulloblastoma in children fails in approximately 30% of patients, and is often accompanied by severe late sequelae. Therefore, more effective drugs are needed that spare normal tissue and diminish long-term side effects. Since radiotherapy plays a pivotal role in the treatment of medulloblastoma, we set out to identify novel drugs that could potentiate the effect of ionizing radiation.Thereto, a small molecule library, consisting of 960 chemical compounds, was screened for its ability to sensitize towards irradiation. This small molecule screen identified the flavonoid quercetin as a novel radiosensitizer for the medulloblastoma cell lines DAOY, D283-med, and, to a lesser extent, D458-med at low micromolar concentrations and irradiation doses used in fractionated radiation schemes. Quercetin did not affect the proliferation of neural precursor cells or normal human fibroblasts. Importantly, in vivo experiments confirmed the radiosensitizing properties of quercetin. Administration of this flavonoid at the time of irradiation significantly prolonged survival in orthotopically xenografted mice. Together, these findings indicate that quercetin is a potent radiosensitizer for medulloblastoma cells that may be a promising lead for the treatment of medulloblastoma in patients.

Loss of Pin1 Suppresses Hedgehog-Driven Medulloblastoma Tumorigenesis

“…We are currently investigating whether pharmacological inhibition of PIN1 by either juglone or the flavonoid epigallocatechin gallate improves survival in mouse models of Hh-medulloblastoma. Interestingly, we note that quercetin, another flavonoid which inhibits PIN1, was recently identified in a chemical screen as a putative radiosensitizer for human medulloblastoma cells [39] . If our hypothesis is validated, i.e., PIN1 inhibitors can improve survival, it will strongly justify testing the clinical relevance of PIN1 blockade in Hh-medulloblastoma patients, either alone or in combination treatment regimens, e.g., in combination with SMO antagonists, which are currently being tested in clinical trials [40] .…”

Piperine sensitizes radiation‐resistant cancer cells towards radiation and promotes intrinsic pathway of apoptosis

“…Some natural compounds such as curcumin, quercetin, genistein, (Nicholson et al., 1995) danshsensu, wortmannin, and so on, are reported for inducing radiosensitization in cancer cells (Cao et al., 2017; Javvadi, Segan, Tuttle, & Koumenis, 2008; Lagerweij et al., 2016; Ortiz, Lopez, Burguillos, Edreira, & Pinero, 2004; Tang et al., 2018). Natural products owing to their antioxidant and immune‐enhancing effects may have improved effects as biological and radiation protectors for normal cells.…”

Inhalation anesthesia and shielding devices to allow accurate preclinical irradiation of mice with clinical linac-based systems: Design and dosimetric characteristics

“…Moreover, the target box setup allowed us to anesthetize with isoflurane, position, and radiate up to 12 mice within 5 minutes. The target box has already proven its value in the identification of radiosensitizers for the treatment of pediatric brain tumors and glioblastoma [17,18], whilst the TBI box has been used in several studies, such as those for head-and-neck cancer [19]. In conclusion, the target box allows easy immobilization and positioning of the mice, the mice remain well controlled under anesthesia during the radiations, and both devices support accurate administration of the radiation dose.…”