神经酰胺的代谢在肿瘤化疗和耐药中的作用

引言肿瘤耐药是肿瘤治疗失败最为重要的原因之一,癌症患者如果失去了手术根除病灶的时机便很少再有通过化疗治愈的可能。肿瘤细胞可通过多种机制引发耐药:减少细胞内药物的浓度,如P-糖蛋白(P-gp)介导的肿瘤多药耐药;加快药物的分解代谢;细胞内药物靶点的表达发生改变或突变;癌细胞的自我修复能力加强;癌细胞的生存能力,如抗凋亡能力加强等等。上世纪九十年代以来,大量研究发现神经酰胺(Ceramide,Cer)及其代谢产物作为鞘脂类家族成员,不仅是构成细胞膜结构的重要组分之一,还可作为脂质第二信使调节细胞的凋亡和增殖,并参与肿瘤细胞的耐药机制;此后又发现Cer的代谢与P-gp在诱导肿瘤多药耐药的过程中存在联系,改变了以往对于P-gp过于简单化的认识。本文主要就近年来对Cer的代谢在肿瘤治疗和耐药中的作用及耐药逆转策略的研究情况作一综述。1Cer的代谢过程及其代谢产物的生物学功能Cer是鞘磷脂(Sphingomylin,SM)的基本单位,多种因素可刺激其产生,如生长因子剥夺、细胞因子、离子射线、热休克、细胞毒性物质及环境变化等,此外许多配体亦可以通过和相应受体结合启动Cer介导的细胞信号转导,如1,25-二羟-VitD3、...     

葡萄糖神经酰胺合成酶基因在人耐多柔比星乳腺癌细胞株MCF-7/ADR中的表达及意义

背景与目的:多药耐药是肿瘤化疗失败的主要原因,近年来神经酰胺的糖基化水平增高与多药耐药的关系引起了广泛关注.本研究旨在探讨葡萄糖神经酰胺合成酶(GCS)基因在人乳腺癌细胞株MCF-7和人耐多柔比星(阿霉素)乳腺癌细胞株MCF-7/ADR中的表达及意义.方法:采用四氮唑盐(MTT)法检测多柔比星对MCF-7/ADR和MCF-7的抑制率和IC50,用浓度为5、10、20μmol/L的GCS抑制剂D,L-threo-1-phenyl-2-decanoyl-amino-3-morpholino-1-propanol(PDMP)预处理MCF-7/ADR 24、48 h后检测抑制率和IC50;应用实时荧光定量PCR(real time PCR)检测MCF-7、MCF-7/ADR以及PDMP预处理后MCF-7/ADR中GCS mRNA的表达.结果:MCF-7/ADR 对MCF-7的耐药倍数为22.69倍,PDMP作用后多柔比星对MCF-7/ADR的抑制率升高,IC50从(19.0±0.5)μg/ml 下降到(5.6±0.6)μg/ml.MCF-7/ADR中GCS mRNA的表达高于MCF-7(P<0.01),PDMP使MCF-7/ADR中GCS mRNA的表达水平GCSN(48±17)下降到(21±4).结论:GCS可能参与乳腺癌的发生过程,并在MCF-7/ADR多药耐药中起重要作用.     

GCS在人乳腺癌细胞多药耐药中的作用及与P-gP的关系

目的探讨葡萄糖神经酰胺合成酶（GCS）在人乳腺癌细胞多药耐药中的作用及其与P-糖蛋白（P-gP）的关系。方法采用MTT法检测多柔比星（阿霉素）对人乳腺癌耐药细胞株MCF-7／Adr和敏感株MCF-7的抑制率和IC50。以GCS抑制剂D，L-threo-1-phenyl-2-decanoyl—amino-3-morpholino-1-propanol（PDMP）预处理MCF-7／Adr后检测抑制率和IC50。运用流式细胞术（FCM）检测人MCF-7及MCF-7／Adr中GCS、P-gp的表达，以PDMP预处理细胞后检测GCS、P-gP的表达。FCM法检测细胞中ADM的荧光强度。结果MCF-7／Adr对MCF-7的耐药倍数为22．7倍，PDMP作用后阿霉素对MCF-7／Adr的抑制率升高，IC50下降（P〈0．05）。MCF-7／Adr中GCS和P-gp的表达均高于MCF-7，PDMP使MCF-7／Adr中GCS表达下降（P〈0．05），对P—gp表达无明显影响（P〉0．05）。FCM检测显示PDMP可使阿霉素在MCF-7内潴留增多。结论GCS在MCF-7／Adr多药耐药中起重要作用，PDMP能影响P-gP功能，GCS与P-gP有-定关系。     

