WO2023092463A1 - 盐酸阿霉素在抑制Mcl-1中的应用 - Google Patents

盐酸阿霉素在抑制Mcl-1中的应用 Download PDF

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WO2023092463A1
WO2023092463A1 PCT/CN2021/133568 CN2021133568W WO2023092463A1 WO 2023092463 A1 WO2023092463 A1 WO 2023092463A1 CN 2021133568 W CN2021133568 W CN 2021133568W WO 2023092463 A1 WO2023092463 A1 WO 2023092463A1
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apoptotic
protein
mcl
doxorubicin hydrochloride
bcl
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French (fr)
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袁曙光
陈柳青
崔文强
王世玉
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中国科学院深圳先进技术研究院
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  • the invention belongs to the field of medicine, in particular to the application of doxorubicin hydrochloride in inhibiting Mcl-1.
  • Apoptosis also known as programmed cell death
  • Apoptosis function can cause various diseases, such as neurodegenerative diseases, autoimmune diseases and cancers. So far, there are two mature apoptotic pathways studied by people: death receptor-mediated pathway (extrinsic apoptotic pathway) and mitochondria-mediated pathway (intrinsic apoptotic pathway).
  • Bcl-2 family proteins can target the mitochondrial outer membrane, change its permeability, release cytochrome c, activate apoptosis protease, and finally cause cell death.
  • the regulation of apoptosis is mainly realized by Bcl-2 family proteins.
  • Bcl-2 family proteins are mainly divided into two categories: one is anti-apoptotic proteins, including Bcl-2, Mcl-1, and Bcl-XL; the other is pro-apoptotic proteins, including Bax, Bak, Bim, Noxa and Puma et al.
  • Pro-apoptotic proteins form oligomerization in the mitochondrial outer membrane, prompting the opening of the mitochondrial outer membrane pores, causing the release of cytochrome c from the mitochondria to the cytoplasm, and finally leading to apoptosis.
  • Anti-apoptotic proteins Bcl-2, Mcl-1, and Bcl-XL inhibit apoptosis by interacting with pro-apoptotic proteins and inhibiting the formation of Bax and Bak oligomerization.
  • Mcl-1 has a role in the survival of dopamine neurons, and these neurons are selectively killed in the progression of Parkinson's disease, suggesting that Mcl-1 is a potential target for the treatment of Parkinson's disease.
  • Doxorubicin hydrochloride is an anti-tumor antibiotic. By inhibiting the synthesis of nucleic acid in the genetic material of cancer cells, this product has a wide anti-tumor spectrum and can kill a variety of tumor cells. However, there is no relevant report on its interaction with Mcl-1 in the prior art.
  • the present invention provides a novel Mcl-1 protein inhibitor or competitive binding agent.
  • One aspect of the present invention provides the use of doxorubicin hydrochloride in the preparation of inhibitors of anti-apoptotic proteins.
  • anti-apoptotic protein is selected from anti-apoptotic proteins of the Bcl-2 protein family.
  • anti-apoptotic protein is selected from Mcl-1.
  • One aspect of the present invention provides the use of doxorubicin hydrochloride in the preparation of a competitive binding agent for anti-apoptotic proteins.
  • anti-apoptotic protein is selected from anti-apoptotic proteins of the Bcl-2 protein family.
  • anti-apoptotic protein is selected from Mcl-1.
  • the competitive binding agent is a reagent that competes with the pro-apoptotic protein of the Bcl-2 protein family for binding to the anti-apoptotic protein Mcl-1.
  • pro-apoptotic protein of Bcl-2 protein family is selected from Bax, Bak, Bim, Noxa, Puma and derivatives thereof.
  • Another aspect of the present invention provides the use of doxorubicin hydrochloride in the preparation of a reagent for promoting mitochondria-mediated apoptosis.
  • Another aspect of the present invention provides the use of doxorubicin hydrochloride in the preparation of medicaments for treating Parkinson's disease.
  • Another aspect of the present invention provides a reagent for inhibiting the activity of anti-apoptotic protein, the active ingredient in the reagent is doxorubicin hydrochloride.
  • anti-apoptotic protein is selected from anti-apoptotic proteins of the Bcl-2 protein family.
  • anti-apoptotic protein is selected from Mcl-1.
  • the preparation further includes a dispersion medium.
  • the dispersion medium is a solution.
  • Another aspect of the present invention provides a reagent capable of competitively binding to an anti-apoptotic protein, and the active ingredient in the reagent is doxorubicin hydrochloride.
  • anti-apoptotic protein is selected from anti-apoptotic proteins of the Bcl-2 protein family.
  • anti-apoptotic protein is selected from Mcl-1.
  • the preparation further includes a dispersion medium.
