胰腺癌细胞中抗凋亡蛋白BAG-3的过度表达

目的 本文通过检测和比较人胰腺癌组织、正常胰腺组织和胰腺癌细胞株中BAG-3基因的mRNA转录和蛋白表达水平，揭示抗凋亡蛋白BAG-3与胰腺癌的关系。方法 采用Northern blot和Western blot的方法定性检测BAG-3在胰腺癌中的表达，采用原位杂交和免疫组织化学的方法定位检测BAG-3在胰腺癌中的表达。结果 在mRNA和蛋白水平BAG-3在所有的胰腺癌标本和胰腺癌细胞株中存在中度到高度表达，而在正常胰腺组织中呈低水平表达。原位杂交和免疫组织化学分析发现，BAG-3主要在胰腺癌组织中的肿瘤细胞表达。结论 胰腺癌细胞中抗凋亡蛋白BAG-3表达水平增高，可能与胰腺癌浸润性生长的生物学行为及体内治疗反应性差有关。     

胰腺癌组织中神经激肽3受体的表达及组织学定位

目的研究神经激肽3受体(NK3R)在胰腺癌组织中mRNA和蛋白水平的表达,以及该受体在胰腺癌中的组织学定位。方法应用逆转录聚合酶链反应技术检测正常胰腺和胰腺癌组织中NK3R的mRNA水平,应用Westernblot检测其蛋白的表达水平,应用免疫组织化学技术进行组织学定位。结果与正常胰腺相比,胰腺癌组织中NK3RmRNA过度表达,胰腺癌组织中NK3R蛋白也过度表达,正常胰腺组织NK3R蛋白表达为11±05,胰腺癌组织为146±36,P<001。免疫组织化学检查结果显示正常胰腺中有较弱的NK3R表达,胰腺癌的导管细胞、神经纤维、炎性细胞中均有较强的NK3R表达。结论胰腺癌组织中NK3R的表达水平明显上升。     

Bak和Bcl-xL蛋白在胰腺癌中表达的临床病理学意义

目的:观察促进细胞凋亡的Bak蛋白与抑制细胞凋亡的Bcl-xL蛋白对胰腺癌发生、进展、转移及预后的影响.方法:免疫组织化学方法(SABC法)检测10例正常胰腺组织、59例胰腺癌及65例胰周淋巴结组织内的Bak和Bcl-xL蛋白表达;TUNEL法检测胰腺癌组织内的凋亡细胞.结果:Bak、Bcl-xL蛋白在正常胰腺组织表达率分别为2/10,4/10,凋亡率为2/10;在胰腺癌组织的表达率分别为79.7%(47/59),32.2%(19/59);凋亡率为74.6%(44/59).Bak蛋白在正常胰腺、高分化胰腺癌、中分化胰腺癌中的表达逐渐增高;在转移淋巴结与非转移淋巴结中表达率分别为86.4%(19/22),23.3%(10/43),二者差异有统计学意义(P＜0.05).中、高分化胰腺癌Bak蛋白高表达,术后平均生存时间长.结论:Bak蛋白的表达与细胞凋亡呈正相关趋势,Bcl-xL则呈负相关趋势.细胞凋亡主要影响胰腺癌的发展、转移及预后.Bak蛋白可作为胰腺癌预后评估的一项指标和一种抗癌基因有望用于胰腺癌治疗.     