膀胱癌组织中GCS的表达研究

目的:研究神经酰胺合成酶(GGS)在膀胱癌中的表达及作用.方法:采用Western-Blot及免疫组化技术检测神经酰胺合成酶(GCS)在膀胱肿瘤组织和正常组织胞膜中的表达情况.结果:Western-Blot及免疫组化结果均证实,相对于正常组织,GCS在膀胱肿瘤中有较高的表达水平(P＜0.01),GCS光密度值的测量也显示,GCS不仅在膀胱癌中的表达明显高于正常组织中(P＜0.01),而且在膀胱癌复发组的表达也明显高于未复发组(P＜0.05).结论:GCS在膀胱癌肿瘤组织发生、发展过程中可能起重要的调控作用,是判断膀胱癌分化、预后的一种理想指标.     

胃癌组织LRP和GST-π及GCS表达临床意义的研究

目的:研究多药耐药蛋白肺耐药蛋白(LRP)、葡萄糖神经酰胺合成酶(GCS)、谷胱甘肽转移酶(GST-π)在胃癌组织中的表达及临床意义。方法:采用免疫组化法对经收集的63例胃癌组织标本及30例非癌性胃组织标本中及LRP、GST-π、GCS的表达情况进行研究,并且观察三者的表达与胃癌的组织学类型、浸润深度、年龄、性别、有无淋巴结转移等的关系。结果:LRP、GST-π及GCS在胃癌组织中的表达均高于非癌性胃组织,其阳性表达率分别为66.7%与43.3%、63.5%与40.0%及49.2%与23.3%(P值均<0.05)。LRP、GST-π、GCS在胃癌组织中的阳性表达率与有无淋巴结转移、年龄、性别、分化程度、不同的侵犯深度等均无明显关系。胃癌组织中LRP与GST-π(r=0.233,P=0.066)、LRP与GCS(r=0.225,P=0.077)、GST-π与GCS(r=0.153,P=0.232)的表达则无明显相关性。结论:LRP、GCS、GST-π在胃癌组织中存在高表达,是引起胃癌原发性耐药的重要多药耐药相关蛋白;它们在介导胃癌多药耐药时相互独立,且其表达与临床及病理学特征无明显相关性。     

GCS在胃癌组织中的表达及意义

目的 研究多药耐药蛋白葡萄糖神经酰胺合成酶（GCS）在胃癌组织中的表达。方法 免疫组化法检测63例胃癌组织及30例非癌性胃组织标本中GCS的表达情况,分析其与年龄、性别、组织学类型、分化程度、淋巴结转移的相关性。结果 GCS表达在胃癌组织中高于非癌性胃组织,阳性表达率分别为49.2％和23.3％（P＜0.05）;GCS表达与年龄、性别、分化程度、浸润深度、淋巴结转移均无明显相关性。结论 GCS蛋白在胃癌组织中存在高表达,可能是引起胃癌原发性多药耐药的因素之一。     

抗肿瘤多药耐药的研究进展

肿瘤多药耐药(multidrug resistance,MDR)逆转剂通过抑制药物转运泵功能,逆转耐药;与此不同,抗肿瘤MDR药物则通过直接抑制或杀伤MDR肿瘤克服肿瘤MDR。近年来,抗肿瘤MDR药物的研究越来越受到重视。本文在总结以P-糖蛋白(P-glycoprotein,P—gp)与凋亡调控以及神经酰胺信号系统与MDR的关系为代表的MDR机制研究新进展基础上,首次将抗肿瘤MDR药物分为MDR相关抗肿瘤药物的结构修饰物、破坏MDR机制的抗MDR药、诱导caspase非依赖型凋亡的抗MDR药、干扰神经酰胺代谢的抗MDR药和机制未明的抗MDR药五类,并讨论它们的主要特点和作用机理。     

