Honokiol作为一种具有新的抗肿瘤机制的小分子药物的研究
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摘要
研究背景
和厚朴酚(Honokiol)是联苯类木脂素的代表,主要来源于传统中药厚朴。它具有多重药理作用,包括抗感染、抗焦虑、抗氧化等。近年来,其抗肿瘤作用受到重视,已有一些文献报道和厚朴酚可诱导一些肿瘤细胞株的凋亡。最近,两篇来自美国哈佛大学Dana-Farber肿瘤研究所的报道指出其可诱导原代B-细胞慢性淋巴细胞白血病(B-cell chronic lymphocytic leukemia)和多发性骨髓瘤细胞(multiple myeloma)凋亡。但是,由于其多重药理功能,和厚朴酚被认为是一种功能众多,靶点“模糊”的活性小分子。
“模糊”的小分子例如反应停,阿司匹林等都是到目前为止适应面极广的抗肿瘤明星药物。例如,阿斯匹林除了镇痛、抗关节炎,还有很多其他功能如降低血液粘稠度、抗血小板凝集、抗孕前惊厥、抗肿瘤作用等。同理,本课题组研究的其他具有体内外广谱抗肿瘤作用的小分子药物,例如五味子乙素,左旋紫草素无不是作用多个靶点,干预多条信号通路。而且,从病因学以及病理学上来说,恶性肿瘤是一个高度复杂的整体,它包含了多条信号通路以及很多关节点。可以说,恶性肿瘤是一个多因素的问题,只有采用针对多因素的办法来解决。因此,我们认为:凡是具有开发潜力的抗肿瘤药物,其优势应该是“模糊的”即一药“多功能”——从多个环节打击肿瘤。这也能解释许多单一靶点药(如伊瑞莎)失败的原因:其高度的专一性,太容易因为多机制的耐药性而失效。
肿瘤耐药性是化疗的主要障碍,与90%肿瘤相关的死亡直接的或间接的与肿瘤耐药有关。从当前研究成果看,肿瘤耐药可能机制具体主要包括(1)药物转运泵的表达增高或活性增强,例如P-gp、MRP-1、BCRP的过量表达;(2)凋亡相关通路的改变:尽管临床使用的化疗药有不同的靶位和机理,但一般均引起肿瘤细胞的凋亡,由于肿瘤组成的异质性以及其基因组的高度不稳定性,肿瘤细胞即使开始对凋亡诱导较敏感,但最终会产生凋亡耐受。因此,抗癌的小分子药物的药效好坏与否,与肿瘤细胞对这些小分子的耐药机制有关。而且,越来越多的证据表明(比如MDR逆转剂研制,伊瑞莎、格列卫的使用),最佳解决肿瘤耐药的方法还是在治疗过程中避免耐药的产生,而不是等到有了不良结果后才去弥补,这也是更新一代抗癌药物的开发原则。
本课题组一直从事有关抗肿瘤耐药性的研究工作。本文以报道和厚朴酚能够绕开传统的耐药机制,以一种非凋亡的线粒体通透性转换孔依赖的死亡方式攻击肿瘤细胞的基础研究为主干,兼顾和厚朴酚在临床原代样本以及体内模型的应用性研究。目前,尚无他人报道本研究成果。
研究目的
明确和厚朴酚对于多药耐药的肿瘤细胞的药效;研究和厚朴酚是否可以通过非凋亡的其他程序性死亡机制诱导肿瘤细胞死亡;探索和厚朴酚是通过何种机制引起非凋亡的细胞死亡;评估和厚朴酚对原代细胞的药效及探索其可能机制;要将一个有潜力的抗肿瘤小分子推向临床,那么临床前体内实验必不可少,通过建立荷HL60的NOD/SCID小鼠模型来明确和厚朴酚对白血病细胞移植瘤的体内药效。
研究内容
第一部分Honokiol对MDR细胞与亲本细胞的抗肿瘤作用的探讨
(1)以K562/ADR与K562,HL60/ADR与HL60,MCF-7/ADR与MCF-7,Bcap37/MDR与Bcap37为研究模型。四对细胞株经Honokiol诱导后,用MTT法检测Honokiol对所有MDR细胞株与亲本细胞株的IC_(50)。通过与三种常规化疗药物比较,发现Honokiol具有对亲本细胞和MDR细胞效应相当的特点。结合本课题组过去的研究报告,我们认为Honokiol非药泵的底物;(2)为了进一步研究Honokiol的抗肿瘤机制,我们检测经药物诱导后细胞的Caspase-3的活性,发现至少在HL60/ADR与HL60,MCF-7/ADR与MCF-7细胞中Caspase凋亡通路没有被激活。通过电镜观察,发现HL60/ADR与HL60,MCF-7/ADR与MCF-7细胞死亡过程中检测不到凋亡细胞;(3)因为Honokiol具有对亲本细胞和MDR细胞效应相当的特点,所以研究Honokiol对亲本细胞的作用机制便具有代表性。在K562、HL60、MCF-7、Bcap37细胞上,通过Hoechst染色、台盼蓝染色确证,Honokiol的抗肿瘤作用除了诱导细胞发生凋亡,也可以诱导细胞发生非凋亡的死亡。
第二部分Honokiol能够以一种可调控的非凋亡的方式诱导肿瘤细胞死亡
以HL60细胞株为研究非凋亡死亡方式的模型,发现该死亡方式有以下特点:(1)流式细胞仪AV/PI双染、PI拒染法发现HNK主要引起时间依赖性且浓度依赖性的细胞膜完整性受损;(2)HNK对HL60细胞周期无明显影响,DNA电泳也不出现梯带化,Caspase总抑制剂z-VAD-FMK不能抑制细胞死亡;(3)免疫荧光检测AIF转位实验,证实AIF介导的凋亡也未参与过程;(4)而且这种死亡不受凋亡耐受影响,因为过表达Bcl-2或者Bcl-xL无法抑制该药物的诱导死亡作用;(5)用15μg/ml的和厚朴酚处理HL60细胞不同时间长度后,将药物洗净,换上新鲜的培养液,测定细胞死亡率。继续培养24小时后,再次测定细胞死亡率。结果可见,药物处理1或2小时后撤药,细胞死亡比例增加很少,死亡基本可逆。而随着药物处理时间增长,死亡增加比例也随之增高,但仍然低于15μg/ml的和厚朴酚连续处理24小时的死亡率。Wash out实验证实该死亡作用是可逆的;(6)线粒体PT孔抑制剂Cyclosporin A(CsA)可以抑制细胞死亡;(7)在MCF-7细胞上也发现和厚朴酚能引起类似HL60的死亡作用。
第三部分线粒体通透性转换孔(PT pore)是Honokiol新的抗肿瘤机制的关键