凋亡抑制蛋白2在胰腺癌中的表达及其与化疗耐药的关系

目的 观察细胞凋亡抑制蛋白2(c-IAP2)在胰腺癌组织中的表达,探讨c-IAP2表达与胰腺癌细胞对化疗药物耐药性的关系.方法 收集胰腺癌标本32例,应用免疫组织化学染色法观察c-IAP2在胰腺癌及癌旁正常胰腺组织中的表达;体外培养胰腺癌细胞PANC-1,间歇浓度递增法诱导胰腺癌细胞株PANC-1对吉西他滨(Gem)的耐药,噻唑蓝(MTT)检测处理前后细胞对Gem的药物敏感性,免疫荧光和免疫印迹检测c-IAP2蛋白表达水平.结果 c-IAP2在胰腺癌组织均有表达(32/32,100.0%)、癌旁正常胰腺组织(8/18,44.4%)中有表达,胰腺癌表达水平显著强于癌旁正常胰腺组织.c-IAP2的表达强度在不同分化程度的肿瘤组织中的差异有统计学意义(P<0.05).药物培养3个月后,PANC-1对Gem的半数有效浓度(IC50)由(6.03±0.27)mg/L升高至(41.60±1.14)mg/L(P<0.05),免疫荧光和免疫印迹结果显示耐药亚株c-LAP2蛋白表达水平较亲本株升高,差异有统计学意义(P<0.05).结论 C-IAP2在胰腺癌分化程度和对吉西他滨耐药过程中有一定作用.     

过氧化物酶体增殖因子活化受体γ在胰腺癌中的表达及其意义

目的：研究过氧化物酶体增殖因子活化受体（PPAR）在胰腺癌中的表达，探讨其可能意义。方法：分别应用免疫组织（细胞）化学和逆转录-聚合酶链式反应（RT-PCR）检测正常胰腺组织、24例胰腺癌组织和胰腺癌细胞株PC-3及PANC-1中PPARα、δ、γ表达。结果：RT-PCR显示正常胰腺组织PPAR各亚型mRNA均无表达，而胰腺癌组织和胰腺癌细胞株PPARγmRNA高表达，PPARα和PPARδmRNA则无表达。免疫组织（细胞）化学显示胰腺癌组织及细胞株PPAR（呈高表达，在胰腺癌组织表达总阳性率为79.17％。结论：本文初步观察到核内受体PPARγ在人胰腺癌组织及人胰腺癌细胞株中表达上调。PPARα为今后胰腺癌化学预防一个新的靶点。     

胰腺癌中雌激素受体和雌激素诱导基因的表达

有关胰腺癌表达雌激素受体的问题迄未阐明，作者采用RNA印迹法、原位杂交和免疫组织化学观察正常人体和胰腺癌组织的雌激素受体表达．同时也测定了雌激素诱导蛋白、孕激素受体、pS_2和ERD_5，结果如下：1二雌激素受体RNA印迹分析测定胰腺癌、胰腺炎和正常胰腺标本，可见6．2kb转录物，其大小与MCF7乳腺癌细胞所表达的相同。经激光密度计读数校正后在癌肿和正常组织中的雌激素受体mRNA表达无数量上差异。雌激素受体的原位杂交和免疫组化技术均未能定位雌激素受体表达。胰腺癌的平均雌激素受体值为0．5fmol／mg，而正常胰腺组织则为1．…     

TRAIL受体在胰腺癌中的表达及意义

目的:研究肿瘤坏死因子相关凋亡诱导配体(TRAIL)受体在胰腺癌中的表达及意义。方法:应用半定量RT-PCR,检测TRAILR mRNA在胰腺癌组织,正常胰腺组织及胰腺癌细胞系ASPC-1、Can-pan-2中的表达。结果:死亡受体DR4、DR5在所有胰腺癌组织、正常胰腺组织及胰腺癌细胞系中均有表达,诱骗受体DcR1、DcR2在所有正常胰腺组织及细胞系中均有表达。死亡受体DR4、DR5在胰腺癌组织中有较高的表达,而在正常胰腺组织中呈中低水平表达(P<0.01)。胰腺癌细胞系中死亡受体DR4、DR5呈高水平表达,而诱骗受体DcR1、DcR2仅呈中低水平表达。结论:TRAIL受体在胰腺癌普遍表达,并存在受体类型的表达差异;死亡受体在胰腺癌中高表达,可能在TRAIL诱导胰腺癌细胞凋亡的机制中发挥重要的作用。     