左金丸对小鼠S180肿瘤细胞获得性多药耐药P-gp的表达及血清肿瘤标志物的影响

目的:研究左金丸、黄连和吴茱萸对小鼠获得性多药耐药S180腹水肿瘤细胞生长的抑制作用,以及对肿瘤细胞P-gp的表达和血清4种肿瘤标志物:(TM)酸性磷酸酶(ACP)、碱性磷酸酶(AKP)、醛缩酶(ALD)和乳酸脱氢酶(LDH)活力的影响. 方法: PFC方案建立S180多药耐药细胞模型,将耐药后S180细胞悬液以每只小鼠0.2 ml接种于腹腔,黄连、吴茱萸及左金丸灌胃给药7d,观察小鼠体重、脾指数、肝指数、生命延长率(ILS),流式细胞仪测定P-糖蛋白(P-gp)的表达率,试剂盒检测血清中肿瘤标志物的活力.结果: 左金丸给药组对小鼠S180多药耐药细胞增长有明显的抑制作用,能有效降低肝指数,提高脾指数,提高生命延长率(ILS)(60.26%)的作用明高于黄连(21.85%)和吴茱萸单独给药(20.53%)(P<0.01).同时,左金丸给药组能有效逆转S180肿瘤细胞中P-gp的表达(2.69%)至接近S180细胞对照组水平(1.65%),显著低于模型组(16.07%),也强于黄连(5.69%)及吴茱萸(9.15%)单独给药时的逆转效果.并且左金丸可有效降低血清中ALD(75.94±12.47 U·L-1)和LDH(1632.92±494.48 U·L-1 )的活力,提高血清中ACP( 103.28±10.36 U·100ml-1)和AKP(34.56±4.91 U·100ml-1)的活力,与黄连、吴茱萸给药组比较有显著性差异( P<0.01).结论:黄连和吴茱萸合用能产生明显的配伍协同抗肿瘤作用,对P-gp的表达和血清中肿瘤标志物的影响可能是其抗肿瘤和逆转多药耐药的潜在机制.     

人肝癌移植瘤多药耐药模型的建立及耐药机制的探讨

背景与目的肿瘤多药耐药是肿瘤化疗的主要障碍和研究热点,本研究拟建立人肝癌裸小鼠皮下及肝原位移植多药耐药模型,探讨其生物学特性和耐药机制的异同,为研究体内逆转肿瘤多药耐药提供理想的动物模型。方法人肝癌细胞系HepG2裸鼠肝原位、皮下移植后,用阿霉素腹腔注射诱导耐药。MTT法检测耐药细胞对抗肿瘤药的敏感性,流式细胞仪检测癌细胞膜蛋白P-糖蛋白(P-gp)、多药耐药相关蛋白(MRP)、肺耐药蛋白(LRP)的表达和细胞对罗丹明(R123)的外排作用,逆转录PCR检测耐药细胞中三种膜蛋白mRNA的表达。结果肝原位和皮下移植瘤耐药细胞形态及生物学行为符合人肝癌特征;对多种药物产生较明显的耐药性,其中对阿霉素的耐药倍数分别为26.4和24.6;肝皮下移植和原位移植组耐药细胞膜蛋白P-gp、MRP和LRP的阳性率均增高,分别为(77.3±2.1)%和(78.1±1.9)%,(72.1±4.3)%和(72.7±5.1)%,(31.1±1.0)%和(32.2±1.4)%。多药耐药基因的阳性率也明显增高,细胞对R123的外排作用增强;肝原位移植瘤组与皮下移植瘤组比较,多药耐药性差异没有统计学意义(P>0.05)。结论所建立的裸鼠肝原位及皮下移植瘤多药耐药模型符合人肿瘤多药耐药特征,为研究体内逆转多药耐药提供了理想的动物模型。     

ABCG2介导的多药耐药机制及其逆转

多药耐药(MDR)是肿瘤化疗失败最常见的原因.ABCG2属于ABC转运蛋白超家族的一员,在多种肿瘤细胞中表达,能高效转运多种化疗药物.ABCG2的高表达既是侧群(sP)细胞的标志,又是肿瘤对化疗药物抵抗的重要原因.ABCG2的拮抗剂可在逆转肿瘤MDR中发挥一定作用.     

