JZUS - Journal of Zhejiang University SCIENCE

Journal of Zhejiang University SCIENCE B

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CUDC-101 as a dual-target inhibitor of EGFR and HDAC enhances the anti-myeloma effects of bortezomib by regulating G2/M cell cycle arrest

Author(s): Wen CAO, Shunnan YAO, Anqi LI, Haoguang CHEN, Enfan ZHANG, Liqin CAO, Jinna ZHANG, Yifan HOU, Zhenfeng DAI, Jing CHEN, Xi HUANG, Li YANG, Zhen CAI
Affiliation(s): Bone Marrow Transplantation Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China; more
Corresponding email(s): caiz@zju.edu.cn, liyanghz@zju.edu.cn
Key Words: CUDC-101; Multiple myeloma; Bortezomib; Epidermal growth factor receptor (EGFR); Cell cycle

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Wen CAO, Shunnan YAO, Anqi LI, Haoguang CHEN, Enfan ZHANG, Liqin CAO, Jinna ZHANG, Yifan HOU, Zhenfeng DAI, Jing CHEN, Xi HUANG, Li YANG, Zhen CAI. CUDC-101 as a dual-target inhibitor of EGFR and HDAC enhances the anti-myeloma effects of bortezomib by regulating G2/M cell cycle arrest[J]. Journal of Zhejiang University Science B,in press.Frontiers of Information Technology & Electronic Engineering,in press.https://doi.org/10.1631/jzus.B2200465

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author="Wen CAO, Shunnan YAO, Anqi LI, Haoguang CHEN, Enfan ZHANG, Liqin CAO, Jinna ZHANG, Yifan HOU, Zhenfeng DAI, Jing CHEN, Xi HUANG, Li YANG, Zhen CAI",
journal="Journal of Zhejiang University Science B",
year="in press",
publisher="Zhejiang University Press & Springer",
doi="https://doi.org/10.1631/jzus.B2200465"
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%T CUDC-101 as a dual-target inhibitor of EGFR and HDAC enhances the anti-myeloma effects of bortezomib by regulating G2/M cell cycle arrest
%A Wen CAO
%A Shunnan YAO
%A Anqi LI
%A Haoguang CHEN
%A Enfan ZHANG
%A Liqin CAO
%A Jinna ZHANG
%A Yifan HOU
%A Zhenfeng DAI
%A Jing CHEN
%A Xi HUANG
%A Li YANG
%A Zhen CAI
%J Journal of Zhejiang University SCIENCE B
%P 442-454
%@ 1673-1581
%D in press
%I Zhejiang University Press & Springer
doi="https://doi.org/10.1631/jzus.B2200465"

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T1 - CUDC-101 as a dual-target inhibitor of EGFR and HDAC enhances the anti-myeloma effects of bortezomib by regulating G2/M cell cycle arrest
A1 - Wen CAO
A1 - Shunnan YAO
A1 - Anqi LI
A1 - Haoguang CHEN
A1 - Enfan ZHANG
A1 - Liqin CAO
A1 - Jinna ZHANG
A1 - Yifan HOU
A1 - Zhenfeng DAI
A1 - Jing CHEN
A1 - Xi HUANG
A1 - Li YANG
A1 - Zhen CAI
J0 - Journal of Zhejiang University Science B
SP - 442
EP - 454
%@ 1673-1581
Y1 - in press
PB - Zhejiang University Press & Springer
ER -
doi="https://doi.org/10.1631/jzus.B2200465"

Abstract
Chinese Summary
Academic Network
Reviewer Comment

Abstract: CUDC-101, an effective and multi-target inhibitor of epidermal growth factor receptor (EGFR), histone deacetylase (HDAC), and human epidermal growth factor receptor 2 (HER2), has been reported to inhibit many kinds of cancers, such as acute promyelocytic leukemia and non-Hodgkin’s lymphoma. However, no studies have yet investigated whether CUDC-101 is effective against myeloma. Herein, we proved that CUDC-101 effectively inhibits the proliferation of multiple myeloma (MM) cell lines and induces cell apoptosis in a time- and dose-dependent manner. Moreover, CUDC-101 markedly blocked the signaling pathway of EGFR/phosphoinositide-3-kinase (PI3K) and HDAC, and regulated the cell cycle G2/M arrest. Moreover, we revealed through in vivo experiment that CUDC-101 is a potent anti-myeloma drug. Bortezomib is one of the important drugs in MM treatment, and we investigated whether CUDC-101 has a synergistic or additive effect with bortezomib. The results showed that this drug combination had a synergistic anti-myeloma effect by inducing G2/M phase blockade. Collectively, our findings revealed that CUDC-101 could act on its own or in conjunction with bortezomib, which provides insights into exploring new strategies for MM treatment.

EGFR和HDAC双靶点抑制剂CUDC-101通过调控G2/M期阻滞增强硼替佐米抗骨髓瘤的作用

曹文^1,2，姚舜楠³，李安琦^1,2，陈昊光^1,2，张恩帆^1,2，曹丽芹^1,2，张锦娜^1,2，侯怡帆^1,2，戴振峰^1,2，陈晶^1,2，黄系^1,2，杨励²，蔡真^1,2
¹浙江大学医学院附属第一医院骨髓移植中心，中国杭州市， 310006
²浙江大学血液病研究所，中国杭州市， 310058
³浙江大学医学院，中国杭州市， 310058
摘要：多发性骨髓瘤（MM）是一种高度异质性的疾病。硼替佐米作为第一代蛋白酶体抑制剂，大大提高了MM的治疗效果和疾病预后，延长了患者的总生存期和生活质量。然而，部分患者在接受硼替佐米治疗后仍会出现疾病复发和进展，且由硼替佐米引起的周围神经病变严重影响了患者的生活质量。因此，寻找新的MM治疗药物，或减少硼替佐米治疗的副作用，对MM患者是一个非常重要的临床需求。本研究旨在探索表皮生长因子受体（EGFR）和组蛋白去乙酰化酶（HDAC）双靶点抑制剂CUDC-101对MM治疗的潜在疗效，并阐述其潜在机制。结果表明，CUDC-101可通过抑制EGFR/PI3K和HDAC信号通路，诱导MM细胞系或原代CD138阳性MM细胞的细胞周期阻滞，显著抑制细胞增殖，诱导细胞凋亡。同时，CUDC-101在MM异种移植物模型中也表现出明显的生长抑制作用。此外，我们证实了CUDC-101和治疗MM的最常用的药物之一硼替佐米之间的协同作用。利用MM细胞系和异种移植模型，我们还发现了它可以显著抑制细胞增殖和肿瘤生长。总之，我们确定了CUDC-101在单药或联合硼替佐米治疗MM中的有效性。这一结果为MM患者的治疗提供了一种新的策略。

关键词组：CUDC-101；多发性骨髓瘤（MM）；硼替佐米；表皮生长因子受体（EGFR）；细胞周期

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EGFR和HDAC双靶点抑制剂CUDC-101通过调控G2/M期阻滞增强硼替佐米抗骨髓瘤的作用

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