胰腺癌中bcl-2的表达与细胞凋亡及癌基因c-myc表达的关系

目的：探讨人胰腺癌中bcl-2的变化情况与细胞凋亡及c-myc表达的关系。方法：采用免疫组织化学（SP法）和分子原位杂交法检测bcl-2及c-myc在胰腺癌病人癌组织（50例）和胰腺癌转移灶组织（15例）中的表达。采用TUNEL法检测细胞凋亡。结果：细胞凋亡的变化规律与胰腺癌的发生发展和临床病理特征有着内在联系。在mRNA和蛋白水平上bcl-2基因和c-myc基因分布一致。bcl-2蛋白的表达影响胰腺癌中细胞凋亡,并与c-myc蛋白在胰腺癌和胰腺癌转移灶组中的表达协同关系。结论：bcl-2和c-myc基因在胰腺癌发生和发展过程中发挥着重要作用。     

软骨寡聚基质蛋白在慢性胰腺炎损伤中退变腺泡细胞内的表达

目的 研究正常胰腺、慢性胰腺炎与胰腺癌组织中软骨寡聚基质蛋白(cartilage oligomeric matrix protein,COMP)mRNA和蛋白表达水平的差异,揭示COMP在慢性胰腺炎样损伤中的意义。方法 采用Northern印迹法、Western印迹法、原位杂交法与免疫组化方法对14例慢性胰腺炎、14例胰腺癌及15例正常胰腺组织进行分析。结果 在慢性胰腺炎组织中和胰腺癌组织中类似慢性胰腺炎损伤的退变腺泡细胞胞浆内,存在高水平的COMP mRNA信号与免疫反应;而在胰腺癌细胞、正常胰腺组织的导管细胞与胰岛细胞的胞浆内,COMP mRNA信号与免疫反应微弱或缺如。结论 COMP在慢性胰腺炎及胰腺癌中类似慢性胰腺炎损伤的退变腺泡细胞内高表达,可能与慢性胰腺炎中腺泡细胞功能异常有关。     

神经生长因子、趋化因子受体在神经流通浸润型胰腺癌组织中的表达及其临床意义

目的 观察神经生长因子(NGF)和趋化因子受体(CXCR4)在胰腺癌组织中的表达及其对胰腺癌神经浸润的影响.方法 采用S-100免疫组织化学染色和电镜观察45例胰腺癌组织和28例正常胰腺组织中神经浸润情况,应用免疫组织化学SP法和GMIAS2.0图像分析系统测定NGF、CXCR4蛋白在各组中表达的平均灰度值,利用逆转录-聚合酶链反应(RT-PCR)分析NGFmRNA、CXCR4 mRNA在各组中表达水平.结果 胰腺癌神经浸润的发生率达到80%,NGF蛋白在神经浸润型、无神经浸润型胰腺癌组织中表达的平均灰度值分别为(203.6800±20.7749)、(129.2200±15.9874),两者差异有统计学意义(P＜0.05).CXCR4蛋白在神经浸润型胰腺癌组织、无神经浸润型胰腺癌组织中表达的平均灰度值分别为(182.3800±18.3524)、(123.3600±15.2737),两者差异有统计学意义(P＜0.05).胰腺癌神经浸润型NGF mRNA表达水平为(0.7719±0.0634),明显高于胰腺癌无神经浸润型(0.2922±0.0288)和正常胰腺组织(0.2123±0.0231,P＜0.01);胰腺癌神经浸润型CXCR4 mRNA表达水平为(0.6892±0.0573),明显高于胰腺癌无神经浸润型(0.2877±0.0255)和正常胰腺组织(0.2076±0.0204),差异均有统计学意义(P＜0.01).结论 NGF、CXCR4在胰腺癌神经浸润过程中发挥重要作用,其机制可能与促进肿瘤细胞侵袭和生长,诱导肿瘤细胞向神经组织作定向运动有关.     

