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《天津医科大学学报》[ISSN:1006-8147/CN:12-1259/R]

卷:

28卷

期数:

2022年05期

页码:

478-482

栏目:

基础医学

出版日期:

2022-09-20

文章信息/Info

Title:

Histone deacetylase inhibitor LBH589 inhibits the growth and metastasis of basal-like breast cancer

文章编号:

1006-8147(2022)05-0478-05

作者:

庄慧萍

（天津医科大学肿瘤医院肿瘤研究所生物化学与分子生物学研究室；国家肿瘤临床医学研究中心；天津市“肿瘤防治”重点实验室；天津市恶性肿瘤临床医学研究中心；乳腺癌防治教育部重点实验室，天津300060）

Author(s):

ZHUANG Hui-ping

（Department of Biochemistry and Molecular Biology，Tianjin Medical University Cancer Institute and Hospital；National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy，Tianjin；Tianjin′s Clinical Research Center for Cancer; Key Laboratory of Breast Cancer Prevention and Therapy，Tianjin Medical University，Ministry of Education，Tianjin 300060，China）

关键词:

HDACIs; LBH589; 基底样乳腺癌; 增殖; 转移

Keywords:

HDACIs; LBH589; basal-like breast cancer; proliferation; metastasis

分类号:

R737.9

DOI:

-

文献标志码:

A

摘要:

目的：探究组蛋白去乙酰化酶抑制剂LBH589对基底样乳腺癌（BLBC）生长和转移的抑制作用。方法：通过MTT法和平板克隆实验检测LBH589对人乳腺癌细胞系MDA-MB-231和小鼠乳腺癌细胞系4T1增殖能力的影响；Transwell实验检测LBH589对细胞迁移和侵袭能力的影响；实时荧光定量PCR和免疫印迹实验检测LBH589对细胞上皮-间质转化的作用；构建4T1乳腺癌细胞Balb/c小鼠脂肪垫成瘤模型，腹腔注射LBH589，观察4T1细胞成瘤和转移能力。结果：体外实验结果显示，与对照组相比，LBH589显著抑制MDA-MB-231和4T1细胞的增殖能力（t=11.37，P<0.05；t=18.18，P<0.05）、克隆形成能力（t=7.76，P<0.05；t=15.22，P<0.05）、迁移（t=8.8，P<0.05；t=18.0，P<0.05）和侵袭能力（t=8.24，P<0.05；t=15.99，P<0.05）；与对照组相比，LBH589上调细胞的上皮标志物CDH1的mRNA（t=7.33，P<0.05）表达水平，抑制细胞的间充质标志物VIM和FN1的mRNA（t=5.57，P<0.05；t=6.3，P<0.05）和蛋白（t=8.37，P<0.05；t=11.3，P<0.05）表达水平；体内实验结果表明，给予LBH589治疗显著抑制肿瘤的生长（t=6.3，P<0.05），并抑制其肺转移（P<0.05）。结论：LBH589能够抑制BLBC细胞增殖和转移，具有潜在的临床应用价值。

Abstract:

Objective: To investigate the inhibitory effect of histone deacetylase inhibitors LBH589 on the growth and metastasis of basal-like breast cancer. Methods: The effects of LBH589 on the proliferation，migration and invasion of human breast cancer cell line MDA-MB-231 and mouse breast cancer cell line 4T1 were determined by MTT assay，colony formation assay and Transwell assay.The effect of LBH589 on epithelial-mesenchymal transformation was detected by RT-qPCR and Western blotting. The abdominal mammary fat pads tumor-forming model of 4T1 breast cancer cells was established in Balb/c mice，and LBH589 was intraperitoneally injected to observe the effect on the tumor-forming ability of 4T1 cells and visceral metastasis. Results: Compared with control group，in vitro results showed that LBH589 significantly inhibited the proliferation（t=11.37，P<0.05；t=18.18，P<0.05），colony formation ability（t=7.76，P<0.05；t=15.22，P<0.05），migration（t= 8.8，P<0.05；t=18.0，P<0.05），and invasive ability（t=8.24，P<0.05；t=15.99，P<0.05）.Compared with control group，LBH589 upregulated the expression level of epithelial marker CDH1 mRNA（t=7.33，P< 0.05），and inhibited mesenchymal marker VIM，FN1 mRNA（t=5.57，P< 0.05；t =6.3，P<0.05） and protein（t=8.37，P<0.05；t=11.3，P<0.05）.In vivo results showed that treatment with LBH589 significantly inhibited tumor growth and lung metastasis. Conclusion:LBH589 can inhibit the proliferation and metastasis of basal-like breast cancer，which has potential clinical application value.

参考文献/References:

[1] ALEXANDROU S，GEORGE S M，ORMANDY C J，et al. The proliferative and apoptotic landscape of basal-like breast cancer[J]. Int J Mol Sci，2019，20（3）：667.
[2] BORRI F，GRANAGLIA A. Pathology of triple negative breast cancer[J]. Semin Cancer Biol，2021，72：136-145.
[3] ZUCCHETTI B，SHIMADA A K，KATZ A，et al. The role of histone deacetylase inhibitors in metastatic breast cancer[J]. Breast，2019，43：130-134.
[4] SINGH A K，BISHAYEE A，PANDEY A K. Targeting histone deacetylases with natural and synthetic agents：an emerging anticancer strategy [J]. Nutrients，2018，10（6）：731.
[5] LEE A，DJAMGOZ M B A. Triple negative breast cancer：emerging therapeutic modalities and novel combination therapies[J]. Cancer Treat Rev，2018，62：110-122.
[6] PARK S Y，JUN J A，JEONG K J，et al. Histone deacetylases 1，6 and 8 are critical for invasion in breast cancer[J]. Oncol Rep，2011，25（6）：1677-1681.
[7] MüLLER B M，JANA L，KASAJIMA A，et al. Differential expression of histone deacetylases HDAC1，2 and 3 in human breast cancer--overexpression of HDAC2 and HDAC3 is associated with clinicopathological indicators of disease progression[J]. BMC Cancer，2013，13：215.
[8] RODRíGUEZPAREDES M，ESTELLER M. Cancer epigenetics reaches mainstream oncology [J]. Nat Med，2011，17（3）：330-339.
[9] SUN Y，SUN Y，YUE S，et al. Histone deacetylase inhibitors in cancer therapy [J]. Curr Top Med Chem，2018，18（28）：2420-2428.
[10] PENG J，LI S J，FU X，et al. Chidamide acts on the histone deacetylase-mediated miR-34a/Bcl-2 axis to regulate NB4 cell line proliferation and apoptosis[J]. Kaohsiung J Med Sci，2020，36（12）：1004-1013.
[11] HEERS H，STANISLAW J，HARRELSON J，et al. Valproic acid as an adjunctive therapeutic agent for the treatment of breast cancer [J]. Eur J Pharmacol，2018，835：61-74.
[12] LIANG X，LIU H，ZHANG Y. Novel-targeted therapy for hematological malignancies with JAK and HDAC dual inhibitors [J]. Future Med Chem，2019，11（15）：1849-1852.
[13] GREGORETTI I V，LEE Y M，GOODSON H V. Molecular evolution of the histone deacetylase family： functional implications of phylogenetic analysis [J]. J Mol Biol，2004，338（1）：17-31.
[14] MARKS P A. The clinical development of histone deacetylase inhibitors as targeted anticancer drugs[J]. Expert Opin Investig Drugs，2010，19（9）：1049-1066.
[15] SAN JOS?魪EN?魪RIZ E，GIMENEZCAMINO N，AGIRRE X，et al. HDAC inhibitors in acute myeloid leukemia[J]. Cancers （Basel），2019，11（11）：1794.
[16] WIERZBICKI K，RAVI K，FRANSON A，et al. Targeting and therapeutic monitoring of H3K27M-mutant glioma[J]. Curr Oncol Rep，2020，22（2）：19.
[17] BAJBOUJ K，ALALI A，RAMAKRISHNAN R K，et al. Histone modification in NSCLC：molecular mechanisms and therapeutic targets[J]. Int J Mol Sci，2021，22（21）：11701.
[18] FEDELE P，ORLANDO L，CINIERI S. Targeting triple negative breast cancer with histone deacetylase inhibitors[J]. Expert Opin Investig Drugs，2017，26（11）：1199-1206.
[19] LANDGREN O，ISKANDER K. Modern multiple myeloma therapy： deep，sustained treatment response and good clinical outcomes [J]. J Intern Med，2017，281（4）：365-382.
[20] HESHAM H M，LASHEEN D S，ABOUZID KAM. Chimeric HDAC inhibitors：comprehensive review on the HDAC-based strategies developed to combat cancer [J]. Med Res Rev，2018，38（6）：2058-2109.
[21] ZHAO C，DONG H，XU Q，et al. Histone deacetylase（HDAC） inhibitors in cancer： a patent review （2017-present） [J]. Expert Opin Ther Pat，2020，30（4）：263-274.
[22] ATADJA P. Development of the pan-DAC inhibitor panobinostat （LBH589）：successes and challenges[J]. Cancer Lett，2009，280（2）：233-241.
[23] SINGH A，PATEL P，JAGESHW A R，et al. The safety，efficacy and therapeutic potential of histone deacetylase inhibitors with special reference to panobinostat in gastrointestinal tumors：a review of preclinical and clinical studies[J]. Curr Cancer Drug Targets，2018，18（8）：720-736.
[24] SCHMITZ R L，WEISSBACH J，KLEILEIN J，et al. Targeting HDACs in pancreatic neuroendocrine tumor models[J]. Cells，2021，10（6）：1408.
[25] QIN G，LI Y，XU X，et al. Panobinostat（LBH589） inhibits Wnt/β-catenin signaling pathway via upregulating APCL expression in breast cancer [J]. Cell Signal，2019，59：62-75.
[26] LEE Y J，HO S R，GRAVES J D，et al. CGRRF1，a growth suppressor，regulates EGFR ubiquitination in breast cancer[J]. Breast Cancer Res，2019，21（1）：134.
[27] L?譈?魻ND F，SUGIYAMA N，BILL R，et al. Distinct contributions of partial and full EMT to breast cancer malignancy[J]. Dev Cell，2021，56（23）：3203-3221.
[28] THIERY J P，ACLOQUE H，HUANG R Y J，et al. Epithelial-mesenchymal transitions in development and disease[J]. Cell，2009，139（5）：871-890.
[29] KAI M，KANAYA N，WU S V，et al. Targeting breast cancer stem cells in triple-negative breast cancer using a combination of LBH589 and salinomycin[J]. Breast Cancer Res Treat，2015，151（2）：281-294.
[30] HOGG S J，BEAVIS P A，DAWSON M A，et al. Targeting the epigenetic regulation of antitumour immunity[J]. Nat Rev Drug Discov，2020，19（11）：776-800.

相似文献/References:

备注/Memo

备注/Memo:

作者简介 庄慧萍（1994-），女，硕士在读，研究方向：肿瘤与分子生物学，E-mail：zhuanghuiping 1111@163.com。

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更新日期/Last Update: 2022-09-20