  • the dispersion medium is a solution.
  • Another aspect of the present invention provides a drug for treating Parkinson's disease, the active ingredient in the drug is doxorubicin hydrochloride.
  • the medicine contains pharmaceutically acceptable excipients.
  • Another aspect of the present invention provides a method for inhibiting the activity of an anti-apoptotic protein, the method comprising the step of contacting doxorubicin hydrochloride with the anti-apoptotic protein.
  • the anti-apoptotic protein Mcl-1 of the anti-apoptotic protein Bcl-2 protein family is the anti-apoptotic protein Mcl-1 of the anti-apoptotic protein Bcl-2 protein family.
  • Yet another aspect of the present invention provides a method for binding anti-apoptotic proteins competitively with pro-apoptotic proteins, said method comprising the step of contacting doxorubicin hydrochloride with said anti-apoptotic proteins and pro-apoptotic proteins.
  • the anti-apoptotic protein Mcl-1 of the anti-apoptotic protein Bcl-2 protein family, and the pro-apoptotic protein are selected from the Bcl-2 protein family pro-apoptotic proteins Bax, Bak, Bim, Noxa, Puma and derivatives thereof.
  • the present invention discovers for the first time that doxorubicin hydrochloride can act on the anti-apoptotic protein Mcl-1, and promotes the separation of the pro-apoptotic protein bound to it through competitive binding to Mcl-1, thereby achieving the effect of inhibiting the anti-apoptotic protein.
  • the pro-apoptotic protein released at the same time can play a pro-apoptotic role, and then test the anti-tumor and anti-Parkinson effects, and the IC50 of doxorubicin hydrochloride against Mcl-1 is 6.84 ⁇ M.
  • Figure 1 is a diagram showing the inhibition of Mcl-1 activity by different concentrations of doxorubicin hydrochloride compounds, the abscissa is the compound concentration ( ⁇ M), and the ordinate is the ratio of fluorescence intensity at 520nM and 620nM. As the concentration of the compound increases, the fluorescence intensity ratio decreases, that is, the inhibitory effect increases.
  • the Mcl-1 protein coding gene was synthesized by Shanghai Sunny Biotechnology Co., Ltd. and connected to the pET28a expression plasmid.
  • the expression plasmid was formulated into a solution with a concentration of 100 ng/ ⁇ L, and 1 ⁇ L of the plasmid solution was transformed into the expression strain Escherichia coli BL21 (DE3) by the chemically competent transformation method to express and purify the recombinant protein Mcl-1.
  • Mcl-1 The specific purification steps of Mcl-1 are:
  • Cell disruption Suspend the cells collected in the centrifuge bucket with lysis buffer (20mM Tris, 0.5M NaCl, 20mM imidazole, pH 8.0). Pre-cool the high-pressure homogenizer to 4°C in advance, remove the 20% ethanol used for storage, wash the machine 1-2 times with deionized water, and then wash the machine 1-2 times with lysis buffer. Increase the machine pressure to about 800bar to crush the bacteria.
  • lysis buffer 20mM Tris, 0.5M NaCl, 20mM imidazole, pH 8.0.
  • Bacterial cell precipitation put the collected broken cell liquid into a centrifuge tube, centrifuge at 12000rpm for 20min, and collect the supernatant.
  • Protein concentration put the collected Mcl-1 eluate into an ultrafiltration concentration tube, and use preservation buffer (20mM Tris, 100mM NaCl, 2mM DTT) as a diluent to remove imidazole from the target protein and concentrate Mcl-1. 1Concentration higher than 1mg/mL.
  • the doxorubicin hydrochloride was prepared into 370 ⁇ M, 123 ⁇ M, 41.2 ⁇ M, 13.7 ⁇ M, 4.57 ⁇ M, 1.52 ⁇ M and 0.50 ⁇ M stock solutions at a dilution factor of 3 times.
  • FITC-BAK-BH3 is the natural ligand of Mcl-1
  • Anti-His Tb-labeled donor can bind to the His tag on Mcl-1
  • Tb metal can bind to FITC-BAK on Mcl-1 -BH3 undergoes fluorescence resonance energy transfer (FRET);
  • FRET fluorescence resonance energy transfer
  • doxorubicin hydrochloride competitively binds to Mcl-1
  • the FITC-BAK-BH3 polypeptide will dissociate from Mcl-1; therefore, doxorubicin hydrochloride can be reflected by FRET intensity
  • the strength of the ability of the protein to bind Mcl-1 Therefore, the fluorescence values at 620nm and 520nm were read respectively, and the ratio of the two fluorescence intensities was used as an indicator of the inhibitory effect of the compound.
  • the experimental results are shown in Figure 1.
  • the results in Figure 1 show that doxorubicin hydrochloride exhibits an inhibitory effect on Mcl-1 protein, and as the concentration increases, the inhibitory effect is dose-dependent.
  • the IC50 value of doxorubicin hydrochloride against Mcl-1 was further calculated.
  • the IC50 value of doxorubicin hydrochloride against Mcl-1 was 6.84 ⁇ M.