Effects of sequential treatments with chemotherapeutic drugs followed by TRAIL on prostate cancer in vitro and in vivo

BACKGROUND: Tumor necrosis factor related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo-2L) is a novel anticancer agent, capable of inducing apoptosis preferentially in tumor and transformed cells. TRAIL-R1/death receptor (DR)4 and TRAIL-R2/DR5 are members of the tumor necrosis factor (TNF) receptor family, and can be activated by the TRAIL. We examined the clinical potential of chemotherapeutic drugs and TRAIL for the treatment of prostate cancer. METHODS: Prostate and bladder cancer cells were exposed to chemotherapeutic drugs (paclitaxel, vincristine, vinblastine, etoposide, doxorubicin, and camptothecin) and TRAIL. Cell viability was measured by sodium 3'[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis (4-methoxy-6-nitro) assay; expressions of death receptors and Bcl-2 family members were measured by Western blotting, ELISA and ribonuclease protection assay. PC-3 tumor cells xenografted athymic nude mice were exposed to chemotherapeutic drugs and TRAIL, either alone or in combination, to measure tumor growth and survival of mice. Apoptosis was measured by annexin V-FITC/propidium iodide staining, and terminal deoxynucleotidyltransferase-mediated nick end labeling assay. Caspase-3 activity was measured by the Western blotting and immunohistochemistry. RESULTS: TRAIL induced apoptosis with varying sensitivity. Chemotherapeutic drugs (paclitaxel, vincristine, vinblastine, etoposide, doxorubicin, and camptothecin) significantly augmented TRAIL-induced apoptosis in cancer cells through up-regulation of DR4, DR5, Bax, and Bak, and induction of caspase activation. Mitochondrial pathway enhanced the synergistic interactions between drugs and TRAIL. The sequential treatment of mice with chemotherapeutic drugs followed by TRAIL induced caspase-3 activity, and apoptosis, inhibited angiogenesis, completely eradicated the established tumors, and enhanced survival of mice. CONCLUSIONS: Chemotherapeutic drugs can be used to enhance the therapeutic potential of TRAIL in prostate cancer.     

Differential expression of TRAIL and its receptors in benign and malignant prostate tissues

PURPOSE: Because TRAIL (tumor necrosis factor related apoptosis inducing ligand) selectively kills cancer cells without damaging normal cells, a gene therapy approach using TRAIL is feasible for treating patients with cancer. However, recent publications suggest that significant portions of human tumors appear to be TRAIL resistant. Furthermore, there is some controversy about whether TRAIL receptor composition influences TRAIL sensitivity in cancer cells. Our recent studies suggest that TRAIL receptor composition is the major modulator of TRAIL sensitivity, as demonstrated using prostate, breast and lung cancer cells. We investigated TRAIL and TRAIL receptor expression profiles during prostate carcinogenesis to evaluate their potential as biomarkers and predict the feasibility of a related gene therapy approach. MATERIALS AND METHODS: Paraffin embedded prostate tissues of 44 patients with benign prostatic hyperplasia, 28 with organ confined prostate carcinoma and 26 with advanced prostate carcinoma were analyzed using immunohistochemical staining procedures. RESULTS: Significant levels of TRAIL-R4 decoy receptor expression were detected in patients with benign prostatic hyperplasia, and organ confined and advanced prostate carcinoma. All TRAIL markers tested appear to be valuable markers for separating patients with benign prostatic hyperplasia from patients with organ confined prostate carcinoma or advanced prostate carcinoma. CONCLUSIONS: Due to high TRAIL-R4 expression in all patient groups complementary gene therapy modalities might be needed to bypass potential TRAIL-R4 induced resistance.     