Overexpression of glucosylceramide synthase in associated with multidrug resistance of leukemia cells

Ceramide, as a second messenger, initiates one of the major signal transduction pathways in tumor apoptosis. Glucosylceramide synthase (GCS) catalyzes glycosylation of ceramide and produces glucosylceramide. Through GCS, ceramide glycosylation allows cellular escape from ceramide-induced programmed cell death. Here we investigated the expression of GCS in human leukemia cells and an association between GCS and multidrug resistance of leukemia cells. Using RT-PCR technique the level of GCS gene was detected in 65 clinical multidrug resistance/non-resistance cases with leukemia, and in K562 and K562/A02 cell lines. AlamarBlue Assay was applied to confirm the multidrug resistant of K562/A02 cells. PPMP, which is a chemical inhibitor for GCS, was used to determine the relationship between GCS and drug-resistance in K562/A02 cells. In addition, multidrug resistance gene (mdr1), Bcl-2 and Bax mRNA was also analyzed by RT-PCR. The expression of GCS and mdr1 mRNA in clinic multidrug resistance samples exhibited significantly increased compared with clinic drug sensitive group (P<0.05). There was the positive correlation both the expression of GCS and mdr1 genes in leukemia samples (P<0.01, gamma=0.7). AlamarBlue Assay showed that the K562/A02 cell line was 115-fold more resistant to adriamycin and 36-fold more resistant to vincristine compared with drug-sensitive K562 cell line. There also was significant expression difference of GCS and mdr1 genes between K562 and K562/A02 cells. Bcl-2 gene exhibited higher expressions whatever in clinic drug-resistance samples or K562/A02 cells, whereas the expressions of Bax gene were higher in drug-sensitive samples and K562 cells. PPMP increased sensitivity to adriamycin toxicity by inhibiting GCS in K562/A02 cells. Therefore, it is suggested that a high level of GCS in leukemia is possible contributed to multidrug resistance of leukemia cells. Abnormally expressions of the genes in associated with cell apoptosis might be one of the main molecular pathology mechanisms of multidrug resistance caused by GCS gene.     

The chemosensitizing activity of inhibitors of glucosylceramide synthase is mediated primarily through modulation of P-gp function

Glucosylceramide synthase (GCS) is a key enzyme engaged in the biosynthesis of glycosphingolipids and in regulating ceramide metabolism. Studies exploring alterations in GCS activity suggest that the glycolase may have a role in chemosensitizing tumor cells to various cancer drugs. The chemosensitizing effect of inhibitors of GCS (e.g. PDMP and selected analogues) has been observed with a variety of tumor cells leading to the proposal that the sensitizing activity of GCS inhibitors is primarily through increases in intracellular ceramide leading to induction of apoptosis. The current study examined the chemosensitizing activity of the novel GCS inhibitor, Genz-123346 in cell culture. Exposure of cells to Genz-123346 and to other GCS inhibitors at non-toxic concentrations can enhance the killing of tumor cells by cytotoxic anti-cancer agents. This activity was unrelated to lowering intracellular glycosphingolipid levels. Genz-123346 and a few other GCS inhibitors are substrates for multi-drug resistance efflux pumps such as P-gp (ABCB1, gP-170). In cell lines selected to over-express P-gp or which endogenously express P-gp, chemosensitization by Genz-123346 was primarily due to the effects on P-gp function. RNA interference studies using siRNA or shRNA confirmed that lowering GCS expression in tumor cells did not affect their responsiveness to commonly used cytotoxic drugs.     

Possible role of ceramide as an indicator of chemoresistance: decrease of the ceramide content via activation of glucosylceramide synthase and sphingomyelin synthase in chemoresistant leukemia.

We investigated the possibility of the proapoptotic lipid ceramide as an indicator of chemoresistance in leukemia. Doxorubicin (DOX) increased the ceramide level and apoptosis in drug-sensitive HL-60 cells but not in drug-resistant HL-60/ADR cells, under the condition that the uptake of DOX was not different between the two cell lines. In addition, exogenous N-acetylsphingosine (C2-ceramide) enhanced DOX-induced apoptosis in HL-60/ADR cells without affecting the expression of multidrug resistant-1 protein (MDR 1) and the uptake of DOX. A lower level of ceramide with higher activities of glucosylceramide synthase (GCS) and sphingomyelin synthase (SMS) was detected in HL-60/ADR cells than in HL-60 cells. In contrast, HL-60/GCS cells, overexpressing GCS, significantly inhibited DOX-induced ceramide increase and apoptosis. These observations suggest the involvement of ceramide regulation in drug resistance of leukemia cells. In vivo, the level of ceramide was lower in chemoresistant leukemia patients (6.4 +/- 1.8 pmol/nmol phosphate; n = 14) than in chemosensitive patients (9.5 +/- 2.7 pmol/nmol phosphate; n = 9), and the activities of GCS and SMS were more than 2-fold higher in chemoresistant leukemia cells than in chemosensitive cells. MDR-1 protein was faintly expressed in one of four chemoresistant patients, but Bcl-2 were clearly detected in four patients. Therefore, it is suggested that a decrease of the ceramide level via activation of GCS and SMS is associated with the chemoresistant condition in leukemia, probably in relation to Bcl-2 but not to MDR-1 expression.     

