番红花球茎蛋白聚糖抗肿瘤研究及其在愈伤组织中的诱导
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摘要
恶性肿瘤一直是全世界人类的主要致死原因,每年剥夺超过600万人的生命。化疗是目前治疗恶性肿瘤的主要手段之一。虽然国内外抗肿瘤药众多,但是大多数药物都伴随着严重的毒副作用,因此继续寻找高效低毒的新型抗肿瘤药物成为研究的热点。从中药活性成份中筛选治疗癌症的药物是目前本领域研究的一个重要方面。
本研究采用50mM,pH8.0的三羟甲基氨基甲烷.盐酸缓冲液(Tris-HCl),其中含有1mM的苯甲基磺酰氟(PMSF)、5mM的二硫苏糖醇(DTT)对番红花(Crocus sativus L.)球茎中的多糖进行提取,经DEAE柱层析和反相HPLC,纯化得到了一个单一的多糖组分。硫酚法和Folin-酚法结果表明该多糖中糖和蛋白质分别为94.88%和5.12%,该多糖属于蛋白聚糖(proteoglycan,PG)。PMP衍生法和间羟联苯法,检测结果表明该蛋白聚糖是一个杂聚多糖,主要由鼠李糖(28.03%),半乳糖(13.14%),岩藻糖(8.20%),木糖(19.31%),甘露糖(23.40%)和糖醛酸(7.92%)组成。氨基酸自动分析仪结果表明该蛋白聚糖的蛋白质部分主要由Asp,Glu,Gly,Ala和Leu等5种氨基酸组成(占50%以上)。FTIR和~(13)C核磁共振结果证明该蛋白聚糖具有典型的多糖和蛋白的结构官能团,并确定其主链可能为β-(1,4)-D甘露糖,侧链包括β-(1,6)-D甘露糖及其他种类单糖,如鼠李糖等。
蛋白聚糖的体内外抗肿瘤作用进行了初步研究。SRB法体外毒性试验结果表明,该蛋白聚糖对肿瘤细胞具有强烈的体外杀伤作用,对人肺癌A549细胞,人子宫颈癌Hela细胞,人肝癌SMMC-7721细胞,人乳腺癌MCF7细胞,人胃癌SGC-7901细胞等5种人组织来源的肿瘤细胞和1种鼠源的肉瘤S180细胞的IC_(50)在10-40μg/ml之间。进一步的研究表明,该蛋白聚糖(PG)引起的细胞毒性机理在于:PG减少S180细胞的胞内活性氧含量(ROS),将细胞周期阻滞在G0/G1期,随后发生细胞凋亡,引起细胞膜结构完整性的变化,最终导致细胞的死亡。利用建立的S180荷瘤小鼠模型,通过三种给药方式(腹腔注射给药,静脉注射给药和瘤内注射给药)连续给药10天,观察20天内,蛋白聚糖对小鼠体重、瘤体积的影响,20天后处死小鼠,取出瘤块,计算抑瘤率,结果表明3种给药方式都具有显著的抑制S180肉瘤生长的作用,结合实验小鼠的体重抑制情况,静脉注射0.4mg kg~(-1)day~(-1)。被推荐为以后研究的手段。
本研究建立了番红花球茎愈伤组织诱导体系,确定其最佳的培养条件为:球茎芽点周围表皮为外植体,在MS+5.0mg/L 6-BA+8.0mg/L NAA+30g/L蔗糖的培养基,暗处,22+2℃培养。对继代培养的方案进行筛选,获得了积累蛋白聚糖最多的培养条件:2.5mg/L 2,4-D+0.5mg/L 6-BA+30g/L蔗糖3000 lux,12h/12h光照下培养。利用细胞体外毒性证明了所提取得到的蛋白聚糖与球茎中的提取获得的相一致,具有体外细胞毒性作用。
Cancer continues to represent the largest cause of mortality in the world and claims over 6 million lives each year. Chemotherapeutics is still playing an important role in the treatment for malignant tumor. Although, there were majorities of anti-tumor drugs in clinical, the toxicity of this drugs can not be ignored. Thus search of new compound with high therapeutic effect and low side effect is concerned by most researchers. The screenig for new anti-tumor drugs from bioactve component of folklore medicine is a hot pot in this area.