Effect of the XIAP inhibitor Embelin on TRAIL-induced apoptosis of pancreatic cancer cells

BACKGROUND: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in a wide variety of tumor cells, while it has no toxicity for the majority of normal cells.Therefore, TRAIL may be a suitable agent for anticancer therapy. We previously reported that a number of pancreatic cancer cell lines show resistance to TRAIL-induced apoptosis via overexpression of XIAP and FLIP. The present study was conducted to further examine TRAIL-based therapeutic strategies by aiming to restore functional apoptotic pathways in resistant pancreatic cancer cells. METHODS: In various pancreatic cancer cell lines, TRAIL-induced apoptosis was evaluated in the presence or absence of an XIAP-inhibitor (Smac peptide). Second, TRAIL-induced apoptosis was evaluated in TRAIL-resistant AsPC-1 cells with or without FLIP antisense. Third, the combined effect of Smac peptide and FLIP antisense was tested, and the activation of apoptosis-related caspases and poly (ADP-ribose) polymerase was evaluated. Finally, TRAIL-induced apoptosis was evaluated in the presence or absence of FLIP antisense and an XIAP inhibitor (embelin). RESULTS: Smac peptide enhanced TRAIL-induced apoptosis in a dose-dependent manner for several pancreatic cancer cell lines, but showed no effect on TRAIL-resistant AsPC-1 cells. Smac peptide alone had no influence on cell viability. TRAIL-induced apoptosis was restored in TRAIL-resistant AsPC-1 cells by exposure to FLIP antisense, which suppressed the expression of FLIP. The effect of TRAIL was augmented by the combination of FLIP antisense and Smac peptide. Similarly, TRAIL-induced apoptosis was restored by the combination of FLIP antisense and embelin. Activation of apoptotic caspases and cleavage of poly (ADP-ribose) polymerase was observed after sensitization of TRAIL-resistant pancreatic cancer cells. CONCLUSIONS: Pancreatic cancer cells gain resistance to TRAIL-induced apoptosis via expression of the antiapoptotic proteins XIAP and FLIP. Smac peptide and FLIP antisense could restore the apoptotic effect of TRAIL. An XIAP inhibitor, embelin, enhanced the effect of TRAIL in the presence of FLIP antisense. These findings may provide useful information for the development of TRAIL-based therapeutic strategies by restoring functional apoptotic pathways in resistant pancreatic cancer cells. In addition, a low molecular weight XIAP inhibitor like embelin could be a lead compound for the development of effective XIAP inhibitors.     

Regulation of the resistance to TRAIL-induced apoptosis as a new strategy for pancreatic cancer

BACKGROUND: Tumor necrosis factor-related, apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in a wide variety of tumor cells, but it does not cause toxicity in the majority of normal cells. Therefore, TRAIL could become a suitable agent for anticancer therapies. However, a number of tumor cell lines are known to be resistant to TRAIL-induced apoptosis. The purpose of this study was to determine the mechanisms of resistance to TRAIL in pancreatic cancer cells. METHODS: In human pancreatic cancer cell lines, the sensitivity to TRAIL-induced apoptosis was tested. The expression of TRAIL receptors (DR4, DR5, DcR1, and DcR2) and the expression of death signal-transducing proteins were investigated. In the TRAIL-resistant pancreatic cancer cells, effects of cycloheximide, a protein synthesis inhibitor, on death signal-transducing proteins were tested. Finally, the effects of the combined treatment with cycloheximide and TRAIL on the induction of apoptosis and on the expression of death signal-transducing proteins were examined. RESULTS: Pancreatic cancer cells responded to TRAIL in a different way. Resistant cell lines, AsPC-1, Suit-2, and CFPAC-1, expressed higher levels of FLIP-S protein, one of the splice variants of FLIP. Cycloheximide reduced the expression of FLIP in the resistant cells. Combined treatment with cycloheximide and TRAIL induced cleaved forms of caspases and simultaneously restored the sensitivity to TRAIL-induced apoptosis in the resistant cells. CONCLUSIONS: Pancreatic cancer cells are resistant to TRAIL-induced apoptosis via strong expression of the anti-apoptotic protein FLIP-S. Suppression of FLIP-S by cycloheximide restored sensitivity to TRAIL-induced apoptosis in resistant cancer cells. These findings may provide useful information for the development of TRAIL-based therapeutic strategies aimed at restoring the functionality of apoptotic pathways in pancreatic cancer cells.     

