Data from APR-246 enhances colorectal cancer sensitivity to radiotherapy

Abstract

<div>Abstract<p>p53 mutation is common and highly related to radiotherapy resistance in rectal cancer. APR-246, as a small molecule, can restore the tumor-suppressor function to mutant p53. As there is currently no existing study on combining APR-246 with radiation in rectal cancer, our objective was to investigate whether APR-246 could enhance the sensitivity of colorectal cancer cells, regardless of their p53 status, to radiation treatment. The combination treatment had synergistic effects on HCT116<sup>p53-R248W/−</sup> (p53Mut) cells, followed by HCT116<sup>p53+/+</sup> [wild-type p53 (p53WT)] cells, and exhibited an additive effect on HCT116<sup>p53−/−</sup> (p53Null) cells through inhibiting proliferation, enhancing reactive oxygen species, and apoptosis. The results were confirmed in zebrafish xenografts. Mechanistically, p53Mut and p53WT cells shared more activated pathways and differentially expressed genes following the combination treatment, compared with p53Null cells, although the combination treatment regulated individual pathways in the different cell lines. APR-246 mediated radiosensitization effects through p53-dependent and -independent ways. The results may provide evidence for a clinical trial of the combination in patients with rectal cancer.</p></div>

New Radiation Oncology Optimization Principles Based On In-Vivo Predictive Assay and Recent Developments in Molecular Radiation Biology

“…In a tumor growth assay, 20 μM APR 246 and 6 Gy both halved the mut xenograft size, whereas the combination brought it down to ≈1/5, but wt cells showed only a 30% APR 246 reduction, and null and mut cells were similar [37]. Interestingly, Venn diagrams of significantly enriched pathways and genes for combined and radiation-alone treatments were also included for wt, mut, and TP53 null cells [110]. APR 246 and PRIMA-1 are therefore very interesting compounds to improve the treatment possibilities of the multitude of LDRR tumors (cf the U1690 SCLC cell survival in Figure 33) that have a mutant TP53 pathway (>50% of all tumors) and therefore otherwise may need ion therapy to counteract their LDRR phenotype property as the treatment response is then generally more independent of the p53 status.…”

APR-246 as a radiosensitization strategy for mutant p53 cancers treated with alpha-particles-based radiotherapy

“…In the context of low-LET RT, a recent study indicated that APR-246 is mediating radiosensitization effects through both p53dependent as well as p53-independent manners [42].…”