高三尖杉酯碱对白血病K562细胞增殖和DNA损伤相关蛋白表达的影响

Abstract
Figure/Table
References (26)
Related Citation (7)

Download: PDF (799 KB) HTML (1 KB)
Export: BibTeX | EndNote (RIS)

Abstract Objective To study the effects of homoharringtonine (HHT) on proliferation and DNA damage related protein expression in human leukemic K562 cells. Methods Human leukemia K562 cells were cultured in vitro, and divided into HHT group and control group. HHT group was further divided into HHT subgroups with different concentrations of 5×10-9, 1×10-8, 5×10-8 and 1×10-7 mol/L. The effects of HHT at different concentrations on the proliferation of K562 cells were detected by CCK-8 method. The effects of different HHT concentrations on K562 cells proliferation (rabbit anti human cyclin D1 [Cyclin D1] and rabbit anti human nuclear protein MKI67 [KI-67]) and the expression of DNA damage (rabbit anti human histone H2AX phosphorylation [γ-H2AX] and phosphorylated rabbit anti human ataxia telangiectasia mutated protein kinase [p-ATM]) relative protein were analyzed by Western blot. Results HHT significantly inhibited human leukemic K562 cells, with HHT inhibition rates (4.70±0.45)%, (9.80±0.35)%, (34.00±0.29)%, and (41.00±0.64)% at different concentrations (5×10-9, 1×10-8, 5×10-8 and 1×10-7 mol/L), respectively. Compared with the control group, Cyclin D1 protein expression could be down-regulated in 5×10-9, 1×10-8, 5×10-8 and 1×10-7 mol/L HHT groups, and the differences were statistically significant (all P ＜ 0.05). Compared with the control group, Ki-67 expression levels in 5×10-8 and 1×10-7 mol/L HHT group were significantly down-regulated, with statistically significant differences (all P ＜ 0.05). Compared with the control group, the upregulation of the expression of γ-H2AX proteins were induced in 5×10-8 and 1×10-7 mol/L HHT groups, with statistically significant differences (all P ＜ 0.05). Compared with the control group, p-ATM levels were increased in the 1×10-8, 5×10-8 and 1×10-7 mol/L HHT groups, with statistically significant differences (all P ＜ 0.05). Conclusion HHT can inhibit the proliferation of leukemic K562 cells by down-regulating the expression of proliferation-related proteins, and may induce cell DNA damage.

Key words： Homoharringtonine K562 cells Proliferation DNA damage

	Service

	E-mail this article
	Add to my bookshelf
	Add to citation manager
	E-mail Alert
	RSS
	Articles by authors
	KE Bo1 YU Juhong2 TU Liyan2 CHENG Hongbo1

Cite this article:

KE Bo1 YU Juhong2 TU Liyan2 CHENG Hongbo1. Effects of homoharringtonine on proliferation and DNA damage related protein expression in leukemia K562 cells[J]. 中国医药导报, 2020, 17(32): 24-28.

URL:

http://www.yiyaodaobao.com.cn/EN/ OR http://www.yiyaodaobao.com.cn/EN/Y2020/V17/I32/24