Tumor necrosis factor-related apoptosis inducing ligand-R4 decoy receptor expression is correlated with high Gleason scores, prostate-specific antigen recurrence, and decreased survival in patients with prostate carcinoma

OBJECTIVE: Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) has recently been investigated because of its ability to selectively kill cancer cells. Despite recent publications mainly focusing on TRAIL resistance in cancer cells, little is known about how TRAIL contributes to the carcinogenesis process. Because the expression patterns of TRAIL and its receptors in patients with prostate carcinoma have recently been reported, this study investigated the significance of TRAIL and TRAIL receptor expression in connection to serum prostate-specific antigen (PSA) and Gleason scoring. MATERIALS AND METHODS: A total of 98 patients were included in the study. Gleason scores, PSA, TRAIL, and TRAIL receptor expressions were used for the comparison purposes. The Spearman rho correlation test was administered to reveal the correlations among the variants. The Kruskal Wallis-Mann Whitney U or Friedman-Wilcoxon signed ranks test determined the statistical significance between the pairs. Multinomial and/or multiple binary logistic regression analyses were deployed to test whether TRAIL markers were independent variables to predict the prognosis of prostate cancer. Kaplan-Meier and log-rank tests were used to determine the survival rates. RESULTS: High-serum PSA levels were correlated with higher levels of TRAIL and TRAIL receptor expressions. Patients with high Gleason scores had higher levels of TRAIL-R4 decoy receptor expression but lower levels of TRAIL death ligand expression. CONCLUSIONS: TRAIL-R4 decoy receptor expression is strongly correlated with PSA recurrence, which is suggestive of poor prognosis. High levels of TRAIL-R4 expression but low levels of TRAIL death ligand expression are connected to decreased survival.     

Sensitivity of prostate cells to TRAIL-induced apoptosis increases with tumor progression: DR5 and caspase 8 are key players

BACKGROUND: As advanced prostate cancers are resistant to currently available chemotherapies, we evaluated the cytotoxic effect of TNF-related apoptosis-inducing ligand (TRAIL) and characterized the involvement of its five receptors DR4, DR5, DcR1, DcR2, and osteoprotegerin (OPG) and of the death-inducing signaling complex (DISC)-forming proteins caspase 8 and c-FLIP in prostate cell lines. METHODS: We used six prostate cell lines, each corresponding to a particular stage in prostate tumorigenesis, and analyzed TRAIL sensitivity in relation to TRAIL receptors' expression. RESULTS: TRAIL sensitivity was correlated with tumor progression and DR5 expression levels and apoptosis was exclusively mediated by DR5. DcR2 was significantly more abundant in tumor cells than in non-neoplastic ones and may contribute to partial resistance to TRAIL in some prostate tumor cells. Conversely, non-tumoral cells secreted high levels of OPG, which can protect them from apoptosis. Finally, caspase 8 expression levels were as DR5 directly correlated to TRAIL sensitivity in prostate tumor cells. CONCLUSION: TRAIL-induced apoptosis is closely related to the balanced expression of its different receptors in prostate cancer cells and their modulation could be of potential clinical value for advanced tumor treatment.     

Survivin inhibits apoptosis induced by TRAIL, and the ratio between survivin and TRAIL receptors is predictive of recurrent disease in neuroblastoma

Purpose

Novel treatment strategies for high-risk and disseminated neuroblastoma (NB) are actively sought because of the dismal prognosis of advanced stage disease. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a recently identified member of the tumor necrosis factor family. TRAIL is capable of inducing apoptosis in multiple tumor cell types, with little or no cytotoxicity against normal cells.