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Abstract

提供了盐酸阿霉素在制备抗凋亡蛋白Mcl-1抑制剂中的应用，具体涉及盐酸阿霉素作为Mcl-1蛋白的抑制剂或竞争性结合剂的用途。进一步提供了其作为潜在治疗帕金森症药物中的应用。盐酸阿霉素能够作用于抗凋亡蛋白Mcl-1，通过竞争性结合Mcl-1，促使与之结合的促凋亡蛋白分离，进而达到抑制抗凋亡蛋白的作用。同时释放的促凋亡蛋白能够发挥促凋亡的作用，其中盐酸阿霉素针对Mcl-1的IC50为6.84μM。

Description

盐酸阿霉素在抑制Mcl-1中的应用 技术领域
本发明属于药物领域，具体涉及盐酸阿霉素在抑制Mcl-1中的应用。
背景技术
细胞凋亡(又称程序性细胞死亡)是一种保守进化的细胞过程，对胚胎的发育和组织稳态起着十分重要的作用。细胞凋亡功能的异常会引起多种疾病，比如神经退行性疾病、自身免疫性疾病和癌症等。目前为止，人们研究的比较成熟的凋亡途径主要有两种：死亡受体介导途径(外源性凋亡途径)和线粒体介导途径(内源性凋亡途径)。
在线粒体介导的途径中，Bcl-2家族蛋白可通过靶向线粒体外膜，改变其通透性，进而释放细胞色素c，激活细胞凋亡蛋白酶，最终引起细胞死亡。细胞凋亡的调控主要通过Bcl-2家族蛋白实现。Bcl-2家族蛋白主要分为两类：一类是抗凋亡蛋白，包括Bcl-2、Mcl-1、和Bcl-XL；另一类是促凋亡蛋白，包含Bax、Bak、Bim、Noxa和Puma等。促凋亡蛋白在线粒体外膜形成寡聚化，促使线粒体外膜孔道打开，引起细胞色素c从线粒体释放到细胞质，最终导致凋亡发生。而抗凋亡蛋白Bcl-2、Mcl-1、和Bcl-XL则通过与促凋亡蛋白相互作用，抑制Bax和Bak寡聚化的形成而抑制凋亡。近年来，有研究表明Mcl-1对多巴胺神经元的存活有作用，而这些神经元在帕金森疾病进展中选择性死亡，这表明Mcl-1是治疗帕金森疾病的潜在靶点。
盐酸阿霉素是一种抗肿瘤抗生素，通过抑制癌细胞遗传物质核酸的合成，本品抗瘤谱较广，对多种肿瘤细胞均有杀灭作用。但是现有技术中并未有其于Mcl-1相互作用的相关报道。
发明内容
本发明为克服现有技术中的问题，提供了一种新的Mcl-1蛋白的抑制剂或竞争性结合剂。
本发明一个方面提供了盐酸阿霉素在制备抗凋亡蛋白的抑制剂中的用途。
所述盐酸阿霉素结构如式I所示：
Figure PCTCN2021133568-appb-000001
进一步地，抗凋亡蛋白选自Bcl-2蛋白家族的抗凋亡蛋白。
进一步地，抗凋亡蛋白选自Mcl-1。
本发明一个方面提供了盐酸阿霉素在制备抗凋亡蛋白的竞争性结合剂中的用途。
进一步地，抗凋亡蛋白选自Bcl-2蛋白家族的抗凋亡蛋白。
进一步地，抗凋亡蛋白选自Mcl-1。
进一步地，所述竞争性结合剂为与Bcl-2蛋白家族促凋亡蛋白竞争性结合抗凋亡蛋白Mcl-1的试剂。
进一步地，Bcl-2蛋白家族促凋亡蛋白选自Bax、Bak、Bim、Noxa、Puma及其衍生物。
本发明另一个方面提供了盐酸阿霉素在制备促进线粒体介导途径的细胞凋亡的试剂中的用途。
