海洋放线菌来源的化合物卡拉霉素（Kalamycin）的抗肿瘤作用和机制研究
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摘要
海洋生态环境的特殊性决定了海洋中往往含有结构奇特、新颖的化学物质,海洋药物具有药理特异性、高活性和多样性,已成为药物研发热点领域,海洋抗肿瘤药物也是其中之一。卡拉霉素(kalamycin)来源于海洋放线菌M097的聚酮类化合物,我们实验室用体外增殖抑制试验发现了卡拉霉素(kalamycin)的抗肿瘤作用。有报道其类似物lactoquinomycin和frenolicin B是肿瘤靶点AKT抑制剂,并由此推断吡喃萘醌骨架在AKT抑制过程中发挥主要作用,我们发现虽然卡拉霉素(kalamycin)含有吡喃萘醌骨架,但是并不抑制AKT及其下游信号系统;继而对卡拉霉素(kalamycin)的体外抗肿瘤作用及其机理进行了系统的分析。
采用磺酰罗丹明B(SRB)法检测卡拉霉素(kalamycin)对10株肿瘤细胞株的体外增殖抑制作用,结果表明,卡拉霉素(kalamycin)能明显抑制各种组织来源的肿瘤细胞生长,具有广泛的细胞增殖抑制作用,除对一株肺癌细胞A549抑制作用不明显外,对9株肿瘤细胞株的IC50平均值为2.5μM,并且对各个细胞株生长抑制曲线形态基本一致。采用流式细胞术证实,卡拉霉素(kalamycin)能剂量依赖地诱导结肠癌细胞HCT-116和肝癌细胞SMMC-7721发生G2/M期周期阻滞,可以诱导黑色素瘤A375细胞发生凋亡。
基于前人的报道,我们用Western blot方法检测卡拉霉素(kalamycin)对AKT信号系统的影响,用量从1μM增加到16μM,AKT、mTOR和磷酸化AKT、mTOR、GSK3β的总量都没有变化;因此我们判断卡拉霉素(kalamycin)不是通过AKT系统发挥作用,而是有另外的机制。细胞凋亡和周期阻滞的很多过程是和P53相关的,我们用卡拉霉素(kalamycin)对P53野生和缺失的HCT-116细胞的增殖抑制和凋亡诱导来分析该抑制作用是否和P53相关,结果显示卡拉霉素(kalamycin)对两种细胞的生长抑制和诱导凋亡作用无明显差异,其作用和P53途径是不相关的。
卡拉霉素(kalamycin)细胞增殖抑制作用的非选择性,表明该化合物是一个广谱的细胞增殖抑制剂。我们用体外酶反应实验分析了卡拉霉素(kalamycin)对拓扑酶的抑制作用,结果显示卡拉霉素(kalamycin)对Topo I没有抑制作用,在20μM时几乎完全抑制Topo II,呈现出显著的浓度依赖效应,抑制作用大约比VP16强十倍。用DNA伸展实验和Topo II介导的负超螺旋pBR322切割实验,证实卡拉霉素(kalamycin)不是DNA嵌入剂和Topo II毒剂,而是一个催化抑制剂。在体外模拟Topo II的催化反应步骤,把整个过程分解,发现卡拉霉素(kalamycin)可以抑制Topo II介导的DNA的切割,但是对再连接没有作用;卡拉霉素(kalamycin)能抑制ATP水解的作用,但是在较高剂量时抑制作用要比阳性对照弱得多。因此,卡拉霉素(kalamycin)可能主要通过抑制Topo II介导的DNA的切割发挥作用。
肿瘤新血管生成是原发性肿瘤赖以发生、生长和转移的物质基础。我们用了多个新生血管生成模型对卡拉霉素(kalamycin)的抗新生血管生成作用进行了检测,发现卡拉霉素(kalamycin)对内皮细胞管腔形有抑制作用,其作用效果呈现明显的剂量依赖性。卡拉霉素(kalamycin)在对内皮细胞HMEC-1在12小时内的IC50是4.39μM ,在没有显著增殖抑制作用的剂量下,对HMEC-1管腔形成依然具有抑制作用,提示卡拉霉素(kalamycin)的抗新生血管生成作用并非完全来源于其增殖抑制作用。通过体外酶反应、western blot和双荧光素酶报告基因系统分析卡拉霉素(kalamycin)抑制肿瘤新血管生成的信号途径,结果发现这种抑制作用不是依赖于酪氨酸激酶和HIF-lα途径的。
综上所述,卡拉霉素(kalamycin)不是一个AKT抑制剂,它通过专一性的抑制Topo II使肿瘤细胞发生周期阻滞和细胞凋亡,主要抑制Topo II介导的DNA的切割和ATP水解作用。同时卡拉霉素(kalamycin)可以抑制肿瘤血管管腔形成,抑制作用不依赖酪氨酸激酶和HIF-lα途径。
Especial environment of ocean determines usually novel various structure of the marinechemical substances, reaearch on marine drug has been a hotspot for their pharmacological specificity, excellent activity and diversity. Marine anti-cancer drugs is an important area of the reaearch. kalamycin, a poly ketone type compound, isolated from marine actinomycetes M097. It’s has been reported that lactoquinomycin and frenolicin B, analogues of kalamycin, can inhibit AKT for the pyran naphthoquinone skeleton they have. We found that although kalamycin has pyran naphthoquinone skeleton, but did not suppress AKT and its downstream signal system, then we make a sytematic analysis on the in vitro anti-tumor effect and mechanism of kalamycin.