通过第一部分电镜的观察,我们发现药物诱导的早期,细胞的线粒体便发生了形态学的改变,说明线粒体在细胞死亡中起着关键的作用。它在细胞死亡信号传递中起着承上启下的整合作用。(1)15μg/ml的和厚朴酚处理HL60细胞0、6、12、18小时后,线粒体染料JC-1染色,流式细胞仪检测到JC-1~(LOW)细胞(即低线粒体膜电位细胞)比例增多,3.1%±1.2%,15.2%±3.4%,35.0%±3.5%,55.1%±6.2%。而加入5μM的CsA后,以12小时为例,JC-1~(LOW)细胞比例有所下降,24.1%±2.4%。用15μg/ml的和厚朴酚处理HL60细胞0、1、3、6、12小时后,ROS特异性荧光染料H_2DCFDA孵育半小时,流式细胞仪检测荧光水平,各样本均与正常细胞对照组相比,取其荧光强度比值进行分析。ROS的水平在和厚朴酚作用后,呈时间依赖性上升,加入5μM的CsA后ROS升高可被部分抑制;(2)15μg/ml的和厚朴酚处理6小时后,加入1mM的calcein-AM荧光染料及5mM的CoCl室温避光反应15分钟。加入CoCl是为了淬灭胞浆中的染料,只留下线粒体部分的荧光。当PT孔开放时,calcein-AM从线粒体溢出,线粒体荧光强度降低,由此检测PT孔开放情况。激光共聚焦显微镜观察结果显示,和厚朴酚处理组PT孔开放,绿色荧光明显较对照组减弱。加入5μM的CsA后,可抑制这一现象。我们推测,CsA的PT孔抑制作用是通过结合其靶蛋白亲环蛋白D(Cyclophilin D)来抑制孔道开放,继而影响细胞死亡的;(3)用SiRNA的办法Knock down肿瘤细胞内的亲环蛋白D表达水平,可影响Honokiol对肿瘤细胞的药敏。这就说明Honokiol抗肿瘤作用是线粒体PT孔道依赖性的;(4)有趣的是,我们还发现在药物诱导肿瘤细胞死亡的早期阶段,亲环蛋白D无论从mRNA水平还是蛋白水平都会升高;但是,在HNK诱导肿瘤细胞如K562凋亡的情况下(CsA不能抑制凋亡),亲环蛋白D的表达水平不发生变化。
第四部分Honokiol对原代白血病细胞的抗肿瘤作用的研究
为了进一步阐明和厚朴酚的抗肿瘤作用在临床上的应用前景。我们收集了15例急性白血病病人的血样。(1)测定对原代白血病细胞的LC_(50),发现Honokiol对于大多数原代白血病细胞有一定效果,24小时的LC_(50)在30μg/ml左右,且该效应浓度对正常人外周血单个核细胞无毒;(2)在其中10个病例中,与HL60类似,发现Honokiol在原代样本中还是具有新的抗肿瘤机制,表现为:PS不外翻,细胞膜完整性早期受损;z-VAD-FMK不能抑制细胞死亡,CsA可以抑制细胞死亡;Cyclophilin D表达升高;(3)我们还做了集落形成实验,将Honokiol或者AraC预处理过的白血病细胞在甲基纤维素基质上培养14天,发现Honokiol抑制集落形成的能力与化疗药物阿糖胞苷相当。以上的结果证实和厚朴酚的抗肿瘤作用是具有一定的临床应用价值。
第五部分Honokiol对荷HL60小鼠的体内抗肿瘤作用的前瞻性研究
(1)和厚朴酚可以有效延长荷HL60小鼠的生存时间。在尾静脉接种HL60组,对照和加药组的小鼠生存中值天数分别是17天,以及29天。在腹腔接种HL60组中,对照和加药组的小鼠生存中值天数分别是24.5天,以及37.5天;(2)Honokiol对腹腔接种产生的HL60移植瘤的抑制作用不理想(P＞0.05);(3)但是,通过免疫组化检测小鼠各重要组织中人源CD45细胞的阳性比例来确定HL60的浸润情况,发现Honokiol能减轻肿瘤细胞对脏器的浸润。
研究结论
1.Honokiol对MDR肿瘤细胞株和亲本肿瘤细胞株药效相近。
2.Honokiol能够诱导以HL60为代表的肿瘤细胞株发生非凋亡的可调控的死亡,该死亡不受凋亡耐受影响。
3.Honokiol所诱导的非凋亡的可调控的死亡是线粒体通透性转换孔依赖性的。
4.Honokiol对原代急性髓系白血病细胞的作用机制包含了类似于其对HL60作用的抗肿瘤新机制。
5.Honokiol能够延长荷HL60小鼠的生存时间,并且可以减轻HL60细胞的浸润。
Background
Honokiol,a naturally occurring phenyl lignan present in Magnolia grandiflora, is a representative with a pair of hydroxy groups(-OH)in its structure.It is of multiple medicinal uses against microbial infection,anxiety,oxidative stress,platelet aggregation,among others.Previous reports have demonstrated the anticancer activities of HNK by induction of apoptosis in cancer cell lines.Recently,two important studies from Dana-Farber cancer institute of Harvad University demonstrated that HNK efficiently induced apoptosis in apoptotic resistant B-cell chronic lymphocytic leukemia(B-CLL)from B-CLL patients and multiple myeloma (MM)cells from relapsed refractory MM patients.Honokiol qualifies as a "promiscuous" rather than a "selective" agent based on its known mulitiple pharmacologic effect.