Glucosylceramide synthase blockade down-regulates P-glycoprotein and resensitizes multidrug-resistant breast cancer cells to anticancer drugs

Overexpression of glucosylceramide synthase (GCS), a pivotal enzyme in glycolipid biosynthesis, contributes to cancer cell resistance to chemotherapy. We previously showed that transfection of doxorubicin-resistant MCF-7-AdrR cells with GCS antisense restored cell sensitivity to doxorubicin and greatly enhanced sensitivity to vinblastine and paclitaxel. In that study, doxorubicin promoted generation of ceramide in MCF-7-AdrR/GCS antisense cells; the present study implicates factors in addition to ceramide that augment sensitivity to chemotherapy. Although GCS antisense cells showed enhanced ceramide formation compared with MCF-7-AdrR when challenged with paclitaxel, GCS antisense cells also showed a 10-fold increase in levels of intracellular drug (paclitaxel and vinblastine). In addition, transfected cells had dramatically decreased expression (80%) of P-glycoprotein and a 4-fold decrease in the level of cellular gangliosides. Chemical inhibition of GCS produced the same effects as antisense transfection: exposure of MCF-7-AdrR cells to the GCS inhibitor 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP, 5.0 micromol/L, 4 days) decreased ganglioside levels, restored sensitivity to vinblastine, enhanced vinblastine uptake 3-fold, and diminished expression of MDR1 by 58%, compared with untreated controls. A similar effect was shown in vinblastin-resistant KB-V0.01 cells; after 7 days with PPMP (10 micromol/L), MDR1 expression fell by 84% and P-glycoprotein protein levels decreased by 50%. MCF-7-AdrR cells treated with small interfering RNAs to specifically block GCS also showed a dramatic decrease in MDR1 expression. This work shows that limiting GCS activity down-regulates the expression of MDR1, a phenomenon that may drive the chemosensitization associated with blocking ceramide metabolism. The data suggest that lipids play a role in the expression of multidrug resistance.     

Inhibition of NADPH oxidase by glucosylceramide confers chemoresistance

The bioactive sphingolipid ceramide induces oxidative stress by disrupting mitochondrial function and stimulating NADPH oxidase (NOX) activity, both implicated in cell death mechanisms. Many anticancer chemotherapeutics (anthracyclines, Vinca alkaloids, paclitaxel, and fenretinide), as well as physiological stimuli such as tumor necrosis factor α (TNFα), stimulate ceramide accumulation and increase oxidative stress in malignant cells. Consequently, ceramide metabolism in malignant cells and, in particular the up-regulation of glucosylceramide synthase (GCS), has gained considerable interest in contributing to chemoresistance. We hypothesized that increases in GCS activity and thus glucosylceramide, the product of GCS activity, represents an important resistance mechanism in glioblastoma. In our study, we determined that increased GCS activity effectively blocked reactive oxygen species formation by NOX. We further showed, in both glioblastoma and neuroblastoma cells that glucosylceramide directly interfered with NOX assembly, hence delineating a direct resistance mechanism. Collectively, our findings indicated that pharmacological or molecular targeting of GCS, using non-toxic nanoliposome delivery systems, successfully augmented NOX activity, and improved the efficacy of known chemotherapeutic agents.     

Suppression of glucosylceramide synthase restores p53-dependent apoptosis in mutant p53 cancer cells

Tumor suppressor p53 plays an essential role in protecting cells from malignant transformation by inducing cell-cycle arrest and apoptosis. Mutant p53 that is detected in more than 50% of cases of cancers loses its role in suppression of tumors but gains in oncogenic function. Strategies to convert mutant p53 into wild-type p53 have been suggested for cancer prevention and treatment, but they face a variety of challenges. Here, we report an alternative approach that involves suppression of glucosylceramide synthase (GCS), an enzyme that glycosylates ceramide and blunts its proapoptotic activity in cancer cells. Human ovarian cancer cells expressing mutant p53 displayed resistance to apoptosis induced by DNA damage. We found that GCS silencing sensitized these mutant p53 cells to doxorubicin but did not affect the sensitivity of cells with wild-type p53. GCS silencing increased the levels of phosphorylated p53 and p53-responsive genes, including p21(Waf1/Cip1), Bax, and Puma, consistent with a redirection of the mutant p53 cells to apoptosis. Reactivated p53-dependent apoptosis was similarly verified in p53-mutant tumors where GCS was silenced. Inhibition of ceramide synthase with fumonisin B1 prevented p53 reactivation induced by GCS silencing, whereas addition of exogenous C6-ceramide reactivated p53 function in p53-mutant cells. Our findings indicate that restoring active ceramide to cells can resuscitate wild-type p53 function in p53-mutant cells, offering preclinical support for a novel type of mechanism-based therapy in the many human cancers harboring p53 mutations.     

