CN106389476A - Lycogen在用于制备促进糖尿病伤口愈合及辅助抑制癌移转的医药组合物中的应用 - Google Patents
Lycogen在用于制备促进糖尿病伤口愈合及辅助抑制癌移转的医药组合物中的应用 Download PDFInfo
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Abstract
本发明涉及一种类茄红素在用于制备促进糖尿病伤口修复的类茄红素组合物中的应用，该类茄红素组合物包含有效剂量的类茄红素萃取物。本发明还涉及一种类茄红素在用于制备辅助抑制癌移转的类茄红素组合物中的应用，该类茄红素组合物包含有效剂量的类茄红素萃取物。该类茄红素萃取物包含的活性成分选自ζ‑胡萝卜素、链孢红素、球形烯醇及/或甲氧基链孢红素。
Description
技术领域
本发明涉及一种类茄红素在用于制备促进糖尿病患者的伤口修复，以及在用于制备辅助抑制癌转移的类茄红素组合物中的应用。
背景技术
糖尿病在现今社会中是一常见的疾病，在台湾每年有超过一百万人次因糖尿病而求医。然而糖尿病是一种无法根治的慢性病，一旦罹患糖尿病则病患终其一生都须进行严谨的血糖控制，以避免其严重影响生活质量甚至威胁生命。根据卫服部统计，糖尿病目前已高居国人十大死因前五名。
然而有许多糖尿病患并不知自己罹病，原因是糖尿病的症状常常是慢慢发展，因此在病程刚开始时往往不易察觉。而长期处于高血糖及代谢异常的状态则会影响身体的血管及神经异常，因而带来许多慢性并发症，包括小血管病变(如视网膜病变、肾脏病变)及大血管病变(又称动脉硬化症)。一旦病情控制不佳，易引起心脏病、中风，造成眼睛、肾脏、下肢血管等并发症，甚至造成失明、洗肾和截肢。
许多糖尿病患者因神经系统受到损伤导致反应迟钝而没有注意到身体有伤口。又因血管病变使得受伤部位周边组织缺血缺氧、生长因子不足、白血球、红血球、血小板也会受到影响，且血液黏稠度增加，使得伤口反复感染机会更高，导致伤口需花费更长时间复原。因此若能在伤口刚发生时给予辅助加速伤口愈合、阻隔伤口碰触到外界污染，则可避免伤口反复感染扩大伤口范围。故本发明提供一类茄红素组合物，以促进糖尿病者的整体伤口愈合速度及外观表皮修复的应用。
目前在台湾癌症已是十大死因的第一名，而几乎所有的癌症都可能成为转移性肿瘤。而一旦发生远程转移，癌细胞会移转至身体各处，造成治愈机率将大大降低。癌细胞的转移(metastasis)扩散往往是造成癌症病人病灶复发致死的最主要原因之一。癌细胞的转移包含了细胞与细胞外基质(extracellular matrix,ECM)之间结合能力(adhesion)的改变，细胞与细胞间相互作用力的破坏，细胞外基质的分解，紧接着癌细胞会穿过细胞外基质，侵入到循环系统中的血管或淋巴管(invasion)，逃过免疫系统的防护，最后贴附在内皮细胞上，穿破血管或淋巴管到达新的组织器官，接着大量的增殖并诱发血管增生(angiogenesis)。癌细胞便藉新生的血管夺取正常组织器官的养分而造成正常组织器官功能的耗弱，最后造成癌症病人的死亡。
换言之，血管增生的发生，主要是由于肿瘤能够产生诱导血管新生的血管生成因子，促使血管内皮细胞进行血管增生作用，新生的血管可以为肿瘤的生长带来营养和氧气。近几十年来，已有许多动物及人体研究也证实肿瘤生长与移转是需要依靠血管增生作用。因此，若能抑制癌细胞的转移或侵入至循环系统，则可降低癌病患因癌移转导致的死亡机率。故本发明提供一类茄红素组合物，以辅助抗癌药物应用于抑制癌转移之功效的应用。
在发明人先前的研究中发现，Lycogen可明显抑制细胞内基质金属蛋白酶-2(matrix metalloproteinases-2，MMP-2)的分泌。MMP和血管内皮细胞的血管增生息息相关为微血管内皮细胞最初形成新生血管的首要成分，其主要功能为协助血管内皮细胞移行及分解细胞间基质，以利新血管的形成。其中以MMP-2及MMP-9具有分解基底膜基质第五型胶原蛋白的能力，与血管增生及癌细胞转移最为相关。而且在癌细胞转移的过程中，血管增生扮演着重要关键的角色。因此，Lycogen是否具有抑制血管增生是值得探讨的。而本发明进一步证实Lycogen与抗癌药物可发生协同作用，抑制MMP的活性与分泌，进而辅助抗癌药物的作用。