"Promiscuity" is not unique to honokiol because many known successful drugs as well as a number of promising natural anticancer agents such as thiladomide and asprin which are promiscuous.The best known example of a widely used drug that can be classified as promiscuous type is aspirin.In addition to its pain-relieving and antiarthritic effects,aspirin exhibits many other pharmacologic effects including blood thinning,reduction of platelet aggregation,prevention of preeclampsia(a hypertensive disorder during pregnancy),and anticancer effects.Likewise,recent studies including those from our own laboratory have revealed that many promising anticancer nature product(e.g,schisandrin B and shikonin)targeted multiple signal transduction pathways in various cell types to inhibit cancer cell growth in vitro and in vivo.Because the etiology and pathogenesis of cancer is highly complex involving abnormalities in multiple cellular checkpoints and signal transduction pathways,we are in agreement with the idea that promiscuity may be of advantage as potential anticancer agents.The indirect evidence to support this notion is that some recently developed anticancer agents with exceptionally high selectivity have failed to live up to the expectations(e.g.,specific epidermal growth factor receptor inhibitor Iressa).
Cancer drug resistance is the major obstacle to the successful cancer chemotherapy.Drug resistnce is directly or indirectly associated with 90%of cancer related death.The most important causes of cancer drug resistance are(1) Overexpressed drug transporter,such as P-gp,MRP-1,BCRP;(2)Abnormal apoptotic machinery:conventional anticaneer agents,regardless of their targets and mechanisms,mostly induce apoptosis,cancer cells are usually sensitive to apoptotic induction initially,but become resistant eventually because its heterogeneity and genomic instability.Thus,the potency of anticancer drugs is largely determined by the resistance machinery of the cancer cell.More and more evidence(Such as MDR reversal agents,Iressa,Gleevac)have indicated that the best way to overcome conventional cancer drug resistance was to bypass the resistance,which is also one of the the strategy to develop new generation of anticancer agent.
In this study we report that honokiol could circumvent the conventional drug resistance,and kill cancer cell by activating a programmed cell death associated with mitochondria PT pore.The study from primary leukemia cells and in vivo model are also involved in this work.To our best knowledge,this is the first report to document all these results.
Objects
To investigate the effect of honokiol on MDR cancer cells;To investigate whether honokiol could induce a nonapoptotic cell death on cancer cells;To analyze the mechanism of the nonapoptotic cell death triggered by honokiol;To evaluate the effect of honokiol on primary cancer cells and its assoicated mechanism;we also determined the effect(lifespan,tumor size,and invasion)of bonokiol on female NOD/SCID mice bearing implanted HL60 cells.
Results
1.The anticancer effect of honokiol on MDR and sensitive cancer cells
(1)Using four pairs of MDR and their parental cancer cell lines,K562/ADR and K562,HL60/ADR and HL60,MCF-7/ADR and MCF-7,Beap37/ADR and Bcap37, we determined the drug sensitivity of all these cell lines using MTT assay. Paticularly important,we found honokiol had the same efficacy in killing MDR cells and their parental drug-sensitive cells.Combined with our previous report,we believe honokiol is not the substrate of the MDR pump;(2)Caspase-3 is the most important apoptotic marker,thus we examined if it was activated in the cells treated with honokiol.There was no caspase-3 activation in HL60,MCF-7 and their MDR cells.Consistently,no apoptotie morphological changes under electronic microscopy were found.Thus,we thought that honokiol may trigger cell death other than apoptosis;(3)Using drug-sensitive parental cells as representatives to explore the truth of killing effect of honokiol,we adopt Hoechst staining to measure apoptotic cell death and Trypan blue exclusion assay to measure the total cell death. The discrepancy between the apoptotic death rate and total death rate was confirmed, which led to the conclusion that honokiol could induce nonapoptotic cell death in cancer cells.