In this study, a single polysaccharide were isolated from corm of saffron (Crocus sativus L.) by homogenized in 50 mM Tris-HCl buffer, pH 8.0, containing 1 mM phenylmethyl sulfonylfluoride (PhMeSO_2F) and 5 mM 1,4-dithio-DL-threitol (DTT) and purified by ion exchange chromatography with Macro-Prep DEAE column (16mmx300 mm) and reverse-phase high performance liquid chromatography with Supelcosil LC-304 C-4 column (4.6x250 mm). The polysaccharide was consisted of 94.88 % polysaccharide and 5.12 % protein, analyzed with Lowry method and phenol-sulfuric acid method. This result showed PG was belong to proteoglycan. The result of PMP labeled monosaccharide analysis and m-hydroxydiphenyl method analysis of uronic proteoglycan (PG) showed the polysaccharide part of PG was composed of rhamnose (28.03 %), galactose (13.14 %), fucose (8.20 %), xylose (19.31 %), mannose (23.40 %) and uronic acid (7.92 %). while the protein of PG is mainly consist of Asp, Glu, Gly, Ala and Leu (account to more than 50 % ) analyzed with auto amino acid analyzer. FTIR and ~(13)C NMR spectra showed main functional group of polysacharide and protein in PG, and the main skeletons was acertained to beβ-(1,4)-D linkaged mannose accompanied with branched chain ofβ-(1,6)-D mannose and other monosaccharide, such as rhamnose.
The antitumor effect of PG were studied both in vitro and in vivo. PG has servere cytotoxic effect on 5 human tumor cell lines (Hela, A549, MCF7, SGC-7901 and SMMC-7721 cell) and one mouse cell line (S180 cell) in vitro, with IC_(50) ranged form 10 to 40μg/ml. Further study showed the mechanism of PG induced cytotoxicity was: PG inhibit prduction of intracellular reactive oxygen species (ROS) S180 cell, which resulted in cell cycle arrest in G0/G1 phase, and followed by destory of cell membran intergrity, and cell apoptosis. The transplanted S180 tumor mice model was established, The transplanted S180 tumor mice model was established, and the tumor growth inhibition effect in vivo was detected through 3 different PG administration way (intraperitoneally, intravenously and intratumorally injection). All the results showed the tumor growth inhibition in vivo. According to the inhibition effect on mouse growth, the intravenously administration of PG at dose of 0.4 mg kg~(-1) day~(-1) were recommanded for further study.
Callus Induction System in corm of saffron was Established. And the study showed the most effective culture condition was: use epidermis from corm of saffron around buds as exoplant and cultured in MS meida contain with 5.0 mg/L 6-BA, 8.0 mg/L NAA and 30 g/L surcrose at 22℃, in dark. Analyzed subculture conditon use callus derived from the media mentioned as above, and find calluse were accumulate PG most in the following conditon: MS+2.5 mg/L 2,4-D+0.5 mg/L 6-BA+30 g/L surcose, cultured in a sterile room with controlled ligeht illumination of 3000 lux, 12h/12h, 22±2℃. In vitro cytotoxicity test domenstrated the cytotoxicity of of PG isolated from callus and its similarity with corm of saffron.
本研究采用50mM,pH8.0的三羟甲基氨基甲烷.盐酸缓冲液(Tris-HCl),其中含有1mM的苯甲基磺酰氟(PMSF)、5mM的二硫苏糖醇(DTT)对番红花(Crocus sativus L.)球茎中的多糖进行提取,经DEAE柱层析和反相HPLC,纯化得到了一个单一的多糖组分。硫酚法和Folin-酚法结果表明该多糖中糖和蛋白质分别为94.88%和5.12%,该多糖属于蛋白聚糖(proteoglycan,PG)。PMP衍生法和间羟联苯法,检测结果表明该蛋白聚糖是一个杂聚多糖,主要由鼠李糖(28.03%),半乳糖(13.14%),岩藻糖(8.20%),木糖(19.31%),甘露糖(23.40%)和糖醛酸(7.92%)组成。氨基酸自动分析仪结果表明该蛋白聚糖的蛋白质部分主要由Asp,Glu,Gly,Ala和Leu等5种氨基酸组成(占50%以上)。FTIR和~(13)C核磁共振结果证明该蛋白聚糖具有典型的多糖和蛋白的结构官能团,并确定其主链可能为β-(1,4)-D甘露糖,侧链包括β-(1,6)-D甘露糖及其他种类单糖,如鼠李糖等。
蛋白聚糖的体内外抗肿瘤作用进行了初步研究。SRB法体外毒性试验结果表明,该蛋白聚糖对肿瘤细胞具有强烈的体外杀伤作用,对人肺癌A549细胞,人子宫颈癌Hela细胞,人肝癌SMMC-7721细胞,人乳腺癌MCF7细胞,人胃癌SGC-7901细胞等5种人组织来源的肿瘤细胞和1种鼠源的肉瘤S180细胞的IC_(50)在10-40μg/ml之间。进一步的研究表明,该蛋白聚糖(PG)引起的细胞毒性机理在于:PG减少S180细胞的胞内活性氧含量(ROS),将细胞周期阻滞在G0/G1期,随后发生细胞凋亡,引起细胞膜结构完整性的变化,最终导致细胞的死亡。利用建立的S180荷瘤小鼠模型,通过三种给药方式(腹腔注射给药,静脉注射给药和瘤内注射给药)连续给药10天,观察20天内,蛋白聚糖对小鼠体重、瘤体积的影响,20天后处死小鼠,取出瘤块,计算抑瘤率,结果表明3种给药方式都具有显著的抑制S180肉瘤生长的作用,结合实验小鼠的体重抑制情况,静脉注射0.4mg kg~(-1)day~(-1)。被推荐为以后研究的手段。
