The Novel MDM4 Inhibitor CEP-1347 Activates the p53 Pathway and Blocks Malignant Meningioma Growth In Vitro and In Vivo

被引：4

作者：

Mitobe, Yuta ^{[1
,2
]}

Suzuki, Shuhei ^{[1
,3
]}

Nakagawa-Saito, Yurika ^{[1
]}

Togashi, Keita ^{[1
,4
]}

Sugai, Asuka ^{[1
]}

Sonoda, Yukihiko ^{[2
]}

Kitanaka, Chifumi ^{[1
,5
]}

Okada, Masashi ^{[1
]}

机构：

[1] Yamagata Univ, Sch Med, Dept Mol Canc Sci, 2-2-2 Iida Nishi, Yamagata 9909585, Japan

[2] Yamagata Univ, Sch Med, Dept Neurosurg, 2-2-2 Iida Nishi, Yamagata 9909585, Japan

[3] Yamagata Univ, Sch Med, Dept Clin Oncol, 2-2-2 Iida Nishi, Yamagata 9909585, Japan

[4] Yamagata Univ, Sch Med, Dept Ophthalmol & Visual Sci, 2-2-2 Iida Nishi, Yamagata 9909585, Japan

[5] Yamagata Univ, Res Inst Promot Med Sci, Fac Med, 2-2-2 Iida Nishi, Yamagata 9909585, Japan

来源：

BIOMEDICINES | 2023年 / 11卷 / 07期

关键词：

MDMX; HDMX; HDM4; MDM2; antagonist; drug repositioning; drug repurposing; brain tumor; PROTEIN; ACETYLATION; THERAPY; CELLS; JNK;

D O I：

10.3390/biomedicines11071967

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A significant proportion of meningiomas are clinically aggressive, but there is currently no effective chemotherapy for meningiomas. An increasing number of studies have been conducted to develop targeted therapies, yet none have focused on the p53 pathway as a potential target. In this study, we aimed to determine the in vitro and in vivo effects of CEP-1347, a small-molecule inhibitor of MDM4 with known safety in humans. The effects of CEP-1347 and MDM4 knockdown on the p53 pathway in human meningioma cell lines with and without p53 mutation were examined by RT-PCR and Western blot analyses. The growth inhibitory effects of CEP-1347 were examined in vitro and in a mouse xenograft model of meningioma. In vitro, CEP-1347 at clinically relevant concentrations inhibited MDM4 expression, activated the p53 pathway in malignant meningioma cells with wild-type p53, and exhibited preferential growth inhibitory effects on cells expressing wild-type p53, which was mostly mimicked by MDM4 knockdown. CEP-1347 effectively inhibited the growth of malignant meningioma xenografts at a dose that was far lower than the maximum dose that could be safely given to humans. Our findings suggest targeting the p53 pathway with CEP-1347 represents a novel and viable approach to treating aggressive meningiomas.

引用

页数：14