2.Honokiol induces a regulated nonapoptotic cell death in cancer cells Here,we show that honokiol can induce a cell death distinct from apoptosis in HL60.After exposure to honokiol,HL-60 exhibited the following characteristics: (1)Using FCM detection,the death characterized with a rapid loss of integrity of plasma membrane which is both time and concentration dependent and without externalization of phosphatidyl serine;(2)Significant change of cell cycle (hypodiploid peak)and DNA ladder,the hallmarks of apoptosis,were not observed. Consistently,the broad caspase inhibitor zVAD-fmk failed to prevent the cell death; (3)Apoptosis-inducing factor(AIF)was not translocated to nuclei in HNK-treated HL60 cells;(4)Honokiol could overcome Bcl-2 or Bcl-X_L mediated apoptotic resistance,because they can not affect the cell death;(5)The cytotoxic effect can be recovered when cells were treated with HNK for relatively short time.And when cells were treated with HNK for longer time,the death ratios increased even after drug was removed,but still below the death ratio without wash-out.This assay prove that the cell death was regulative;(6)Cyclosporin A(CsA),an inhibitor of mitochondria permeability transition pore,effectively prevented HNK-induced cell death;(7)HNK induces similar cell death in MCF-7 cell line.
3.Mitochondrial permeability transition pore is the key to the novel killing mechanism by honokiol
Since ultrastructural studies revealed the damaged mitochondria in HNK-treated cells, we hypothesized that HNK-induced death was probably due to the mitochondrial dysfunction.Mitochondria plays a central role in cell death.It serves as an integrator of upstream death signaling.(1)The Mitochondrial memberane potential (MMP)was examined by JC-1 staining via FCM detection after treatment with 15μg/ml of HNK for 6,12,18 hours.The ratio of JC-1 Low cells increases in HNK group,indicating the loss of MMP,while CsA could partially inhibit this loss.The ROS level was examined by H_2DCFDA staining via FCM detection after treatment with 15μg/ml of HNK for 1,3,6,12 hours.The HNK treated HL60 cells showed increased ROS production in all the time points,while CsA could partially inhibit ROS generation;(2)The opening of PT pore was examined by Calcein-AM staining and observed by confocal microscope after treatment with 15μg/ml of HNK for 6 hours.The green fluorescence in HNK group was weak compared to control, indicating the opening of PT pore,while CsA could partially inhibit this opening. We presumed that CsA,an inhibitor of cyclophilin D(an essential component of mitochondria permeability transition pore),effectively prevented HNK-induced cell death;(3)Inhibition of cyclophilin D by RNA interference blocked honokiol-induced cell death,indicating that the cell death was mechanistically associated with the mitochondria permeability transition(PT)pore regulated by cyclophilin D;(4)Upregulation of cyclophilin D was observed in HL60,MCF-7 with the susceptibility to the death,but not in K562 which underwent apoptosis after exposure to honokiol.
4.The study of the anticancer efficacy of honokiol on primary leukemia cells
To further explore the potential of HNK-induced cell death in clinical application, primary leukemia cells from fifteen untreated patients with acute leukemia were collected.(1)The primary cells were incubated in vitro with various concentrations of HNK for indicated hours and assayed for cell death and LC_(50).The concentration of HNK that caused death of 50%of the cells(LC_(50))(from most of the samples)after 24 hours of incubation with HNK was 30μg/ml.Although HNK was cytotoxic toward normal peripheral blood mononuclear cells(PBMCs)(48 hour LC_(50)is 52μg/ml),primary cancer cells were significantly more susceptible to HNK;(2) Consistent with the result in HL60 cells,in ten patients,HNK induced a dominant caspase-independent and CsA-inhibitable cell death characterized with a loss of plasma membrane integrity(PI positivity)but without a significant externalization of phosphatidyl serine(Annexin V-FITC positive).HNK also significantly upregulated CypD in AML cells like HL60;(3)With the colony forming assay,we found after fourteen days culture in Methocult,the number of CFU derived from the honokiol pretreatment is the same as the Ara C pretreatment.The results indicated that the CypD associated death in human primary AML cells may have potential clinical significance.
5.The pilot study of the in vivo effect of honokiol on female NOD/SCID mice bearing implanted HL60 cells
Furthermore,a prolonged survival time was observed after treatment with HNK in SCID mice transplanted(i.p.or i.v.)with human HL60 cells engrafts.In the i.v. group,the Median survival time(MST)of HNK group was 29 days,compared with the control group(MST 17 days).Consistenly,in the i.p.group,the Median survival time(MST)of HNK group was 37.5 days,compared with the control group(MST 24.5 days).Although in the i.p.group,there was no statical difference between control and honokiol groups on the mean volume of HL60 implanted tumor(P＞0.05), honokiol treatment could mitigate the wide spread invasion of the implanted leukemic cells.
Conclusions
1.Honokiol has the same therapeutic efficacy to MDR and sensitive cancer cells.
2.Honokiol can bypass cancer apoptotic resistance by induction of a regulated nonapoptotic cell death in cancer cells.
3.Honokiol induces a mitochondrial permeability transition pore dependent nonapoptotic cell death.
