Full Text:   <837>

Summary:  <276>

CLC number: 

On-line Access: 2022-08-12

Received: 2022-01-11

Revision Accepted: 2022-04-10

Crosschecked: 2022-08-12

Cited: 0

Clicked: 2041

Citations:  Bibtex RefMan EndNote GB/T7714




-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2022 Vol.23 No.8 P.666-681


HDAC inhibitor chidamide synergizes with venetoclax to inhibit the growth of diffuse large B-cell lymphoma via down-regulation of MYC, BCL2, and TP53 expression

Author(s):  Cancan LUO, Tiantian YU, Ken H. YOUNG, Li YU

Affiliation(s):  Department of Hematology, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China; more

Corresponding email(s):   ndefy02021@ncu.edu.cn

Key Words:  Diffuse large B-cell lymphoma (DLBCL), Histone deacetylase (HDAC) inhibitor, Venetoclax, MYC, BCL2, TP53

Cancan LUO, Tiantian YU, Ken H. YOUNG, Li YU. HDAC inhibitor chidamide synergizes with venetoclax to inhibit the growth of diffuse large B-cell lymphoma via down-regulation of MYC, BCL2, and TP53 expression[J]. Journal of Zhejiang University Science B, 2022, 23(8): 666-681.

@article{title="HDAC inhibitor chidamide synergizes with venetoclax to inhibit the growth of diffuse large B-cell lymphoma via down-regulation of MYC, BCL2, and TP53 expression",
author="Cancan LUO, Tiantian YU, Ken H. YOUNG, Li YU",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T HDAC inhibitor chidamide synergizes with venetoclax to inhibit the growth of diffuse large B-cell lymphoma via down-regulation of MYC, BCL2, and TP53 expression
%A Cancan LUO
%A Tiantian YU
%A Li YU
%J Journal of Zhejiang University SCIENCE B
%V 23
%N 8
%P 666-681
%@ 1673-1581
%D 2022
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2200016

T1 - HDAC inhibitor chidamide synergizes with venetoclax to inhibit the growth of diffuse large B-cell lymphoma via down-regulation of MYC, BCL2, and TP53 expression
A1 - Cancan LUO
A1 - Tiantian YU
A1 - Ken H. YOUNG
A1 - Li YU
J0 - Journal of Zhejiang University Science B
VL - 23
IS - 8
SP - 666
EP - 681
%@ 1673-1581
Y1 - 2022
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2200016

diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin’s lymphoma. A total of 10%‒15% of DLBCL cases are associated with myelocytomatosis viral oncogene homolog (MYC) and/or B-cell lymphoma-2 (BCL2) translocation or amplification. BCL2 inhibitors have potent anti-tumor effects in DLBCL; however, resistance can be acquired through up-regulation of alternative anti-apoptotic proteins. The histone deacetylase (HDAC) inhibitor chidamide can induce BIM expression, leading to apoptosis of lymphoma cells with good efficacy in refractory recurrent DLBCL. In this study, the synergistic mechanism of chidamide and venetoclax in DLBCL was determined through in vitro and in vivo models. We found that combination therapy significantly reduced the protein levels of MYC, TP53, and BCL2 in activated apoptotic-related pathways in DLBCL cells by increasing BIM levels and inducing cell apoptosis. Moreover, combination therapy regulated expression of multiple transcriptomes in DLBCL cells, involving apoptosis, cell cycle, phosphorylation, and other biological processes, and significantly inhibited tumor growth in DLBCL-bearing xenograft mice. Taken together, these findings verify the in vivo therapeutic potential of chidamide and venetoclax combination therapy in DLBCL, warranting pre-clinical trials for patients with DLBCL.


3美国杜克大学医学院,美国达勒姆,NC 27710
方法:利用生物信息学技术分析表观遗传学HDAC基因与BCL2基因之间的相关性;体外应用DHL细胞株DB(MYC/BCL2重排)和DEL细胞株SUDHL-4(MYCBCL2表达)分别进行单药和联合用药处理,通过CCK-8法检测细胞活力,流式细胞术检测细胞凋亡和周期,RNA测序和蛋白质印迹(western blot)检测MYCBCL2TP53等相关基因的mRNA水平及蛋白的表达;体内建立DLBCL异种移植小鼠模型进行单药和联合用药治疗,分析并评价药物治疗后皮下瘤的大小和病理切片。


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


[1]AdamsCM, HiebertSW, EischenCM, 2016. Myc induces miRNA-mediated apoptosis in response to HDAC inhibition in hematologic malignancies. Cancer Res, 76(3):736-748.

[2]BaluapuriA, WolfE, EilersM, 2020. Target gene-independent functions of MYC oncoproteins. Nat Rev Mol Cell Biol, 21(5):255-267.