Growth inhibition of kalamycin on 10 tumor cell lines was analyzed in vitro by SRB assay, the results showed that kalamycin could inhibit a variety of tissue-derived tumor cell growth except for pulmonary cancer cell line A549. The average IC50 against other nine tumor cell lines is 2.5μM. kalamycin had no significant selectivity against different tissue-derived cell lines, and growth inhibition curve against different cell lines are basically similar. In flow cytometry, kalamycin could dose-dependently induce colon cancer cells HCT-116 and hepatoma cells SMMC-7721 G2/M phase arrest, and induce apoptosis of melanoma A375 cells.
Acording to previous reports, influence of kalamycin on AKT pathway was analyzed by Western blot, with dose increasing from 1μM to 16μM, kalamycin could not decrease AKT, mTOR and phosphorylated AKT, mTOR, GSK3β. So we don’t think kalamycin is a AKT inhibitor. Apoptosis and cycle arrest are usually related to P53 protein, so effect of kalamycin on P53 pathway was analyzed with wild type and P53 missing HCT-116 cell lines, no significant difference in growth inhibition and apoptosis inducement between the two cell lines was fonnd. We conclude that kalamycin can’t influence P53 signal pathway.
Non selectivity of kalamycin indicated it is a cytotoxic drug. Effect of kalamycin on topoisomerae was analyzed by in vitro enzyme assay. The results showed that kalamycin could’t inhibit Topo I, but could dose-dependly inhibit Topo II. kalamycin supress Topo II evidently at concentration of 20μM, the inhibition activity is about ten times of VP16. By DNA stretching assay and Topo II–deraved suppercoiled pBR322 cleavage assay we found kalamycin is not DNA intercalator or Topo II poison but a catalytic inhibitor. Influence of kalamycin on different Topo II catalytical steps was detected, the result showed that kalamycin suppress Topo II–deraved DNA clavage and ATP hydrolysis but not relingation. From semiquantitative analysis, we found inhibition on pre-strand passage DNA cleavage is stronger than post-strand passage DNA cleavage.
Angiogenesis support tumor for it’s generation, growth and metastasis. Anti-angiogenesis function of kalamycin was detected by several models, the result showed kalamycin inhibit tube formation dose-dependly. IC50 of kalamycin against HMEC-1 in 12 hours is 4.39μM, the tube formation suppression appear at low concentration than this, so we conclude cytoxity is not the only reason of it’s inhibition effect. By in vitro enzyme reaction assay, western blot and dual luciferase reporter gene system, we found kalamycin could’t suppress tyrosine kinase and HIF-lαpathway.