4.Honokiol can also induce a cell death distinct from apoptosis in primary leukemic cells via mitochondrial permeability transition pore
5.Honokiol could significantly prolong the lifespan of the NOD/SCID mice bearing implanted HL60 cells,it could also mitigate invasion of the HL60 cells。
和厚朴酚(Honokiol)是联苯类木脂素的代表,主要来源于传统中药厚朴。它具有多重药理作用,包括抗感染、抗焦虑、抗氧化等。近年来,其抗肿瘤作用受到重视,已有一些文献报道和厚朴酚可诱导一些肿瘤细胞株的凋亡。最近,两篇来自美国哈佛大学Dana-Farber肿瘤研究所的报道指出其可诱导原代B-细胞慢性淋巴细胞白血病(B-cell chronic lymphocytic leukemia)和多发性骨髓瘤细胞(multiple myeloma)凋亡。但是,由于其多重药理功能,和厚朴酚被认为是一种功能众多,靶点“模糊”的活性小分子。
“模糊”的小分子例如反应停,阿司匹林等都是到目前为止适应面极广的抗肿瘤明星药物。例如,阿斯匹林除了镇痛、抗关节炎,还有很多其他功能如降低血液粘稠度、抗血小板凝集、抗孕前惊厥、抗肿瘤作用等。同理,本课题组研究的其他具有体内外广谱抗肿瘤作用的小分子药物,例如五味子乙素,左旋紫草素无不是作用多个靶点,干预多条信号通路。而且,从病因学以及病理学上来说,恶性肿瘤是一个高度复杂的整体,它包含了多条信号通路以及很多关节点。可以说,恶性肿瘤是一个多因素的问题,只有采用针对多因素的办法来解决。因此,我们认为:凡是具有开发潜力的抗肿瘤药物,其优势应该是“模糊的”即一药“多功能”——从多个环节打击肿瘤。这也能解释许多单一靶点药(如伊瑞莎)失败的原因:其高度的专一性,太容易因为多机制的耐药性而失效。
肿瘤耐药性是化疗的主要障碍,与90%肿瘤相关的死亡直接的或间接的与肿瘤耐药有关。从当前研究成果看,肿瘤耐药可能机制具体主要包括(1)药物转运泵的表达增高或活性增强,例如P-gp、MRP-1、BCRP的过量表达;(2)凋亡相关通路的改变:尽管临床使用的化疗药有不同的靶位和机理,但一般均引起肿瘤细胞的凋亡,由于肿瘤组成的异质性以及其基因组的高度不稳定性,肿瘤细胞即使开始对凋亡诱导较敏感,但最终会产生凋亡耐受。因此,抗癌的小分子药物的药效好坏与否,与肿瘤细胞对这些小分子的耐药机制有关。而且,越来越多的证据表明(比如MDR逆转剂研制,伊瑞莎、格列卫的使用),最佳解决肿瘤耐药的方法还是在治疗过程中避免耐药的产生,而不是等到有了不良结果后才去弥补,这也是更新一代抗癌药物的开发原则。
本课题组一直从事有关抗肿瘤耐药性的研究工作。本文以报道和厚朴酚能够绕开传统的耐药机制,以一种非凋亡的线粒体通透性转换孔依赖的死亡方式攻击肿瘤细胞的基础研究为主干,兼顾和厚朴酚在临床原代样本以及体内模型的应用性研究。目前,尚无他人报道本研究成果。
研究目的
明确和厚朴酚对于多药耐药的肿瘤细胞的药效;研究和厚朴酚是否可以通过非凋亡的其他程序性死亡机制诱导肿瘤细胞死亡;探索和厚朴酚是通过何种机制引起非凋亡的细胞死亡;评估和厚朴酚对原代细胞的药效及探索其可能机制;要将一个有潜力的抗肿瘤小分子推向临床,那么临床前体内实验必不可少,通过建立荷HL60的NOD/SCID小鼠模型来明确和厚朴酚对白血病细胞移植瘤的体内药效。
研究内容
第一部分Honokiol对MDR细胞与亲本细胞的抗肿瘤作用的探讨
(1)以K562/ADR与K562,HL60/ADR与HL60,MCF-7/ADR与MCF-7,Bcap37/MDR与Bcap37为研究模型。四对细胞株经Honokiol诱导后,用MTT法检测Honokiol对所有MDR细胞株与亲本细胞株的IC_(50)。通过与三种常规化疗药物比较,发现Honokiol具有对亲本细胞和MDR细胞效应相当的特点。结合本课题组过去的研究报告,我们认为Honokiol非药泵的底物;(2)为了进一步研究Honokiol的抗肿瘤机制,我们检测经药物诱导后细胞的Caspase-3的活性,发现至少在HL60/ADR与HL60,MCF-7/ADR与MCF-7细胞中Caspase凋亡通路没有被激活。通过电镜观察,发现HL60/ADR与HL60,MCF-7/ADR与MCF-7细胞死亡过程中检测不到凋亡细胞;(3)因为Honokiol具有对亲本细胞和MDR细胞效应相当的特点,所以研究Honokiol对亲本细胞的作用机制便具有代表性。在K562、HL60、MCF-7、Bcap37细胞上,通过Hoechst染色、台盼蓝染色确证,Honokiol的抗肿瘤作用除了诱导细胞发生凋亡,也可以诱导细胞发生非凋亡的死亡。
第二部分Honokiol能够以一种可调控的非凋亡的方式诱导肿瘤细胞死亡
以HL60细胞株为研究非凋亡死亡方式的模型,发现该死亡方式有以下特点:(1)流式细胞仪AV/PI双染、PI拒染法发现HNK主要引起时间依赖性且浓度依赖性的细胞膜完整性受损;(2)HNK对HL60细胞周期无明显影响,DNA电泳也不出现梯带化,Caspase总抑制剂z-VAD-FMK不能抑制细胞死亡;(3)免疫荧光检测AIF转位实验,证实AIF介导的凋亡也未参与过程;(4)而且这种死亡不受凋亡耐受影响,因为过表达Bcl-2或者Bcl-xL无法抑制该药物的诱导死亡作用;(5)用15μg/ml的和厚朴酚处理HL60细胞不同时间长度后,将药物洗净,换上新鲜的培养液,测定细胞死亡率。继续培养24小时后,再次测定细胞死亡率。结果可见,药物处理1或2小时后撤药,细胞死亡比例增加很少,死亡基本可逆。而随着药物处理时间增长,死亡增加比例也随之增高,但仍然低于15μg/ml的和厚朴酚连续处理24小时的死亡率。Wash out实验证实该死亡作用是可逆的;(6)线粒体PT孔抑制剂Cyclosporin A(CsA)可以抑制细胞死亡;(7)在MCF-7细胞上也发现和厚朴酚能引起类似HL60的死亡作用。