[3]BerendsenMR, StevensWBC, van den BrandM, et al., 2020. Molecular genetics of relapsed diffuse large B-cell lymphoma: insight into mechanisms of therapy resistance. Cancers, 12(12):3553.

[4]BholaPD, LetaiA, 2016. Mitochondria—judges and executioners of cell death sentences. Mol Cell, 61(5):695-704.

[5]BobrowiczM, DwojakM, PyrzynskaB, et al., 2017. HDAC6 inhibition upregulates CD20 levels and increases the efficacy of anti-CD20 monoclonal antibodies. Blood, 130(14):1628-1638.

[6]BurottoM, BerkovitsA, DunleavyK, 2016. Double hit lymphoma: from biology to therapeutic implications. Exp Rev Hematol, 9(7):669-678.

[7]ChanTS, TseE, KwongYL, 2017. Chidamide in the treatment of peripheral T-cell lymphoma. OncoTargets Ther, 10:347-352.

[8]ChenK, YangQY, ZhaJ, et al., 2020. Preclinical evaluation of a regimen combining chidamide and ABT-199 in acute myeloid leukemia. Cell Death Dis, 11(9):778.

[9]ChouTC, 2010. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res, 70(2):440-446.

[10]CroceCM, ReedJC, 2016. Finally, an apoptosis-targeting therapeutic for cancer. Cancer Res, 76(20):5914-5920.

[11]DuffyMJ, O'GradyS, TangMH, et al., 2021. MYC as a target for cancer treatment. Cancer Treat Rev, 94:102154.

[12]EckerJ, ThatikondaV, SigismondoG, et al., 2021. Reduced chromatin binding of MYC is a key effect of HDAC inhibition in MYC amplified medulloblastoma. Neuro Oncol, 23(2):226-239.

[13]FriedbergJW, 2017. How I treat double-hit lymphoma. Blood, 130(5):590-596.

[14]GongP, WangYT, JingYK, 2019. Apoptosis induction by histone deacetylase inhibitors in cancer cells: role of Ku70. Int J Mol Sci, 20(7):1601.

[15]GuanXW, WangHQ, BanWW, et al., 2020. Novel HDAC inhibitor Chidamide synergizes with Rituximab to inhibit diffuse large B-cell lymphoma tumour growth by upregulating CD20. Cell Death Dis, 11(1):20.

[16]HafeziS, RahmaniM, 2021. Targeting BCL-2 in cancer: advances, challenges, and perspectives. Cancers, 13(6):1292.

[17]HataAN, EngelmanJA, FaberAC, 2015. The BCL2 family: key mediators of the apoptotic response to targeted anticancer therapeutics. Cancer Discov, 5(5):475-487.

[18]HeidemanMR, WiltingRH, YanoverE, et al., 2013. Dosage-dependent tumor suppression by histone deacetylases 1 and 2 through regulation of c-Myc collaborating genes and p53 function. Blood, 121(11):2038-2050.

[19]HuangH, WuHW, HuYX, 2020. Current advances in chimeric antigen receptor T-cell therapy for refractory/relapsed multiple myeloma. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 21(1):29-41.

[20]KapoorI, BodoJ, HillBT, et al., 2020. Targeting BCL-2 in B-cell malignancies and overcoming therapeutic resistance. Cell Death Dis, 11(11):941.

[21]LaszigS, BoedickerC, WeiserT, et al., 2020. The novel dual BET/HDAC inhibitor TW09 mediates cell death by mitochondrial apoptosis in rhabdomyosarcoma cells. Cancer Lett, 486:46-57.

[22]LiSY, YoungKH, MedeirosLJ, 2018. Diffuse large B-cell lymphoma. Pathology, 50(1):74-87.

[23]LiWP, GuptaSK, HanWG, et al., 2019. Targeting MYC activity in double-hit lymphoma with MYC and BCL2 and/or BCL6 rearrangements with epigenetic bromodomain inhibitors. J Hematol Oncol, 12:73.

[24]LiX, YanX, GuoWJ, et al., 2017. Chidamide in FLT3-ITD positive acute myeloid leukemia and the synergistic effect in combination with cytarabine. Biomed Pharmacother, 90:699-704.

[25]MatthewsGM, NewboldA, JohnstoneRW, 2012. Intrinsic and extrinsic apoptotic pathway signaling as determinants of histone deacetylase inhibitor antitumor activity. Adv Cancer Res, 116:165-197.

[26]MorinRD, AssoulineS, AlcaideM, et al., 2016. Genetic landscapes of relapsed and refractory diffuse large B-cell lymphomas. Clin Cancer Res, 22(9):2290-2300.

[27]MrakovcicM, KleinheinzJ, FröhlichLF, 2019. p53 at the crossroads between different types of HDAC inhibitor-mediated cancer cell death. Int J Mol Sci, 20(10):2415.

