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.
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.
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Acknowledgments
This work was supported by the National Natural Science Foundation of China (Nos. 81872322, 81900209, and 82100213) and the Zhejiang Key Research and Development Project (No. 2020C03014). We thank to the Key Laboratory of Multi-Organ Transplantation Research, Ministry of Health, the First Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou, China) for providing the experimental platform.
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Wen CAO, Li YANG, and Zhen CAI initiated and designed the study. Wen CAO and Shunnan YAO performed the majority of the experiments. Wen CAO wrote the manuscript. Anqi LI, Haoguang CHEN, Liqin CAO, and Jinna ZHANG performed the research and analyzed the data. Yifan HOU, Zhenfeng DAI, Jing CHEN, and Xi HUANG collected primary samples for the study. Enfan ZHANG, Li YANG, and Zhen CAI supervised the experiments. All authors have read and approved the final manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data.
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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, and Zhen CAI declare that they have no conflict of interest.
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (the Research Ethics Committee of the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China) (No. IIT20220720A) and with the Helsinki Declaration of 1975, as revised in 2013. Informed consent was obtained from all patients for being included in the study. Additional informed consent was obtained from all patients for which identifying information is included in this article. All institutional and national guidelines for the care and use of laboratory animals were followed.
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Cao, W., Yao, S., Li, A. et al. 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. Zhejiang Univ. Sci. B 24, 442–454 (2023). https://doi.org/10.1631/jzus.B2200465
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DOI: https://doi.org/10.1631/jzus.B2200465