第三部分线粒体通透性转换孔(PT pore)是Honokiol新的抗肿瘤机制的关键
通过第一部分电镜的观察,我们发现药物诱导的早期,细胞的线粒体便发生了形态学的改变,说明线粒体在细胞死亡中起着关键的作用。它在细胞死亡信号传递中起着承上启下的整合作用。(1)15μg/ml的和厚朴酚处理HL60细胞0、6、12、18小时后,线粒体染料JC-1染色,流式细胞仪检测到JC-1~(LOW)细胞(即低线粒体膜电位细胞)比例增多,3.1%±1.2%,15.2%±3.4%,35.0%±3.5%,55.1%±6.2%。而加入5μM的CsA后,以12小时为例,JC-1~(LOW)细胞比例有所下降,24.1%±2.4%。用15μg/ml的和厚朴酚处理HL60细胞0、1、3、6、12小时后,ROS特异性荧光染料H_2DCFDA孵育半小时,流式细胞仪检测荧光水平,各样本均与正常细胞对照组相比,取其荧光强度比值进行分析。ROS的水平在和厚朴酚作用后,呈时间依赖性上升,加入5μM的CsA后ROS升高可被部分抑制;(2)15μg/ml的和厚朴酚处理6小时后,加入1mM的calcein-AM荧光染料及5mM的CoCl室温避光反应15分钟。加入CoCl是为了淬灭胞浆中的染料,只留下线粒体部分的荧光。当PT孔开放时,calcein-AM从线粒体溢出,线粒体荧光强度降低,由此检测PT孔开放情况。激光共聚焦显微镜观察结果显示,和厚朴酚处理组PT孔开放,绿色荧光明显较对照组减弱。加入5μM的CsA后,可抑制这一现象。我们推测,CsA的PT孔抑制作用是通过结合其靶蛋白亲环蛋白D(Cyclophilin D)来抑制孔道开放,继而影响细胞死亡的;(3)用SiRNA的办法Knock down肿瘤细胞内的亲环蛋白D表达水平,可影响Honokiol对肿瘤细胞的药敏。这就说明Honokiol抗肿瘤作用是线粒体PT孔道依赖性的;(4)有趣的是,我们还发现在药物诱导肿瘤细胞死亡的早期阶段,亲环蛋白D无论从mRNA水平还是蛋白水平都会升高;但是,在HNK诱导肿瘤细胞如K562凋亡的情况下(CsA不能抑制凋亡),亲环蛋白D的表达水平不发生变化。
第四部分Honokiol对原代白血病细胞的抗肿瘤作用的研究
为了进一步阐明和厚朴酚的抗肿瘤作用在临床上的应用前景。我们收集了15例急性白血病病人的血样。(1)测定对原代白血病细胞的LC_(50),发现Honokiol对于大多数原代白血病细胞有一定效果,24小时的LC_(50)在30μg/ml左右,且该效应浓度对正常人外周血单个核细胞无毒;(2)在其中10个病例中,与HL60类似,发现Honokiol在原代样本中还是具有新的抗肿瘤机制,表现为:PS不外翻,细胞膜完整性早期受损;z-VAD-FMK不能抑制细胞死亡,CsA可以抑制细胞死亡;Cyclophilin D表达升高;(3)我们还做了集落形成实验,将Honokiol或者AraC预处理过的白血病细胞在甲基纤维素基质上培养14天,发现Honokiol抑制集落形成的能力与化疗药物阿糖胞苷相当。以上的结果证实和厚朴酚的抗肿瘤作用是具有一定的临床应用价值。
第五部分Honokiol对荷HL60小鼠的体内抗肿瘤作用的前瞻性研究
(1)和厚朴酚可以有效延长荷HL60小鼠的生存时间。在尾静脉接种HL60组,对照和加药组的小鼠生存中值天数分别是17天,以及29天。在腹腔接种HL60组中,对照和加药组的小鼠生存中值天数分别是24.5天,以及37.5天;(2)Honokiol对腹腔接种产生的HL60移植瘤的抑制作用不理想(P＞0.05);(3)但是,通过免疫组化检测小鼠各重要组织中人源CD45细胞的阳性比例来确定HL60的浸润情况,发现Honokiol能减轻肿瘤细胞对脏器的浸润。
研究结论
1.Honokiol对MDR肿瘤细胞株和亲本肿瘤细胞株药效相近。
2.Honokiol能够诱导以HL60为代表的肿瘤细胞株发生非凋亡的可调控的死亡,该死亡不受凋亡耐受影响。
3.Honokiol所诱导的非凋亡的可调控的死亡是线粒体通透性转换孔依赖性的。
4.Honokiol对原代急性髓系白血病细胞的作用机制包含了类似于其对HL60作用的抗肿瘤新机制。
5.Honokiol能够延长荷HL60小鼠的生存时间,并且可以减轻HL60细胞的浸润。
Background
Honokiol,a naturally occurring phenyl lignan present in Magnolia grandiflora, is a representative with a pair of hydroxy groups(-OH)in its structure.It is of multiple medicinal uses against microbial infection,anxiety,oxidative stress,platelet aggregation,among others.Previous reports have demonstrated the anticancer activities of HNK by induction of apoptosis in cancer cell lines.Recently,two important studies from Dana-Farber cancer institute of Harvad University demonstrated that HNK efficiently induced apoptosis in apoptotic resistant B-cell chronic lymphocytic leukemia(B-CLL)from B-CLL patients and multiple myeloma (MM)cells from relapsed refractory MM patients.Honokiol qualifies as a "promiscuous" rather than a "selective" agent based on its known mulitiple pharmacologic effect.