发明内容
本发明所述的「类茄红素」(Lycogen)为参考中华民国专利公告第I406942号的「类茄红素萃取物及其组合物」，此专利全文内容并入本发明作为参考，本发明依据该专利的实施内容来进行制备类茄红素。该类茄红素萃取物包含活性成分选自ζ-胡萝卜素(ζ-carotene)、链孢红素(neurosporene)、球形烯醇(spheroidenone)及/或甲氧基链孢红素(methoxyneurosporene)。而该类茄红素萃取自突变的光合菌，由野生或培养的原生光合菌经紫外线照射使其变性而来。该突变的光合菌为一球形红杆菌(Rhodobactersphaeroides)，已保藏于布达佩斯条约的德国微生物与细胞搜集中心(DSMZ-DeutscheSammlung von Mikroorganismen und Zellkulturen GmbH)，保藏编号为DSM 25056，保藏地址为德国布伦瑞克茵霍芬大街7B D-38124，保藏日期为2011年8月1日。该菌株也保藏于台湾新竹食品工业发展研究所，保藏标号为BCRC910406。
在一具体实施例中，该ζ-胡萝卜素的含量多于该类茄红萃取物的10重量百分比。在另一具体实施例中，该链孢红素的含量多于该类茄红萃取物的10重量百分比。在另一具体实施例中，该球形烯醇的含量多于该类茄红萃取物的30重量百分比。在另一具体实施例中，该甲氧基链孢红素的含量多于该类茄红萃取物的30重量百分比。
本发明提供一种类茄红素在用于制备促进糖尿病伤口愈合的类茄红素组合物的应用，其中该组合物包含有效剂量的类茄红素萃取物。
本发明透过制造伤口于糖尿病个体的皮肤后给予Lycogen，并观察伤处的复原程度。结果显示Lycogen可减缓受伤区的肉芽组织(Granulation tissue)的生成、并减少组织液的产生，使伤口维持较为干燥的状态，且相较于控制组(并未给予伤口任何处理)显著促进整体伤口的愈合及外观表皮修复。给予Lycogen处理的糖尿病伤口，其白血球浸润情形相较于控制组而言较为减少、胶原组织的排列较有条理、并且较无水肿情形，因此可证明Lycogen具有促进表皮层及角质层复原的功效。
在一具体实施例中，所述类茄红素组合物用于促进糖尿病伤口愈合的有效剂量浓度为1.25-20mg/mL。在另一具体实施例中，所述类茄红素组合物的有效剂量浓度为2.5-10mg/mL。而在一较佳具体实施例中，所述类茄红素组合物的有效剂量浓度为5mg/mL。
本发明还提供一类茄红素在用于制备辅助抗癌药物抑制癌移转(metastasis)的类茄红素组合物的应用，其中该组合物包含有效剂量的类茄红素萃取物。本发明以诱发血管形成，并针对各项血管增生指标进行评估，包括测定细胞的凋亡、移行、脉管形成、MMPs活性等。本发明将Lycogen合并抗癌药物进行血管增生试验，确定Lycogen具有抑制细胞脉管形成的效用，并且可抑制细胞的移动能力和MMP-9的活性。因此Lycogen确实能与抗癌症药物发生协同作用，进而可减少抗癌症药物的使用量，以降低副作用。
在一具体实施例中，该类茄红素组合物抑制癌细胞生长的有效剂量浓度为5-200μM。在另一具体实施例中，所述类茄红素组合物的有效剂量浓度为10-150μM。而在一较佳具体实施例中，所述类茄红素组合物的有效剂量浓度为50-100μM。
在一具体实施例中，该类茄红素组合物辅助抗癌药物用于抑制癌移转的有效剂量浓度为2-200μM。在另一具体实施例中，所述类茄红素组合物的有效剂量浓度为5-150μM。而在一较佳具体实施例中，所述类茄红素组合物的有效剂量浓度为10-100μM。