RNA干扰抑制FANCD2基因对多药耐药骨髓瘤细胞株药物敏感性的影响

目的：探讨FA/BRCA（fanconi anemia/BRCA）中siRNA干扰对多药耐药骨髓瘤细胞株的影响.方法：体外培养多发性骨髓瘤细胞RPMI-8226细胞系,通过相应渐增浓度的马法兰药物处理,选择性获得多药耐药的子代肿瘤细胞株RPMI-8226/R细胞.MTT法检测RPMI-8226和RPMI-8226/R细胞马法兰、ADM、VCR、CTX、Ara-C、VP-16及DDP的敏感性.siRNA干扰抑制FA/BRCA途径FANCD2蛋白表达,观察多发性骨髓瘤多药耐药细胞株对烷化剂药物敏感性的变化.结果：成功构建针对FANCD2基因的siRNA,将其转染多药耐药骨髓瘤细胞株,可以抑制细胞中FANCD2基因表达,转染细胞较转染前细胞FANCD2基因表达降低,对烷化剂的敏感性升高.结论：人多发性骨髓瘤多药耐药细胞株RPMI-8226/R其多药耐药性的产生可能与FA/BRCA途径中FANCD2表达增强有关,可通过抑制FANCD2表达而逆转细胞的耐药性达到增强烷化剂对耐药肿瘤细胞的增殖抑制及诱导凋亡作用.沉默FANCD2表达可以提高多药耐药MM细胞对烷化剂的敏感性,而RNA干扰是一种沉默FANCD2表达的理想方法,因此它可能是一种有潜力的耐药MM辅助治疗新方法.     

Therapeutic potential of targeting ceramide/glucosylceramide pathway in cancer

Sphingolipids including ceramides and its derivatives such as ceramide-1-phosphate, glucosylceramide (GlcCer), and sphingosine-1-phosphate are essential structural components of cell membranes. They now recognized as novel bioeffector molecules which control various aspects of cell growth, proliferation, apoptosis, and drug resistance. Ceramide, the central molecule of sphingolipid metabolism, generally mediates anti-proliferative responses such as inhibition of cell growth, induction of apoptosis, and/or modulation of senescence. There are two major classes of sphingolipids. One of them is glycosphingolipids which are synthesized from the hydrophobic molecule, ceramide. GlcCer, generated by glucosylceramide synthase (GCS) that transfers the glucose from UDP-glucose to ceramide, is an important glycosphingolipid metabolic intermediate. GCS regulates the balance between apoptotic ceramide and antiapoptotic GlcCer. Downregulation or inhibition of GCS results in increased apoptosis and decreased drug resistance. The mechanism underlying the drug resistance which develops with increased glucosylceramide expression is associated with P-glycoprotein. In various types of cancers, overexpression of GCS has been observed which renders GCS a good target for the treatment of cancer. This review summarizes our current knowledge on the structure and functions of glucosylceramide synthase and glucosylceramide and on the roles of glucosylceramide synthase in cancer therapy and drug resistance.     

Glucosylceramide synthase protects glioblastoma cells against autophagic and apoptotic death induced by temozolomide and Paclitaxel

Glioblastoma is a deadly cancer with intrinsic chemoresistance. Understanding this property will aid in therapy. Glucosylceramide synthase (GCS) is associated with resistance and poor outcome; little is known about glioblastomas. In glioblastoma cells, temozolomide and paclitaxel induce ceramide increase, which in turn promotes cytotoxicity. In drug-resistant cells, both drugs are unable to accumulate ceramide, increased expression and activity of GCS is present, and its inhibitors hinder resistance. Resistant cells exhibit cross-resistance, despite differing in marker expression, and cytotoxic mechanism. These findings suggest that GCS protects glioblastoma cells against autophagic and apoptotic death, and contributes to cell survival under chemotherapy.