本发明另一个方面提供了盐酸阿霉素在制备治疗帕金森症的药物中的用途。
本发明再一个方面提供了一种抑制抗凋亡蛋白活性的试剂，所述试剂中的活性成分为盐酸阿霉素。
进一步地，抗凋亡蛋白选自Bcl-2蛋白家族的抗凋亡蛋白。
进一步地，抗凋亡蛋白选自Mcl-1。
进一步地，所述制剂中还进一步包含分散介质。
进一步地，所述的分散介质为溶液。
本发明再一个方面提供了一种能够竞争性结合抗凋亡蛋白的试剂，所述试剂中的活性成分为盐酸阿霉素。
进一步地，抗凋亡蛋白选自Bcl-2蛋白家族的抗凋亡蛋白。
进一步地，抗凋亡蛋白选自Mcl-1。
进一步地，所述制剂中还进一步包含分散介质。
进一步地，所述的分散介质为溶液。
本发明再一个方面提供了一种治疗帕金森症的药物，所述药物中的活性成分为盐酸阿霉素。
进一步地，所述药物中包含可药用辅料。
本发明再一个方面提供了一种抑制抗凋亡蛋白活性的方法，所述方法包括将盐酸阿霉素与所述抗凋亡蛋白接触的步骤。
进一步地，抗凋亡蛋白Bcl-2蛋白家族的抗凋亡蛋白Mcl-1。
本发明再一个方面提供了一种与促凋亡蛋白竞争性结合抗凋亡蛋白的方法，所述方法包括将盐酸阿霉素与所述抗凋亡蛋白以及促凋亡蛋白接触的步骤。
进一步地，抗凋亡蛋白Bcl-2蛋白家族的抗凋亡蛋白Mcl-1，促凋亡蛋白选自Bcl-2蛋白家族促凋亡蛋白Bax、Bak、Bim、Noxa、Puma及其衍生物。
有益效果
本发明首次发现了盐酸阿霉素能够作用于抗凋亡蛋白Mcl-1，通过竞争性结合Mcl-1，促使与之结合的促凋亡蛋白分离，进而达到抑制抗凋亡蛋白的作用。同时释放的促凋亡蛋白能够发挥促凋亡的作用，进而试验抗肿瘤以及抗帕金森的作用，其中盐酸阿霉素针对Mcl-1的IC50为6.84μM。
附图说明
图1为不同浓度的盐酸阿霉素化合物抑制Mcl-1活性图，横坐标为化合物浓度(μM)，纵坐标为520nM和620nM处荧光强度比值。随着化合物浓度增高，荧光强度比值降低，即抑制作用增强。
具体实施方式
为了使本发明的上述目的、特征和优点能够更加明显易懂，下面对本发明的具体实施方式做详细的说明，但不能理解为对本发明的可实施范围的限定。
实施例1 Mcl-1蛋白的表达及纯化
Mcl-1蛋白编码基因由上海桑尼生物科技有限公司合成并连接到pET28a表达质粒。将该表达质粒配制成浓度100ng/μL溶液，取1μL质粒溶液通过化学感受态转化法，转化到表达菌株Escherichia coli BL21(DE3)中，进行重组蛋白Mcl-1的表达及纯化。
具体表达步骤如下：
1.挑取转化于表达菌株E.coli BL21(DE3)的LB平板上的单菌落，接种到含50μg/μL卡那霉素的5mL液体LB培养基试管中，37℃，220rpm条件下过夜培养。
2.按照1％接种量，将1mL过夜培养的菌液加入到含200mL液体LB培养基的三角锥形瓶中，加入终浓度50μg/μL卡那霉素，37℃，220rpm条件下培养～3h，至菌液OD值达到0.4-0.6。
3.将摇床温度降低至20℃，向培养液中添加终浓度为0.1mM的IPTG以诱导蛋白表达，并继续培养16h。