To sum up, kalamycin is not an AKT inhibitor. It induced tumor cells cycle arrest and apoptosis by specific inhibiting Topo II. kalamycin mainly suppress Topo II-mediated DNA clevage and ATP hydrolysis. At the same time, kalamycin can inhibit tumor angiogenesis, while not through tyrosine kinase HIF-lαpathway.
采用磺酰罗丹明B(SRB)法检测卡拉霉素(kalamycin)对10株肿瘤细胞株的体外增殖抑制作用,结果表明,卡拉霉素(kalamycin)能明显抑制各种组织来源的肿瘤细胞生长,具有广泛的细胞增殖抑制作用,除对一株肺癌细胞A549抑制作用不明显外,对9株肿瘤细胞株的IC50平均值为2.5μM,并且对各个细胞株生长抑制曲线形态基本一致。采用流式细胞术证实,卡拉霉素(kalamycin)能剂量依赖地诱导结肠癌细胞HCT-116和肝癌细胞SMMC-7721发生G2/M期周期阻滞,可以诱导黑色素瘤A375细胞发生凋亡。
基于前人的报道,我们用Western blot方法检测卡拉霉素(kalamycin)对AKT信号系统的影响,用量从1μM增加到16μM,AKT、mTOR和磷酸化AKT、mTOR、GSK3β的总量都没有变化;因此我们判断卡拉霉素(kalamycin)不是通过AKT系统发挥作用,而是有另外的机制。细胞凋亡和周期阻滞的很多过程是和P53相关的,我们用卡拉霉素(kalamycin)对P53野生和缺失的HCT-116细胞的增殖抑制和凋亡诱导来分析该抑制作用是否和P53相关,结果显示卡拉霉素(kalamycin)对两种细胞的生长抑制和诱导凋亡作用无明显差异,其作用和P53途径是不相关的。
卡拉霉素(kalamycin)细胞增殖抑制作用的非选择性,表明该化合物是一个广谱的细胞增殖抑制剂。我们用体外酶反应实验分析了卡拉霉素(kalamycin)对拓扑酶的抑制作用,结果显示卡拉霉素(kalamycin)对Topo I没有抑制作用,在20μM时几乎完全抑制Topo II,呈现出显著的浓度依赖效应,抑制作用大约比VP16强十倍。用DNA伸展实验和Topo II介导的负超螺旋pBR322切割实验,证实卡拉霉素(kalamycin)不是DNA嵌入剂和Topo II毒剂,而是一个催化抑制剂。在体外模拟Topo II的催化反应步骤,把整个过程分解,发现卡拉霉素(kalamycin)可以抑制Topo II介导的DNA的切割,但是对再连接没有作用;卡拉霉素(kalamycin)能抑制ATP水解的作用,但是在较高剂量时抑制作用要比阳性对照弱得多。因此,卡拉霉素(kalamycin)可能主要通过抑制Topo II介导的DNA的切割发挥作用。
肿瘤新血管生成是原发性肿瘤赖以发生、生长和转移的物质基础。我们用了多个新生血管生成模型对卡拉霉素(kalamycin)的抗新生血管生成作用进行了检测,发现卡拉霉素(kalamycin)对内皮细胞管腔形有抑制作用,其作用效果呈现明显的剂量依赖性。卡拉霉素(kalamycin)在对内皮细胞HMEC-1在12小时内的IC50是4.39μM ,在没有显著增殖抑制作用的剂量下,对HMEC-1管腔形成依然具有抑制作用,提示卡拉霉素(kalamycin)的抗新生血管生成作用并非完全来源于其增殖抑制作用。通过体外酶反应、western blot和双荧光素酶报告基因系统分析卡拉霉素(kalamycin)抑制肿瘤新血管生成的信号途径,结果发现这种抑制作用不是依赖于酪氨酸激酶和HIF-lα途径的。
综上所述,卡拉霉素(kalamycin)不是一个AKT抑制剂,它通过专一性的抑制Topo II使肿瘤细胞发生周期阻滞和细胞凋亡,主要抑制Topo II介导的DNA的切割和ATP水解作用。同时卡拉霉素(kalamycin)可以抑制肿瘤血管管腔形成,抑制作用不依赖酪氨酸激酶和HIF-lα途径。
Especial environment of ocean determines usually novel various structure of the marinechemical substances, reaearch on marine drug has been a hotspot for their pharmacological specificity, excellent activity and diversity. Marine anti-cancer drugs is an important area of the reaearch. kalamycin, a poly ketone type compound, isolated from marine actinomycetes M097. It’s has been reported that lactoquinomycin and frenolicin B, analogues of kalamycin, can inhibit AKT for the pyran naphthoquinone skeleton they have. We found that although kalamycin has pyran naphthoquinone skeleton, but did not suppress AKT and its downstream signal system, then we make a sytematic analysis on the in vitro anti-tumor effect and mechanism of kalamycin.