[1] Quintás-Cardama A，Kantarjian H，Cortes J. Homoharringtonine，omacetaxine mepesuccinate，and chronic myeloid leukemia circa 2009 [J]. Cancer，2009，115（23）：5382-5393. doi：10.1002/cncr.24601.
[2] Tan M，Zhang Q，Yuan X，et al. Synergistic killing effects of homoharringtonine and arsenic trioxide on acute myeloid leukemia stem cells and the underlying mechanisms [J]. J Exp Clin Cancer Res，2019，38（1）：308. doi：10.1186/s13046-019-1295-8.
[3] Jin J，Wang JX，Chen FF，et al. Homoharringtonine-based induction regimens for patients with de-novo acute myeloid leukaemia：a multicentre，open-label，randomised，controlled phase 3 trial [J]. Lancet Oncol，2013，14（7）：599-608. doi：10.1016/S1470-2045（13）70152-9.
[4] Kantarjian HM，O′Brien S，Cortes J. Homoharringtonine/Omacetaxine Mepesuccinate：The Long and Winding Road to Food and Drug Administration Approval [J]. Clin Lymphoma Myeloma Leuk，2013，13（5）：530-533. doi：10.1016/j.clml.2013.03.017.
[5] Kuroda J，Kamitsuji Y，Kimura S，et al. Anti-myeloma effect of homoharringtonine with concomitant targeting of the myeloma-promoting molecules，Mcl-1，XIAP，and beta-catenin [J]. Int J Hematol，2008，87（5）：507-515. doi：10.1007/s12185-008-0081-8.
[6] Chen J，Mu QT，Li X，et al. Homoharringtonine targets Smad3 and TGF-β pathway to inhibit the proliferation of acute myeloid leukemia cells [J]. Oncotarget，2017，8（25）：40318-40326. doi：10.18632/oncotarget.16956.
[7] Gandhi V，Plunkett W，Cortes JE. Omacetaxine：a protein translation inhibitor for treatment of chronic myelogenous leukemia [J]. Clin Cancer Res，2014，20（7）：1735-1740. doi：10.1158/1078-0432.CCR-13-1283.
[8] Bohlander SK. A new kid on the block for acute myeloid leukemia treatment? Homoharringtonine interferes with key pathways in acute myeloid leukemia cells [J]. Haematologica，2020，105（1）：7-9. doi：10.3324/haematol.2019. 234880.
[9] Li CY，Dong L，Su R，et al. Homoharringtonine exhibits potent anti-tumor effect and modulates DNA epigenome in acute myeloid leukemia by targeting SP1/TET1/5hmC [J]. Haematologica，2020，105（1）：148-160. doi：10.3324/haematol.2018.208835.
[10] 中华医学会血液学分会白血病淋巴瘤学组.成人急性髓系白血病（非急性早幼粒细胞白血病）中国诊疗指南（2017年版）[J].中华血液学杂志，2017，38（3）：177-182. doi：10.3760/cma.j.issn.0253-2727.2017.03.001.
[11] 谢瑜，谭琳，吴迪.HAG方案治疗老年低增生性急性髓系白血病20例疗效观察[J].中国医药导报，2010，33：148-149. doi：CNKI：SUN：YYCY.0.2010-33-099.
[12] Lou YJ，Qian WB，Jin J. Homoharringtonine induces apoptosis and growth arrest in human myeloma cells [J]. Leuk Lymphoma，2007，48（7）：1400-1406. doi：10.1080/10428 190701411466.
[13] 丁亦含，吴晶晶，王倩，等.高三尖杉酯碱通过mTOR通路诱导慢性髓系白血病K562细胞凋亡[J].中国实验血液学杂志，2018，26（1）：105-109. doi：10.7534/j.issn.1009-2137.2018.01.017.
[14] Li S，Bo ZL，Jiang Y，et al. Homoharringtonine promotes BCR-ABL degradation through the p62-mediated autophagy pathway [J]. Oncol. Rep.，2020，43（1）：113-120. doi：10.3892/or.2019.7412.
[15] Ke B，Jin CH，Liu HY，et al. Homoharringtonine enhances idarubicin-induced apoptosis via regulation of the mitochondrial pathway [J]. Int J Clin Exp Med，2019，12（2）：1503-1513.
[16] Du ZY，Tong XM，Ye X. Cyclin D1 promotes cell cycle progression through enhancing NDR1/2 kinase activity independent of cyclin-dependent kinase 4 [J]. J Biol Chem，2013，288（37）：26678-26687. doi：10.1074/jbc.M113. 466433.
[17] Siddiqui MS，Fran?觭ois M，Fenech MF，et al. Persistent γH2AX：A promising molecular marker of DNA damage and aging [J]. Mutat Res Rev Mutat Res，2015，766：1-19. doi：10.1016/j.mrrev.2015.07.001.
[18] Nagelkerke A，Span PN. Staining Against Phospho-H2AX (γ-H2AX) as a Marker for DNA Damage and Genomic Instability in Cancer Tissues and Cells [J]. Adv Exp Med Biol，2016，899：1-10. doi：10.1007/978-3-319-26666-4_1.
[19] Wakasugi M，Sasaki T，Matsumoto M，et al. Nucleotide excision repair-dependent DNA double-strand break formation and ATM signaling activation in mammalian quiescent cells [J]. J Biol Chem，2014，289（41）：28730-28737. doi：10.1074/jbc.M114.589747.
[20] Guo QQ，Wang SS，Zhang SS，et al. ATM-CHK2-Beclin 1 axis promotes autophagy to maintain ROS homeostasis under oxidative stress [J]. EMBO J，2020，39（10）：e103111. doi：10.15252/embj.2019103111.
[21] Popp HD，Kohl V，Naumann N，et al. DNA Damage and DNA Damage Response in Chronic Myeloid Leukemia [J]. Int J Mol Sci，2020，21（4）：1177. doi：10.3390/ijms21041177.
[22] Xu RD，Yu SY，Zhu D，et al. hCINAP regulates the DNA-damage response and mediates the resistance of acute myelocytic leukemia cells to therapy [J]. Nat Commun，2019，10（1）：3812. doi：10.1038/s41467-019-11795-5.
[23] Wu JJ，Wei B，Shi YY，et al. Homoharringtonine enhances the effect of imatinib on chronic myelogenous leukemia cells by downregulating ZFX [J]. Mol Med Rep，2019，20（4）：3233-3239. doi：10.3892/mmr.2019.10539.
[24] Chen J，Mu Q，Li X，et al. Homoharringtonine targets Smad3 and TGF-β pathway to inhibit the proliferation of acute myeloid leukemia cells [J]. Oncotarget，2017，8（25）：40318-40326. doi：10.18632/oncotarget.16956.
[25] Cao W，Liu Y，Zhang R，et al. Homoharringtonine induces apoptosis and inhibits STAT3 via IL-6/JAK1/STAT3 signal pathway in Gefitinib-resistant lung cancer cells [J]. Sci Rep，2015，5：8477. doi：10.1038/srep08477.
[26] Chen XJ，Zhang WN，Chen B，et al. MYCHomoharringtonine deregulates transcriptional expression by directly bin-ding NF-κB repressing factor [J]. Proc Natl Acad Sci U S A，2019，116（6）：2220-2225. doi：10.1073/pnas.1818539116.