4.培养结束后，将菌液倒入500mL离心桶中，5000rpm离心10min收集菌体。
Mcl-1具体纯化步骤为：
1.菌体破碎：利用裂解缓冲液(20mM Tris,0.5M NaCl,20mM imidazole，pH 8.0)将收集于离心桶的菌体悬浮。提前将高压均质机预冷至4℃，去除保存用的20％乙醇，用去离子水清洗机器1-2遍，再用裂解缓冲液清洗机器1-2遍。将机器压力调高至800bar左右，破碎菌体。
2.菌体沉淀：将收集的菌体破碎液放入离心管中，12000rpm离心20min，收集上清液。
3.上柱和纯化：用裂解缓冲液将柱子平衡。将上清液直接倒入镍柱中，利用重力的作用，使上清液流过镍柱填料，进而使蛋白和镍柱填料结合。再用裂解缓冲液将不与镍柱填料特异性结合的杂蛋白洗涤下来。最后，用洗脱缓冲液(包含200mM imidazole的裂解缓冲液)洗脱Mcl-1蛋白。
4.蛋白浓缩：收集的Mcl-1洗脱液放入超滤浓缩管中，用保存缓冲液(20mM Tris,100mM NaCl,2mM DTT)作为稀释液，使目的蛋白最终去除咪唑，并浓缩Mcl-1浓度高于1mg/mL。
实施例2 Mcl-1活性抑制性实验
将盐酸阿霉素以3倍的稀释倍数，分别配制成370μM，123μM,41.2μM,13.7μM,4.57μM,1.52μM,0.50μM的母液。利用测试缓冲液(50mM HEPES，pH 7.2，50mM NaCl，1mM DTT，0.05％Tween-20)将Mcl-1稀释至10nM；将FITC-BAK-BH3肽稀释至1μM；Anti-His Tb-labeled donor稀释至10nM。向白色96孔板测试孔中加入12.5μL Anti-His Tb-labeled donor、17μL测试缓冲液、12.5μL FITC-BAK-BH3肽、7.5μL Mcl-1、及0.5μL不同浓度的上述盐酸阿霉素母液，然后在室温下孵育3h。用Flex Station3多功能酶标仪进行测试，测试模式为TRF，参数为EX340/30nm Em 620/10nm和Ex 340/30nm Em 520nm。分别读取620nm和520nm处荧光值，以二者荧光强度比作为化合物抑制效果的指标。
其中，FITC-BAK-BH3是Mcl-1的天然配体，Anti-His Tb-labeled donor能够与Mcl-1上的His标签结合，结合后，Tb金属可以和Mcl-1上结合的FITC-BAK-BH3发生荧光共振能量转移(FRET)；当盐酸阿霉素竞争性结合到Mcl-1后，FITC-BAK-BH3多肽会从Mcl-1解离；因而，通过FRET强度可以反应出盐酸阿霉素结合Mcl-1能力的强弱。因此，分别读取620nm和520nm处荧光值，以二者荧光强度比作为化合物抑制效果的指标。
实验结果见图1，图1结果显示了盐酸阿霉素显示了对Mcl-1蛋白的抑制作用，且随着浓度的上升，显示出抑制效果具有剂量依赖性。通过上述实验结果进一步计算盐酸阿霉素针对Mcl-1的IC50值盐酸阿霉素针对Mcl-1的IC50值为6.84μM。