"Promiscuity" is not unique to honokiol because many known successful drugs as well as a number of promising natural anticancer agents such as thiladomide and asprin which are promiscuous.The best known example of a widely used drug that can be classified as promiscuous type is aspirin.In addition to its pain-relieving and antiarthritic effects,aspirin exhibits many other pharmacologic effects including blood thinning,reduction of platelet aggregation,prevention of preeclampsia(a hypertensive disorder during pregnancy),and anticancer effects.Likewise,recent studies including those from our own laboratory have revealed that many promising anticancer nature product(e.g,schisandrin B and shikonin)targeted multiple signal transduction pathways in various cell types to inhibit cancer cell growth in vitro and in vivo.Because the etiology and pathogenesis of cancer is highly complex involving abnormalities in multiple cellular checkpoints and signal transduction pathways,we are in agreement with the idea that promiscuity may be of advantage as potential anticancer agents.The indirect evidence to support this notion is that some recently developed anticancer agents with exceptionally high selectivity have failed to live up to the expectations(e.g.,specific epidermal growth factor receptor inhibitor Iressa).
Cancer drug resistance is the major obstacle to the successful cancer chemotherapy.Drug resistnce is directly or indirectly associated with 90%of cancer related death.The most important causes of cancer drug resistance are(1) Overexpressed drug transporter,such as P-gp,MRP-1,BCRP;(2)Abnormal apoptotic machinery:conventional anticaneer agents,regardless of their targets and mechanisms,mostly induce apoptosis,cancer cells are usually sensitive to apoptotic induction initially,but become resistant eventually because its heterogeneity and genomic instability.Thus,the potency of anticancer drugs is largely determined by the resistance machinery of the cancer cell.More and more evidence(Such as MDR reversal agents,Iressa,Gleevac)have indicated that the best way to overcome conventional cancer drug resistance was to bypass the resistance,which is also one of the the strategy to develop new generation of anticancer agent.
In this study we report that honokiol could circumvent the conventional drug resistance,and kill cancer cell by activating a programmed cell death associated with mitochondria PT pore.The study from primary leukemia cells and in vivo model are also involved in this work.To our best knowledge,this is the first report to document all these results.
Objects
To investigate the effect of honokiol on MDR cancer cells;To investigate whether honokiol could induce a nonapoptotic cell death on cancer cells;To analyze the mechanism of the nonapoptotic cell death triggered by honokiol;To evaluate the effect of honokiol on primary cancer cells and its assoicated mechanism;we also determined the effect(lifespan,tumor size,and invasion)of bonokiol on female NOD/SCID mice bearing implanted HL60 cells.
Results
1.The anticancer effect of honokiol on MDR and sensitive cancer cells
(1)Using four pairs of MDR and their parental cancer cell lines,K562/ADR and K562,HL60/ADR and HL60,MCF-7/ADR and MCF-7,Beap37/ADR and Bcap37, we determined the drug sensitivity of all these cell lines using MTT assay. Paticularly important,we found honokiol had the same efficacy in killing MDR cells and their parental drug-sensitive cells.Combined with our previous report,we believe honokiol is not the substrate of the MDR pump;(2)Caspase-3 is the most important apoptotic marker,thus we examined if it was activated in the cells treated with honokiol.There was no caspase-3 activation in HL60,MCF-7 and their MDR cells.Consistently,no apoptotie morphological changes under electronic microscopy were found.Thus,we thought that honokiol may trigger cell death other than apoptosis;(3)Using drug-sensitive parental cells as representatives to explore the truth of killing effect of honokiol,we adopt Hoechst staining to measure apoptotic cell death and Trypan blue exclusion assay to measure the total cell death. The discrepancy between the apoptotic death rate and total death rate was confirmed, which led to the conclusion that honokiol could induce nonapoptotic cell death in cancer cells.