本发明所述的类茄红素组合物单独使用也具有降低癌细胞转移的功效，且仅需5μM的Lycogen即可抑制癌细胞移行(migration)及侵袭(invasion)(如图16及18)，进而可抑制癌移转。
文中所提「糖尿病个体」一词包括那些具有高血糖的个体(包括具有慢性高血糖、胰岛素过多、葡萄糖代谢或耐受受损、及胰岛素抵抗的个体)。高血糖个体的血糖浓度包括，例如，用可靠的诊断仪器确定葡萄糖浓度比正常值高。这种高血糖个体有危险或易于出现明显糖尿病临床症状。此处所提「个体」一词包含但不限于哺乳动物或人类。
该术语「癌症」可以是指上皮癌(carcinoma)、肉瘤(sarcomas)、腺癌、淋巴瘤、白血病、固态癌、及淋巴癌等等。不同类型的癌症例子包括但不限于肺癌(例如：非小型细胞肺癌或是NSCLC)、卵巢癌、前列腺癌、结肠直肠癌、肝癌(即hepatocarcinoma)、肾脏癌(即肾细胞癌，renal cell carcinoma)、膀胱癌、乳癌、甲状腺癌、胸膜癌(pleural cancer)、胰脏癌、子宫癌、子宫颈癌、睪丸癌、肛门癌、胰脏癌、胆管癌、胃肠道类癌瘤、食道癌、胆囊癌、阑尾癌、小肠癌、胃(gastric)癌、中枢神经系统的癌症、皮肤癌、绒毛膜癌；头与颈部癌症、血癌、骨原性肉瘤、纤维肉瘤、神经胚细胞瘤、神经胶瘤、黑色素瘤、B细胞淋巴瘤、非霍奇金氏淋巴瘤(non-Hodgkin's lymphoma)、柏基特氏淋巴瘤(Burkitt's lymphoma)、小细胞淋巴瘤、大细胞淋巴瘤、单核球白血病、骨髓性白血病、急性淋巴球白血病、急性骨髓性白血病(AML)、慢性骨髓性白血病(CML)、及多发性骨髓瘤。在一些特定实施例中，本发明的组合物及方法对于治疗癌症是有用的。
附图说明
图1为各组别对糖尿病鼠的切割伤口愈合结果分析图。
图2为各组别的伤口组织免疫染色图。
图3为各组别的伤口组织免疫染色图。
图4为各组别的胶原蛋白I免疫反应呈色图。
图5为各组别的Vimentin(波形蛋白)表现量图。
图6为各组别的TNF-alpha表现量图。
图7为各组别的IL-1beta表现量图。
图8为各组别的VEGF(血管内皮生长因子)表现量图。
图9为Lycogen对细胞增生的抑制表现结果。
图10为Lycogen结合5-FU对血管增生的抑制效用之结果。
图11为Lycogen结合5-FU对细胞移行的抑制效用之结果。
图12为Lycogen结合5-FU对MMP-9的活性抑制效用之结果。
图13为Lycogen的浓度与细胞存活率。
图14为ERK蛋白活性的免疫染色分析。
图15为AKT蛋白活性的免疫染色分析。
图16为Lycogen结合5-FU对癌细胞移行的抑制效用的统计结果。
图17为Lycogen结合5-FU对癌细胞侵袭的抑制效用的荧光显微镜拍摄结果。
图18为Lycogen结合5-FU对癌细胞侵袭的抑制效用的统计结果。
具体实施方式
下列实施例仅代表本发明的各种态样与特征，并非限制本发明的范围。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
Lycogen用于糖尿病个体之伤口修复
伤口愈合测试
在一实施例中于每一只糖尿病鼠身上利用165℃的铜块(2×2cm)紧密接触糖尿病鼠10秒以制造伤口，形成全层皮肤的烧烫伤口，再分别给予溶剂(vehicle)及Lycogen凝胶持续观察至第15天。溶剂组的伤口每一天涂0.2ml的凝胶，Lycogen组则是涂抹添加了Lycogen于同样的凝胶，Lycogen含量为1mg/0.2ml。
在另一实施例中，于糖尿病鼠身上制造切割伤口，进行15天的涂抹试验，并分成三组，每组4只糖尿病鼠：(A)控制组(wound):切割伤口未涂抹任何物质之糖尿病鼠伤口；(B)溶剂组(vehicle):切割伤口仅涂抹0.2ml乳液；(C)实验组(Lycogen):切割伤口每日涂抹1mg的Lycogen+0.2ml乳液。图1可清楚看出Lycogen组的伤口愈合程度明显比控制组及溶剂组好。利用定量软件圈画出每两天的伤口大小(比例尺为1公分)，再以折线图呈现整体复原情形。计算方式：纯受伤-治疗组(伤口面积％)的各时间积分总和；数值越大代表治疗效果越好。利用纯受伤组与治疗组每天的伤口面积算出图1左上的曲线图，再利用曲线图做出每天的面积总合再相加求平均，做出组别整体的面积，即为AUC(Area under curve曲线下面积图)。