Growth inhibition of kalamycin on 10 tumor cell lines was analyzed in vitro by SRB assay, the results showed that kalamycin could inhibit a variety of tissue-derived tumor cell growth except for pulmonary cancer cell line A549. The average IC50 against other nine tumor cell lines is 2.5μM. kalamycin had no significant selectivity against different tissue-derived cell lines, and growth inhibition curve against different cell lines are basically similar. In flow cytometry, kalamycin could dose-dependently induce colon cancer cells HCT-116 and hepatoma cells SMMC-7721 G2/M phase arrest, and induce apoptosis of melanoma A375 cells.
Acording to previous reports, influence of kalamycin on AKT pathway was analyzed by Western blot, with dose increasing from 1μM to 16μM, kalamycin could not decrease AKT, mTOR and phosphorylated AKT, mTOR, GSK3β. So we don’t think kalamycin is a AKT inhibitor. Apoptosis and cycle arrest are usually related to P53 protein, so effect of kalamycin on P53 pathway was analyzed with wild type and P53 missing HCT-116 cell lines, no significant difference in growth inhibition and apoptosis inducement between the two cell lines was fonnd. We conclude that kalamycin can’t influence P53 signal pathway.
Non selectivity of kalamycin indicated it is a cytotoxic drug. Effect of kalamycin on topoisomerae was analyzed by in vitro enzyme assay. The results showed that kalamycin could’t inhibit Topo I, but could dose-dependly inhibit Topo II. kalamycin supress Topo II evidently at concentration of 20μM, the inhibition activity is about ten times of VP16. By DNA stretching assay and Topo II–deraved suppercoiled pBR322 cleavage assay we found kalamycin is not DNA intercalator or Topo II poison but a catalytic inhibitor. Influence of kalamycin on different Topo II catalytical steps was detected, the result showed that kalamycin suppress Topo II–deraved DNA clavage and ATP hydrolysis but not relingation. From semiquantitative analysis, we found inhibition on pre-strand passage DNA cleavage is stronger than post-strand passage DNA cleavage.
Angiogenesis support tumor for it’s generation, growth and metastasis. Anti-angiogenesis function of kalamycin was detected by several models, the result showed kalamycin inhibit tube formation dose-dependly. IC50 of kalamycin against HMEC-1 in 12 hours is 4.39μM, the tube formation suppression appear at low concentration than this, so we conclude cytoxity is not the only reason of it’s inhibition effect. By in vitro enzyme reaction assay, western blot and dual luciferase reporter gene system, we found kalamycin could’t suppress tyrosine kinase and HIF-lαpathway.
To sum up, kalamycin is not an AKT inhibitor. It induced tumor cells cycle arrest and apoptosis by specific inhibiting Topo II. kalamycin mainly suppress Topo II-mediated DNA clevage and ATP hydrolysis. At the same time, kalamycin can inhibit tumor angiogenesis, while not through tyrosine kinase HIF-lαpathway.
引文
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