Claims (10)

  1. 盐酸阿霉素在制备抗凋亡蛋白的抑制剂中的用途；所述抗凋亡蛋白选自Bcl-2蛋白家族的抗凋亡蛋白Mcl-1。
  2. 盐酸阿霉素在制备抗凋亡蛋白的竞争性结合剂中的用途；所述抗凋亡蛋白选自Bcl-2蛋白家族的抗凋亡蛋白Mcl-1。
  3. 根据权利要求2所述的用途，所述竞争性结合剂为与Bcl-2蛋白家族促凋亡蛋白竞争性结合抗凋亡蛋白Mcl-1的试剂；
    优选地，Bcl-2蛋白家族促凋亡蛋白选自Bax、Bak、Bim、Noxa、Puma、BAK-BH3及其衍生物。
  4. 盐酸阿霉素在制备促进线粒体介导途径的细胞凋亡的试剂中的用途。
  5. 盐酸阿霉素在制备治疗帕金森症的药物中的用途。
  6. 一种抑制抗凋亡蛋白活性的试剂，所述试剂中的活性成分为盐酸阿霉素；
    优选地，抗凋亡蛋白选自Bcl-2蛋白家族的抗凋亡蛋白Mcl-1；
    优选地，所述制剂中还进一步包含分散介质。
  7. 一种能够竞争性结合抗凋亡蛋白的试剂，所述试剂中的活性成分为盐酸阿霉素；
    优选地，抗凋亡蛋白选自Bcl-2蛋白家族的抗凋亡蛋白Mcl-1；
    优选地，所述制剂中还进一步包含分散介质。
  8. 一种治疗帕金森症的药物，所述药物中的活性成分为盐酸阿霉素；
    优选地，所述药物中包含可药用辅料。
  9. 一种抑制抗凋亡蛋白活性的方法，所述方法包括将盐酸阿霉素与所述抗凋亡蛋白接触的步骤；
    优选地，抗凋亡蛋白Bcl-2蛋白家族的抗凋亡蛋白Mcl-1。
  10. 一种与促凋亡蛋白竞争性结合抗凋亡蛋白的方法，所述方法包括将盐酸阿霉素与所述抗凋亡蛋白以及促凋亡蛋白接触的步骤；
    优选地，抗凋亡蛋白Bcl-2蛋白家族的抗凋亡蛋白Mcl-1，促凋亡蛋白选自Bcl-2蛋白家族促凋亡蛋白Bax、Bak、Bim、Noxa、Puma、BAK-BH3及其衍生物。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060257401A1 (en) * 2003-02-07 2006-11-16 Giorgio Stassi Sensitizing cells for apoptosis by selectively blocking cytokines
CN102258470A (zh) * 2010-11-01 2011-11-30 中南大学肝胆肠外科研究中心 盐酸阿霉素纳米脂质体制剂的制备
US20120172285A1 (en) * 2008-12-09 2012-07-05 Walensky Loren D Methods and compositions for specific modulation of mcl-1

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060257401A1 (en) * 2003-02-07 2006-11-16 Giorgio Stassi Sensitizing cells for apoptosis by selectively blocking cytokines
US20120172285A1 (en) * 2008-12-09 2012-07-05 Walensky Loren D Methods and compositions for specific modulation of mcl-1
CN102258470A (zh) * 2010-11-01 2011-11-30 中南大学肝胆肠外科研究中心 盐酸阿霉素纳米脂质体制剂的制备

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CARROLL RICHARD G., HOLLVILLE EMILIE, MARTIN SEAMUS J.: "Parkin Sensitizes toward Apoptosis Induced by Mitochondrial Depolarization through Promoting Degradation of Mcl-1", CELL REPORTS, ELSEVIER INC, US, vol. 9, no. 4, 1 November 2014 (2014-11-01), US , pages 1538 - 1553, XP093068542, ISSN: 2211-1247, DOI: 10.1016/j.celrep.2014.10.046 *
LIU JIE, YU JIEPING, LUO HESHEN, YU HONGGANG: "Effect of Activation of Mc-l1and PI3K Signal Transduction Pathway of Human Gastric Cancer Cells on the Sensitivity to Chemotherapy", WUHAN DAXUE XUEBAO (YIXUE BAN) = WUHAN UNIVERSITY JOURNAL(MEDICAL SCIENCE EDITION), WUHAN DAXUE YIXUEYUAN,, CN, vol. 30, no. 4, 31 July 2009 (2009-07-31), CN , pages 450 - 454, XP093068539, ISSN: 1671-8852, DOI: 10.14188/j.1671-8852.2009.04.032 *
ZHANG, T. ; HU, J. ; DING, W. ; WANG, X.: "Doxorubicin augments rAAV-2 transduction in rat neuronal cells", NEUROCHEMISTRY INTERNATIONAL, ELSEVIER, AMSTERDAM, NL, vol. 55, no. 7, 1 December 2009 (2009-12-01), AMSTERDAM, NL , pages 521 - 528, XP026562417, ISSN: 0197-0186, DOI: 10.1016/j.neuint.2009.05.005 *

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