Department of Natural Medicines, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto862-0973, Japan.
Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto862-0973, Japan.
Chem Res Toxicol. 2022 Sep 19;35(9):1598-1603. doi: 10.1021/acs.chemrestox.2c00202. Epub 2022 Aug 26.
Mutant p53 not only loses its original tumor suppressor function but also acquires new abilities regarding oncogenic progression. Therefore, the strategy of targeting mutant p53 has attracted attention for cancer therapy. We isolated colletofragarone A2 (CF) from the fungus sp. (13S020), which decreases mutant p53 levels in cells, and herein examine its effect on mutant p53. CF showed more potent cytotoxic activities on cells with p53 structural mutants than those with different p53 statuses such as a DNA-contact mutant, wild-type, and null cells. CF markedly decreased tumor cell growth using a mouse xenograft model with HuCCT1 (p53) cells. Cotreatment of SK-BR-3 (p53) cells with CF and cycloheximide decreased mutant p53 levels by promoting p53 degradation. In the presence of MG-132, CF induced the accumulation of the aggregated mutant p53. These results suggest that CF inhibits the function of molecular chaperones such as HSP90.
突变型 p53 不仅丧失了原有的肿瘤抑制功能，而且获得了促进肿瘤进展的新能力。因此，靶向突变型 p53 的策略引起了人们对癌症治疗的关注。我们从真菌 sp.（13S020）中分离出 colletofragarone A2（CF），它可以降低细胞中突变型 p53 的水平，本文研究了它对突变型 p53 的影响。CF 对具有 p53 结构突变的细胞表现出比具有不同 p53 状态（如 DNA 结合突变体、野生型和无细胞）的细胞更强的细胞毒性活性。CF 在用 HuCCT1（p53）细胞建立的小鼠异种移植模型中显著降低了肿瘤细胞的生长。CF 与环磷酰胺联合处理 SK-BR-3（p53）细胞可通过促进 p53 降解来降低突变型 p53 水平。在 MG-132 的存在下，CF 诱导聚集的突变型 p53 积累。这些结果表明 CF 抑制 HSP90 等分子伴侣的功能。