Experimental Design

We examined the activation and regulation of TRAIL-induced apoptosis in several human NB cell lines. The effect of TRAIL was examined in the context of TRAIL receptor (TRAIL-R) and survivin (an antiapoptotic protein) expression in the cell lines. The ratio of survivin/TRAIL-R messenger RNA was determined and evaluated as a marker of recurrent disease in patients with NB.

Results

TRAIL induced apoptotic cell death of NB with variable sensitivities among the cell lines tested. Compared with a sensitive cell line (early passage NB16), the resistant cell lines (NB7 and late passage NB16) expressed lesser amounts of the death-inducing TRAIL-R1 and R2, and greater levels of survivin, an inhibitor of apoptosis. TRAIL sensitivity was enhanced in resistant cell lines by treating with etoposide that concomitantly increased TRAIL-R expression and diminished survivin expression. Survivin overexpression in a TRAIL-sensitive NB line (early passage NB16) rendered it less sensitive to treatment with TRAIL. Conversely, inhibiting survivin expression in NB3 by antisense oligonucleotides enhanced TRAIL sensitivity. A high survivin/TRAIL-R ratio accurately predicted risk for recurrent disease in primary tumor specimens tested.

Conclusions

These findings suggest that TRAIL therapy in combination with specific chemotherapeutic agents may represent an effective therapeutic strategy for NB. The cell's sensitivity to TRAIL is at least partially governed by both TRAIL-R and survivin expression, whereas the ratio between these 2 factors appears to have prognostic value in patients with this disease.     

Role of TNF-related apoptosis-inducing ligand (TRAIL) in the pathogenesis of varicocele-induced testicular dysfunction

The higher frequency of varicocele in men with infertility has drawn attention and resulted in increased research at the molecular level towards treatments. The aim of this study was to investigate the role of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and its receptors in varicocele-induced testicular dysfunction in an experimental rat model. The rats were divided into three groups: control, sham and varicocele. Varicoceles in rats were induced by partial ligation of the left renal vein and left testes. The rats were analyzed 13 weeks after surgery. The degree of DNA fragmentation within cells in the testis was determined using terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) assay. Tubule degeneration was evaluated using the Johnsen score. The expression of TRAIL and its receptors was detected by immunohistochemical and Western blotting techniques. The apoptotic index, Johnsen score and the expression of TRAIL and TRAIL receptors were examined. The data are presented as the mean±s.d. and were analyzed using computer software. The Kruskal–Wallis and Dunn''s multiple comparison tests were used in the statistical analyses. The germ cell apoptotic index was increased in rats with varicoceles when compared with the sham and control groups (P=0.0031). The Johnsen score was significantly decreased in the varicocele group when compared with the sham and control groups (P<0.0001). Immunohistochemical and Western blotting analyses showed that after varicocele induction, the expression of TRAIL-R1 and TRAIL-R4 in germ cells was increased and the expression of TRAIL-R2 was decreased. There are no significant differences among the groups in terms of TRAIL and TRAIL-R3 receptor expression. The results of this study indicate that TRAIL and its receptors may have a potential role in the pathogenesis of varicocele-induced testicular dysfunction.     

TRAIL and Triptolide: An Effective Combination that Induces Apoptosis in Pancreatic Cancer Cells

Introduction  

An emerging therapy in oncology is the induction of apoptotic cell death through anti-death receptor therapy. However, pancreatic cancer is resistant to apoptosis including anti-death receptor therapy. We have previously described how triptolide decreases resistance to apoptosis in pancreatic cancer cells in vitro and in vivo. We hypothesized that triptolide decreases tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in pancreatic cancer cells. The aim of this study was to evaluate the effects that combined therapy with TRAIL and triptolide have on different parameters of apoptosis.