[28]MuthalaguN, JunttilaMR, WieseKE, et al., 2014. BIM is the primary mediator of MYC-induced apoptosis in multiple solid tissues. Cell Rep, 8(5):1347-1353.

[29]NebbiosoA, CarafaV, ConteM, et al., 2017. c-Myc modulation and acetylation is a key HDAC inhibitor target in cancer. Clin Cancer Res, 23(10):2542-2555.

[30]NingZQ, LiZB, NewmanMJ, et al., 2012. Chidamide (CS055/HBI-8000): a new histone deacetylase inhibitor of the benzamide class with antitumor activity and the ability to enhance immune cell-mediated tumor cell cytotoxicity. Cancer Chemother Pharmacol, 69(4):901-909.

[31]NiuXJ, ZhaoJY, MaJ, et al., 2016. Binding of released Bim to Mcl-1 is a mechanism of intrinsic resistance to ABT-199 which can be overcome by combination with daunorubicin or cytarabine in AML cells. Clin Cancer Res, 22(17):4440-4451.

[32]NowakowskiGS, BlumKA, KahlBS, et al., 2016. Beyond RCHOP: a blueprint for diffuse large B cell lymphoma research. JNCI, 108(12):djw257.

[33]PanH, JiangYW, BoiM, et al., 2015. Epigenomic evolution in diffuse large B-cell lymphomas. Nat Commun, 6:6921.

[34]PatriarcaA, GaidanoG, 2021. Investigational drugs for the treatment of diffuse large B-cell lymphoma. Exp Opin Invest Drugs, 30(1):25-38.

[35]PeriniGF, RibeiroGN, NetoJVP, et al., 2018. BCL-2 as therapeutic target for hematological malignancies. J Hematol Oncol, 11:65.

[36]RiedellPA, SmithSM, 2018. Double hit and double expressors in lymphoma: definition and treatment. Cancer, 124(24):4622-4632.

[37]Rodríguez-ParedesM, EstellerM, 2011. Cancer epigenetics reaches mainstream oncology. Nat Med, 17(3):330-339.

[38]RosenthalA, YounesA, 2017. High grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6: double hit and triple hit lymphomas and double expressing lymphoma. Blood Rev, 31(2):37-42.

[39]SantoroF, BotrugnoOA, Dal ZuffoR, et al., 2013. A dual role for Hdac1: oncosuppressor in tumorigenesis, oncogene in tumor maintenance. Blood, 121(17):3459-3468.

[40]SarkozyC, Traverse-GlehenA, CoiffierB, 2015. Double-hit and double-protein-expression lymphomas: aggressive and refractory lymphomas. Lancet Oncol, 16(15):E555-E567.

[41]SermerD, PasqualucciL, WendelHG, et al., 2019. Emerging epigenetic-modulating therapies in lymphoma. Nat Rev Clin Oncol, 16(8):494-507.

[42]ShiYK, JiaB, XuW, et al., 2017. Chidamide in relapsed or refractory peripheral T cell lymphoma: a multicenter real-world study in China. J Hematol Oncol, 10:69.

[43]ShimizuR, KikuchiJ, WadaT, et al., 2010. HDAC inhibitors augment cytotoxic activity of rituximab by upregulating CD20 expression on lymphoma cells. Leukemia, 24(10):1760-1768.

[44]SouersAJ, LeversonJD, BoghaertER, et al., 2013. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med, 19(2):202-208.

[45]StaziG, FioravantiR, MaiA, et al., 2019. Histone deacetylases as an epigenetic pillar for the development of hybrid inhibitors in cancer. Curr Opin Chem Biol, 50:89-100.

[46]SwerdlowSH, CampoE, PileriSA, et al., 2016. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood, 127(20):2375-2390.

[47]VandenbergCJ, CoryS, 2013. ABT-199, a new Bcl-2-specific BH3 mimetic, has in vivo efficacy against aggressive Myc-driven mouse lymphomas without provoking thrombocytopenia. Blood, 121(12):2285-2288.

[48]WangP, WangZ, LiuJ, 2020. Role of HDACs in normal and malignant hematopoiesis. Mol Cancer, 19:5.

[49]WangXG, WaschkeBC, WoolaverRA, et al., 2020. HDAC inhibitors overcome immunotherapy resistance in B-cell lymphoma. Protein Cell, 11(7):472-482.

[50]XuY, ZhangP, LiuY, 2017. Chidamide tablets: HDAC inhibition to treat lymphoma. Drugs Today, 53(3):167-176.

[51]YuanXG, HuangYR, YuT, et al., 2019. Chidamide, a histone deacetylase inhibitor, induces growth arrest and apoptosis in multiple myeloma cells in a caspase-dependent manner. Oncol Lett, 18(1):411-419.

Open peer comments: Debate/Discuss/Question/Opinion


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