本研究建立了番红花球茎愈伤组织诱导体系,确定其最佳的培养条件为:球茎芽点周围表皮为外植体,在MS+5.0mg/L 6-BA+8.0mg/L NAA+30g/L蔗糖的培养基,暗处,22+2℃培养。对继代培养的方案进行筛选,获得了积累蛋白聚糖最多的培养条件:2.5mg/L 2,4-D+0.5mg/L 6-BA+30g/L蔗糖3000 lux,12h/12h光照下培养。利用细胞体外毒性证明了所提取得到的蛋白聚糖与球茎中的提取获得的相一致,具有体外细胞毒性作用。
Cancer continues to represent the largest cause of mortality in the world and claims over 6 million lives each year. Chemotherapeutics is still playing an important role in the treatment for malignant tumor. Although, there were majorities of anti-tumor drugs in clinical, the toxicity of this drugs can not be ignored. Thus search of new compound with high therapeutic effect and low side effect is concerned by most researchers. The screenig for new anti-tumor drugs from bioactve component of folklore medicine is a hot pot in this area.
In this study, a single polysaccharide were isolated from corm of saffron (Crocus sativus L.) by homogenized in 50 mM Tris-HCl buffer, pH 8.0, containing 1 mM phenylmethyl sulfonylfluoride (PhMeSO_2F) and 5 mM 1,4-dithio-DL-threitol (DTT) and purified by ion exchange chromatography with Macro-Prep DEAE column (16mmx300 mm) and reverse-phase high performance liquid chromatography with Supelcosil LC-304 C-4 column (4.6x250 mm). The polysaccharide was consisted of 94.88 % polysaccharide and 5.12 % protein, analyzed with Lowry method and phenol-sulfuric acid method. This result showed PG was belong to proteoglycan. The result of PMP labeled monosaccharide analysis and m-hydroxydiphenyl method analysis of uronic proteoglycan (PG) showed the polysaccharide part of PG was composed of rhamnose (28.03 %), galactose (13.14 %), fucose (8.20 %), xylose (19.31 %), mannose (23.40 %) and uronic acid (7.92 %). while the protein of PG is mainly consist of Asp, Glu, Gly, Ala and Leu (account to more than 50 % ) analyzed with auto amino acid analyzer. FTIR and ~(13)C NMR spectra showed main functional group of polysacharide and protein in PG, and the main skeletons was acertained to beβ-(1,4)-D linkaged mannose accompanied with branched chain ofβ-(1,6)-D mannose and other monosaccharide, such as rhamnose.
The antitumor effect of PG were studied both in vitro and in vivo. PG has servere cytotoxic effect on 5 human tumor cell lines (Hela, A549, MCF7, SGC-7901 and SMMC-7721 cell) and one mouse cell line (S180 cell) in vitro, with IC_(50) ranged form 10 to 40μg/ml. Further study showed the mechanism of PG induced cytotoxicity was: PG inhibit prduction of intracellular reactive oxygen species (ROS) S180 cell, which resulted in cell cycle arrest in G0/G1 phase, and followed by destory of cell membran intergrity, and cell apoptosis. The transplanted S180 tumor mice model was established, The transplanted S180 tumor mice model was established, and the tumor growth inhibition effect in vivo was detected through 3 different PG administration way (intraperitoneally, intravenously and intratumorally injection). All the results showed the tumor growth inhibition in vivo. According to the inhibition effect on mouse growth, the intravenously administration of PG at dose of 0.4 mg kg~(-1) day~(-1) were recommanded for further study.
Callus Induction System in corm of saffron was Established. And the study showed the most effective culture condition was: use epidermis from corm of saffron around buds as exoplant and cultured in MS meida contain with 5.0 mg/L 6-BA, 8.0 mg/L NAA and 30 g/L surcrose at 22℃, in dark. Analyzed subculture conditon use callus derived from the media mentioned as above, and find calluse were accumulate PG most in the following conditon: MS+2.5 mg/L 2,4-D+0.5 mg/L 6-BA+30 g/L surcose, cultured in a sterile room with controlled ligeht illumination of 3000 lux, 12h/12h, 22±2℃. In vitro cytotoxicity test domenstrated the cytotoxicity of of PG isolated from callus and its similarity with corm of saffron.
引文
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