Colletofragarone A2 Inhibits Cancer Cell Growth In Vivo and Leads to the Degradation and Aggregation of Mutant p53

被引：5

作者：

Sadahiro, Yusaku ^{[1
]}

Hitora, Yuki ^{[1
]}

Kimura, Ichiro ^{[1
]}

Hitora-Imamura, Natsuko ^{[1
]}

Onodera, Risako ^{[2
]}

Motoyama, Keiichi ^{[2
]}

Tsukamoto, Sachiko ^{[1
]}

机构：

[1] Kumamoto Univ, Grad Sch Pharmaceut Sci, Dept Nat Med, Kumamoto 8620973, Japan

[2] Kumamoto Univ, Grad Sch Pharmaceut Sci, Dept Phys Pharmaceut, Kumamoto 8620973, Japan

来源：

CHEMICAL RESEARCH IN TOXICOLOGY | 2022年 / 35卷 / 09期

关键词：

CYTOTOXICITY; PROTEASOME;

D O I：

10.1021/acs.chemrestox.2c00202

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 Colletotrichum 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(R175H )structural mutants than those with different [353 statuses such as a DNA-contact mutant, wild-type, and null cells. CF markedly decreased tumor cell growth in vivo using a mouse xenograft model with HuCCT1 (p53(R175H)) cells. Cotreatment of SK-BR-3 (p53(R175H)) 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.

引用

页码：1598 / 1603

页数：6

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