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Journal of Zhejiang University SCIENCE B
ISSN 1673-1581(Print), 1862-1783(Online), Monthly
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
Abstract: 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.
Key words: Diffuse large B-cell lymphoma (DLBCL); Histone deacetylase (HDAC) inhibitor; Venetoclax; MYC; BCL2; TP53
1南昌大学第二附属医院血液科，中国南昌，330006
2江西省血液重点实验室，中国南昌，330006
3美国杜克大学医学院，美国达勒姆，NC 27710
目的：探讨表观遗传学组蛋白去乙酰化酶（HDAC）抑制剂西达本胺与BCL2抑制剂维奈托克的联合对弥漫性大B细胞淋巴瘤（DLBCL）生长的影响及相关机制。
创新点：本研究首次探索了将西达本胺和维奈托克联合作用于MYC+/BCL2+DLBCL，使用二代测序（NGS）开创性地从表观遗传学和基因蛋白层面探讨这种联合用药的效果及作用机制。
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（MYC、BCL2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MYC、BCL2、TP53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。
结论：西达本胺与维奈托克协同抑制DLBCL的生长，通过调控表观遗传的改变，沉默MYC、TP53的表达，降低抗凋亡蛋白BCL2表达以及增加促凋亡蛋白BIM表达，诱导肿瘤细胞的凋亡和细胞周期阻滞。
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References:
[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.
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DOI:
10.1631/jzus.B2200016
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2024-08-27
Received:
2023-10-17
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2024-05-08
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2022-08-12