参照图2，接着将15天后的伤口进行组织染色，由染色结果可看出，控制组的表皮在受伤初期会产生大量白血球浸润情形、组织较为松散、且角质层复原缓慢。而溶剂组相较于正常组则有较好的修复状态，有可能是因为凝胶盖布伤口阻隔感染的情况。在Lycogen组可见到切割伤口白血球浸润情形大量降低、表皮层及角质层复原完整、胶原组织排列较有条理且较无水肿情形，整体而言糖尿病伤口复原状况比正常组及溶剂组良好。结果显示给予Lycogen的治疗组有显著促进糖尿病伤口愈合之作用。(P值计算方式：以wound+vehicle与wound+Lycogen进行T-Test分析。)
图3也可看出在Lycogen组的皮肤深处发炎细胞较少，且有许多纤维母细胞；而表皮处已重新生成表皮层，并分化出角质细胞。然而vehicle组别则较不明显。
胶原蛋白I免疫活性及vimentin含量测试
在一实施例中进行了胶原蛋白I免疫活性及Vimentin表现量的测试。胶原蛋白为伤口愈合的重要因子，用于协助伤口的组织修复。Vimentin(波形蛋白)是一间质细胞的marker，可调控细胞结构完整性、影响细胞贴附和迁移、细胞凋亡及免疫防御等功能。由图4及图5的免疫染色图显示Lycogen组别的胶原蛋白免疫反应性及vimentin的含量分别是控制组(control)的6倍及25倍。Vehicle组为仅给予0.2ml乳液的组别。
TNF-α、IL-1β、VEGF表现量测试
在另一实施例中进行了TNF-α、IL-1β、VEGF含量测试。TNF-α及IL-1β皆为发炎相关因子，有发炎反应时表现量会上升。VEGF(血管内皮生长因子)会在伤口愈合过程中分泌。参考图6至图8，组为无受伤组别、injury组为受伤但未进行任何处理的组别、injury+vehicle组为受伤但仅给予凝胶组、而injury+lycogen组为受伤并给予1mg的Lycogen组别。由图6至图8显示，在injury+lycogen组别的TNF-α、IL-1β及VEGF含量具有显著的下降，并恢复至接近未受伤组别的状态。由图8更可得知，Lycogen具有加速糖尿病个体的伤口愈合的效用，使伤口愈合至后期，所以在取样之际的VEGF含量较少。
Lycogen用于辅助抑制癌转移
细胞增生分析
在一实施例中，将Lycogen溶于四氢呋喃(tetrahydrofuran，THF)以形成不同浓度的Lycogen试剂(0、10、50、及100μM)，并分别与HUVEC细胞培养24-72小时，每组至少三重复，并以MTT试验进行细胞增生分析。试验结果以百分比呈现。
图9显示HUVEC细胞经Lycogen培养24-72小时后，HUVEC细胞数显著地随剂量和时间增加而减少。10μM的Lycogen在培养24-48小时内对细胞并无显著性毒性，但50μM的lycogen则在培养48小时后开始显著地抑制HUVEC细胞的增生。若以100μM的lycogen培养HUVEC细胞，则在24小时便开始显著抑制HUVEC细胞的生长。由此结果可作为日后Lycogen使用剂量及时间的对照依据。
血管增生分析
体外血管增生试验常被用来研究各种抗血管增生营养素或药物的模式，该试验方便性较高且快速。因此，本实施例利用此模式探讨Lycogen能否加乘性地抑制HUVEC细胞脉管形成。本发明先在基质胶(matrigel)中以H2O2诱发脉管形成进行评估Lycogen对于血管增生指标的影响。将HUVEC细胞溶于含有10％血清的培养基里，再将HUVEC细胞以每格1*104颗种在以matrigel披覆的24孔盘里。控制组以外的组别分别以溶剂、5-FU、5-FU加10μMlycogen、5-FU加30μM lycogen、及5-FU加50μM lycogen对HUVEC进行处理。每个条件进行二重复，且此试验重复两次。进行处理后6小时，并以位相差显微显微镜(phase contrastphotomicrograph)以100倍放大倍率进行呈像。