2.Honokiol induces a regulated nonapoptotic cell death in cancer cells Here,we show that honokiol can induce a cell death distinct from apoptosis in HL60.After exposure to honokiol,HL-60 exhibited the following characteristics: (1)Using FCM detection,the death characterized with a rapid loss of integrity of plasma membrane which is both time and concentration dependent and without externalization of phosphatidyl serine;(2)Significant change of cell cycle (hypodiploid peak)and DNA ladder,the hallmarks of apoptosis,were not observed. Consistently,the broad caspase inhibitor zVAD-fmk failed to prevent the cell death; (3)Apoptosis-inducing factor(AIF)was not translocated to nuclei in HNK-treated HL60 cells;(4)Honokiol could overcome Bcl-2 or Bcl-X_L mediated apoptotic resistance,because they can not affect the cell death;(5)The cytotoxic effect can be recovered when cells were treated with HNK for relatively short time.And when cells were treated with HNK for longer time,the death ratios increased even after drug was removed,but still below the death ratio without wash-out.This assay prove that the cell death was regulative;(6)Cyclosporin A(CsA),an inhibitor of mitochondria permeability transition pore,effectively prevented HNK-induced cell death;(7)HNK induces similar cell death in MCF-7 cell line.
3.Mitochondrial permeability transition pore is the key to the novel killing mechanism by honokiol
Since ultrastructural studies revealed the damaged mitochondria in HNK-treated cells, we hypothesized that HNK-induced death was probably due to the mitochondrial dysfunction.Mitochondria plays a central role in cell death.It serves as an integrator of upstream death signaling.(1)The Mitochondrial memberane potential (MMP)was examined by JC-1 staining via FCM detection after treatment with 15μg/ml of HNK for 6,12,18 hours.The ratio of JC-1 Low cells increases in HNK group,indicating the loss of MMP,while CsA could partially inhibit this loss.The ROS level was examined by H_2DCFDA staining via FCM detection after treatment with 15μg/ml of HNK for 1,3,6,12 hours.The HNK treated HL60 cells showed increased ROS production in all the time points,while CsA could partially inhibit ROS generation;(2)The opening of PT pore was examined by Calcein-AM staining and observed by confocal microscope after treatment with 15μg/ml of HNK for 6 hours.The green fluorescence in HNK group was weak compared to control, indicating the opening of PT pore,while CsA could partially inhibit this opening. We presumed that CsA,an inhibitor of cyclophilin D(an essential component of mitochondria permeability transition pore),effectively prevented HNK-induced cell death;(3)Inhibition of cyclophilin D by RNA interference blocked honokiol-induced cell death,indicating that the cell death was mechanistically associated with the mitochondria permeability transition(PT)pore regulated by cyclophilin D;(4)Upregulation of cyclophilin D was observed in HL60,MCF-7 with the susceptibility to the death,but not in K562 which underwent apoptosis after exposure to honokiol.
4.The study of the anticancer efficacy of honokiol on primary leukemia cells
To further explore the potential of HNK-induced cell death in clinical application, primary leukemia cells from fifteen untreated patients with acute leukemia were collected.(1)The primary cells were incubated in vitro with various concentrations of HNK for indicated hours and assayed for cell death and LC_(50).The concentration of HNK that caused death of 50%of the cells(LC_(50))(from most of the samples)after 24 hours of incubation with HNK was 30μg/ml.Although HNK was cytotoxic toward normal peripheral blood mononuclear cells(PBMCs)(48 hour LC_(50)is 52μg/ml),primary cancer cells were significantly more susceptible to HNK;(2) Consistent with the result in HL60 cells,in ten patients,HNK induced a dominant caspase-independent and CsA-inhibitable cell death characterized with a loss of plasma membrane integrity(PI positivity)but without a significant externalization of phosphatidyl serine(Annexin V-FITC positive).HNK also significantly upregulated CypD in AML cells like HL60;(3)With the colony forming assay,we found after fourteen days culture in Methocult,the number of CFU derived from the honokiol pretreatment is the same as the Ara C pretreatment.The results indicated that the CypD associated death in human primary AML cells may have potential clinical significance.
5.The pilot study of the in vivo effect of honokiol on female NOD/SCID mice bearing implanted HL60 cells
Furthermore,a prolonged survival time was observed after treatment with HNK in SCID mice transplanted(i.p.or i.v.)with human HL60 cells engrafts.In the i.v. group,the Median survival time(MST)of HNK group was 29 days,compared with the control group(MST 17 days).Consistenly,in the i.p.group,the Median survival time(MST)of HNK group was 37.5 days,compared with the control group(MST 24.5 days).Although in the i.p.group,there was no statical difference between control and honokiol groups on the mean volume of HL60 implanted tumor(P＞0.05), honokiol treatment could mitigate the wide spread invasion of the implanted leukemic cells.
Conclusions
1.Honokiol has the same therapeutic efficacy to MDR and sensitive cancer cells.
2.Honokiol can bypass cancer apoptotic resistance by induction of a regulated nonapoptotic cell death in cancer cells.
3.Honokiol induces a mitochondrial permeability transition pore dependent nonapoptotic cell death.
4.Honokiol can also induce a cell death distinct from apoptosis in primary leukemic cells via mitochondrial permeability transition pore
5.Honokiol could significantly prolong the lifespan of the NOD/SCID mice bearing implanted HL60 cells,it could also mitigate invasion of the HL60 cells。
引文
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