Full Text:   <465>

Summary:  <195>

Suppl. Mater.: 

CLC number: 

On-line Access: 2023-05-15

Received: 2022-09-25

Revision Accepted: 2023-02-02

Crosschecked: 2023-05-16

Cited: 0

Clicked: 725

Citations:  Bibtex RefMan EndNote GB/T7714

-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2023 Vol.24 No.5 P.442-454

http://doi.org/10.1631/jzus.B2200465


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


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, 2023, 24(5): 442-454.

@article{title="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="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",
volume="24",
number="5",
pages="442-454",
year="2023",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2200465"
}

%0 Journal Article
%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
%V 24
%N 5
%P 442-454
%@ 1673-1581
%D 2023
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2200465

TY - JOUR
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
VL - 24
IS - 5
SP - 442
EP - 454
%@ 1673-1581
Y1 - 2023
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2200465


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: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

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

Reference

[1]AndersonKC, 2016. Progress and paradigms in multiple myeloma. Clin Cancer Res, 22(22):5419-5427.

[2]ArgyriouAA, IconomouG, KalofonosHP, 2008. Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature. Blood, 112(5):1593-1599.

[3]BassAKA, El-ZoghbiMS, NageebESM, et al., 2021. Comprehensive review for anticancer hybridized multitargeting HDAC inhibitors. Eur J Med Chem, 209:112904.

[4]HarbeckN, Penault-LlorcaF, CortesJ, et al., 2019. Breast cancer. Nat Rev Dis Primers, 5:66.

[5]HeJS, ChenQX, GuHY, et al., 2018. Therapeutic effects of the novel subtype-selective histone deacetylase inhibitor chidamide on myeloma-associated bone disease. Haematologica, 103(8):1369-1379.

[6]HuangX, CaoW, YaoSN, et al., 2022. NEDD4L binds the proteasome and promotes autophagy and bortezomib sensitivity in multiple myeloma. Cell Death Dis, 13(3):197.

[7]JiMY, LiZL, LinZH, et al., 2018. Antitumor activity of the novel HDAC inhibitor CUDC-101 combined with gemcitabine in pancreatic cancer. Am J Cancer Res, 8(12):2402-2418.

[8]JiangWQ, FuFF, LiYX, et al., 2012. Molecular biomarkers of colorectal cancer: prognostic and predictive tools for clinical practice. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 13(9):663-675.

[9]JoshuaDE, BryantC, DixC, et al., 2019. Biology and therapy of multiple myeloma. Med J Aust, 210(8):375-380.

[10]KikuchiS, SuzukiR, OhguchiH, et al., 2015. Class IIa HDAC inhibition enhances ER stress-mediated cell death in multiple myeloma. Leukemia, 29(9):1918-1927.

[11]KumarSK, RajkumarV, KyleRA, et al., 2017. Multiple myeloma. Nat Rev Dis Primers, 3:17046.

[12]KumarSK, HarrisonSJ, CavoM, et al., 2020. Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol, 21(12):1630-1642.

[13]LiHY, CuiRH, JiMY, et al., 2021. CUDC-101 enhances the chemosensitivity of gemcitabine-treated lymphoma cells. Leuk Res, 106:106575.

[14]LiYH, YuanJ, 2021. Role of deubiquitinating enzymes in DNA double-strand break repair. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 22(1):63-72.

[15]LiangL, HeYJ, WangHQ, et al., 2020. The Wee1 kinase inhibitor MK1775 suppresses cell growth, attenuates stemness and synergises with bortezomib in multiple myeloma. Br J Haematol, 191(1):62-76.

[16]LuoHM, ZhangD, WangFF, et al., 2021. ALCAM-EGFR interaction regulates myelomagenesis. Blood Adv, 5(23):5269-5282.

[17]MahtoukK, HoseD, RèmeT, et al., 2005. Expression of EGF-family receptors and amphiregulin in multiple myeloma. Amphiregulin is a growth factor for myeloma cells. Oncogene, 24(21):3512-3524.

[18]MatthewsHK, BertoliC, de BruinRAM, 2022. Cell cycle control in cancer. Nat Rev Mol Cell Biol, 23(1):74-88.

[19]MinamiJ, SuzukiR, MazitschekR, et al., 2014. Histone deacetylase 3 as a novel therapeutic target in multiple myeloma. Leukemia, 28(3):680-689.

[20]ShimizuT, LorussoPM, PapadopoulosKP, et al., 2014. Phase I first-in-human study of CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 in patients with advanced solid tumors. Clin Cancer Res, 20(19):5032-5040.

[21]VallabhapurapuSD, NoothiSK, PullumDA, et al., 2015. Transcriptional repression by the HDAC4-RelB-p52 complex regulates multiple myeloma survival and growth. Nat Commun, 6:8428.

[22]van de Donk NWCJ, PawlynC, YongKL, 2021. Multiple myeloma. Lancet, 397(10272):410-427.

[23]von TresckowB, BoellB, EichenauerD, et al., 2014. Anti-epidermal growth factor receptor antibody cetuximab in refractory or relapsed multiple myeloma: a phase II prospective clinical trial. Leuk Lymphoma, 55(3):695-697.

[24]Wallington-BeddoeCT, Sobieraj-TeagueM, KussBJ, et al., 2018. Resistance to proteasome inhibitors and other targeted therapies in myeloma. Br J Haematol, 182(1):11-28.

[25]WangJ, PursellNW, SamsonMES, et al., 2013. Potential advantages of CUDC-101, a multitargeted HDAC, EGFR, and HER2 inhibitor, in treating drug resistance and preventing cancer cell migration and invasion. Mol Cancer Ther, 12(6):925-936.

[26]WuSG, ShihJY, 2018. Management of acquired resistance to EGFR TKI-targeted therapy in advanced non-small cell lung cancer. Mol Cancer, 17:38.

[27]ZhangLS, BoufraqechM, LakeR, et al., 2016. Carfilzomib potentiates CUDC-101-induced apoptosis in anaplastic thyroid cancer. Oncotarget, 7(13):16517-16528.

[28]ZhangMN, ZhangLX, HeiRX, et al., 2021. CDK inhibitors in cancer therapy, an overview of recent development. Am J Cancer Res, 11(5):1913-1935.

[29]ZhangTZ, MaD, WeiDN, et al., 2020. CUDC-101 overcomes arsenic trioxide resistance via caspase-dependent promyelocytic leukemia-retinoic acid receptor alpha degradation in acute promyelocytic leukemia. Anticancer Drugs, 31(2):158-168.

[30]ZhouZL, van der JeughtK, FangYZ, et al., 2021. An organoid-based screen for epigenetic inhibitors that stimulate antigen presentation and potentiate T-cell-mediated cytotoxicity. Nat Biomed Eng, 5(11):1320-1335.

Open peer comments: Debate/Discuss/Question/Opinion

<1>

Please provide your name, email address and a comment





Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2024 Journal of Zhejiang University-SCIENCE