如图10中显示H2O2确实诱发细胞脉管的形成，而溶剂对照组对脉管形成的影响则与控制组相似，因此溶剂对试验并无影响。另外5-FU确实能抑制细胞脉管的形成，而加上不同浓度(10-30μM)Lycogen后证实随着Lycogen剂量增加，5-FU对脉管的抑制能力就越强。
细胞移行分析
在另一实施例中，进行Lycogen对细胞的移行能力分析。以与上述血管增生分析同样的条件进行试验。图11显示5-FU确实能抑制细胞移动的能力；而5-FU再加进不同浓度的Lycogen(以THF为溶剂调制出10-50μM的Lycogen)，则随着Lycogen剂量增加，细胞移动的数量就越低，即表示Lycogen对于5-FU抑制细胞移动的能力具有辅助效果。
在另一实施例中，分析lycogen对人脐静脉内皮细胞株EA.hy926细胞株移行的影响。将EA.hy926细胞株用各种浓度的lycogen(0、2、5、和10μM)或25μg/mL的5-FU处理24小时后，进行EA.hy926细胞株移行的分析，并算出移行面积的差异。
结果如图16显示，5-FU具有抑制癌细胞移行的效果，而5μM及10μM的Lycogen也具有抑制癌细胞移行的效果。且在5-FU与Lycogen共同作用下，仅须2μM的Lycogen即可以明显的增加癌细胞移行的抑制效果。
MMP-9活性分析
MMP(基质金属蛋白酶，Matrix metalloproteinase)和血管内皮细胞的血管增生息息相关，是微血管内皮细胞最初形成新生血管的首要成分，其主要功能为协助血管内皮细胞移行及分解细胞间基质，以利新血管的形成，其中以MMP-2及MMP-9与血管增生最为相关。癌细胞中MMPs会受到活性氧活化而增加合成与分泌量，其作用已证实是用来作局部侵入和远处转移，以便助长癌细胞穿透基底膜，并由血管渗入组织而达到转移的目的。因此，在另一实施例中进行MMP-9的活性分析。图12显示Lycogen与5-FU合并使用后可抑制MMP-9活性，且具剂量关系，即Lycogen剂量越高则MMP-9的活性越低。
癌细胞侵袭分析
利用人脐静脉内皮细胞株EA.hy926分析Lycogen对于抑制癌细胞侵袭的能力。将EA.hy926细胞用各种浓度lycogen的(0、2、5、和10μM)或为25μg/mL的5-FU处理24小时后，利用Matrigel进行侵入分析，并于倒置荧光显微镜拍摄细胞侵入(Invasion)的情形。
Matrigel是从小鼠EHS肉瘤中提取的基质成分，含有LN、IV型胶原、接触蛋白和肝素硫酸多糖，铺在无聚乙烯吡硌烷酮的聚碳酸酯滤膜上，能在DMEM培养基中重建形成膜结构，这种膜结构与天然基质膜结构极为相似。
将细胞培养Transwell细胞培养盘上，培养盘上有一层半透膜，拟生物体内狀况进行细胞入侵的实验，利用肿瘤细胞会破坏基底膜(basal membrane)侵入周围组织的特性，在细胞培养皿中，加入小鼠肉瘤的基底膜萃取物，并以无菌Tip或是棉线刮出一条无细胞通道(acellular space)，接着依据实验需求分别以药剂处理细胞株，最后再将细胞染色并利用荧光显微镜计数膜内的细胞，用以得知细胞是否会移动通过通道的能力。
结果如图17及图18所示，由显微镜下拍摄到的结果可以发现，添加5-FU可以明显看到侵入细胞的数目减少(相对于对照组0μg/ml)，而对于仅添加Lycogen的部分，随着浓度增加2μM、5μM、10μM，侵入的细胞数也有明显的减少趋势，且在5-FU与Lycogen共同作用下，仅须2μM的Lycogen即可有显著抑制癌细胞侵入的效果，显示Lycogen与5-FU具有协同抑制癌细胞侵袭的效应。
Lycogen用于辅助抑制癌细胞分析
抑制癌细胞生长试验
在另一较佳实施例中，以摄护腺癌细胞株DU145与LNCap细胞株进行分析，观察Lycogen对于癌细胞的生长是否有抑制作用，并利用One-way ANOVA及IndependentSamples T-Test统计分析方法进行相关分析。
将摄护腺癌细胞株DU145以抗氧化剂EGCG(Epigallocatechin gallate)处理24及48小时，并分析其结果。请参照表格1，Lycoge均达到显著的抑制摄副腺癌细胞增生的效果(p<0.05)。此结果显示Lycogen对摄副腺癌细胞株DU145具有较迅速的抑制效果。而在细胞株LNCap的试验中，在48小时下，Lycogen也达到显著的抑制癌细胞效果(p<0.05)。由结果显示，Lycogen具有抑制摄护腺癌细胞的存活。
DU145
LNCaP
表格1.摄护腺癌细胞存活率one-way ANOVA显著性分析
接着测试不同浓度的lycogen对DU145的细胞存活率测试分析。图13显示Lycogen在摄护腺癌细胞株DU145中，具有浓度越高则癌细胞存活率越低的趋势。
通过Independent Samples T-Test显著性分析发现，在表格2中，Lycogen在24小时下，40μM的浓度即可有效抑制DU145细胞的生长，在48小时下，5至40μM的浓度均可以有效抑制DU145细胞的生长。
表格2.摄护腺癌细胞存活率Independent Samples T-Test显著性分析
Lycogen用于抑制摄护腺癌细胞的ERK及AKT活性测试
在另一实施例中进行相关蛋白的活性分析，包括ERK及Akt的蛋白活性。Akt透过抑制细胞凋亡的过程而参与细胞存活路径。Akt可以阻断细胞凋亡并促进细胞存活，故已有许多文献证明Akt在多种肿瘤中有主要作用。ERK可与许多的转录因子、磷酸激酶、去磷酸酶以及细胞凋亡蛋白作用，因此当细胞的ERK讯息传导路径持续活化时，会导致细胞增生与存活，进而导致肿瘤的生成。
在图14及图15中显示Lycogen具有抑制ERK及AKT蛋白活性的效果，通过抑制ERK及AKT的磷酸化反应而达到抑制蛋白活性。
Claims (10)
1.一种类茄红素在用于制备促进糖尿病伤口愈合的类茄红素组合物中的应用，其中该组合物包含有效剂量的类茄红素萃取物。
2.如权利要求1所述的应用，其中该类茄红素萃取物包含活性成分选自ζ-胡萝卜素(ζ-carotene)、链孢红素(neurosporene)、球形烯醇(spheroidenone)及/或甲氧基链孢红素(methoxyneurosporene)。
3.如权利要求1项所述的应用，其中该类茄红素萃取物萃取自突变的光合菌。
4.如权利要求3项所述的应用，其中该突变的光合菌为保藏标号为DSM25056的球形红杆菌(Rhodobacter sphaeroides)。
5.如权利要求1项所述的应用，其中该类茄红素组合物具有促进表皮层及角质层复原的功效。
6.一种类茄红素在用于制备辅助抗癌药物抑制癌移转(Metastasis)的类茄红素组合物中的应用，其中该组合物包含有效剂量的类茄红素萃取物。
7.如权利要求6项所述的应用，其中该类茄红素萃取物包含活性成分选自ζ-胡萝卜素(ζ-carotene)、链孢红素(neurosporene)、球形烯醇(spheroidenone)及/或甲氧基链孢红素(methoxyneurosporene)。
8.如权利要求6项所述的应用，其中该类茄红素萃取物萃取自突变的光合菌。
9.如权利要求8项所述的应用，其中该突变的光合菌为保藏标号为DSM25056的球形红杆菌(Rhodobacter sphaeroides)。
10.如权利要求6项所述的应用，其中该类茄红素组合物具有辅助抑制癌细胞增生、癌细胞移行、及/或血管新生的功效。
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