Complex roles of the old drug aspirin in cancer chemoprevention and therapy

The nonsteroidal anti-inflammatory agent aspirin is widely used for preventing and treating cardiovascular and cerebrovascular diseases. In addition, epidemiologic evidences reveal that aspirin may prevent a variety of human cancers, while data on the association between aspirin and some kinds of cancer are conflicting. Preclinical studies and clinical trials also reveal the therapeutic effect of aspirin on cancer. Although cyclooxygenase is a well-known target of aspirin, recent studies uncover other targets of aspirin and its metabolites, such as AMP-activated protein kinase, cyclin-dependent kinase, heparanase, and histone. Accumulating evidence demonstrate that aspirin may act in different cell types, such as epithelial cell, tumor cell, endothelial cell, platelet, and immune cell. Therefore, aspirin acts on diverse hallmarks of cancer, such as sustained tumor growth, metastasis, angiogenesis, inflammation, and immune evasion. In this review, we focus on recent progress in the use of aspirin for cancer chemoprevention and therapy, and integratively analyze the mechanisms underlying the anticancer effects of aspirin and its metabolites. We also discuss mechanisms of aspirin resistance and describe some derivatives of aspirin, which aim to overcome the adverse effects of aspirin.     

Liposomal curcumin with and without oxaliplatin: effects on cell growth, apoptosis, and angiogenesis in colorectal cancer

The role of curcumin (diferuloylmethane), a proapoptotic compound, for the treatment of cancer has been an area of growing interest. Curcumin in its free form is poorly absorbed in the gastrointestinal tract and therefore may be limited in its clinical efficacy. Liposome encapsulation of this compound would allow systemic administration. The current study evaluated the preclinical antitumor activity of liposomal curcumin in colorectal cancer. We also compared the efficacy of liposomal curcumin with oxaliplatin, a standard chemotherapy for this malignancy. In vitro treatment with liposomal curcumin induced a dose-dependent growth inhibition [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt] and apoptosis [poly(ADP-ribose) polymerase] in the two human colorectal cancer cell lines tested (LoVo and Colo205 cells). There was also synergism between liposomal curcumin and oxaliplatin at a ratio of 4:1 in LoVo cells in vitro. In vivo, significant tumor growth inhibition was observed in Colo205 and LoVo xenografts, and the growth inhibition by liposomal curcumin was greater than that for oxaliplatin (P < 0.05) in Colo205 cells. Tumors from animals treated with liposomal curcumin showed an antiangiogenic effect, including attenuation of CD31 (an endothelial marker), vascular endothelial growth factor, and interleukin-8 expression by immunohistochemistry. This study establishes the comparable or greater growth-inhibitory and apoptotic effects of liposomal curcumin with oxaliplatin both in vitro and in vivo in colorectal cancer. We are currently developing liposomal curcumin for introduction into the clinical setting.     

LncRNA PiHL 在奥沙利铂耐药结直肠癌细胞中的作用 及初步机制

目的确定LncRNA PiHL在奥沙利铂耐药的结直肠癌细胞中的作用并探讨其作用机制。方法采用CCK8法检测奥沙利铂对结直肠癌细胞的抑制率,体外构建奥沙利铂耐药的结直肠癌细胞系,qRT-PCR检测结直肠癌细胞中PiHL的表达水平;利用分子克隆技术构建稳定过表达PiHL的正常结直肠癌细胞系和稳定干扰PiHL的奥沙利铂耐药结直肠癌细胞系,CCK8法和流式细胞术检测PiHL表达水平的改变对奥沙利铂作用下细胞的存活率和凋亡比例的影响;TCGA数据库分析和qRT-PCR预测PiHL与多梳抑制复合物2(PRC2)途径基因之间存在的相关性;RNA pull-down和western blot确定PiHL与Zeste增强子同源物2(EZH2)之间的作用关系;RNA-seq与qRT-PCR结合确定PRC2表观遗传作用靶点。结果耐药细胞系中PiHL的表达水平较正常细胞显著升高。稳定过表达PiHL细胞后对奥沙利铂的敏感性降低。同时,在耐药结直肠癌细胞系中,干扰PiHL表达组药物作用下细胞存活率明显低于对照组,细胞对奥沙利铂敏感性增加。TCGA数据库分析发现PiHL表达和PRC2的组成成分EZH2、SUZ12、EED的表达水平存在显著正相关,qRT-PCR确认结直肠癌组织样本中PiHL的表达与EZH2呈正相关;在HCT116细胞中,RNA pull-down和western blot结果显示,体外转录的LncRNA PiHL可以与细胞中EZH2蛋白直接结合;过表达或敲除PiHL后,EZH2蛋白的表达水平并不改变。PiHL表达下调可以显著增加细胞周期蛋白依赖性激酶抑制剂2B(CDKN2B)、KLF2、KLF6、人类RUNT相关转录因子3(RUNX3)等抑癌基因的表达。结论 PiHL在奥沙利铂耐药结直肠癌细胞中高表达。PiHL可以促进结直肠癌细胞奥沙利铂耐药,耐药细胞中干扰PiHL表达可以抑制细胞增殖,促进药物诱导的细胞凋亡,提高奥沙利铂的敏感性。PiHL通过与多梳抑制复合物中的EZH2蛋白结合表观遗传抑制的抑癌基因CDKN2B、KLF2、KLF6、RUNX3的表达。     

Chemopreventive effect of nonsteroidal anti-inflammatory drugs on the development of a new colorectal polyp or adenoma in a high-risk population: a meta-analysis

Background

Although many experimental, epidemiologic, and clinical studies have suggested that aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in reducing and preventing colorectal adenomas, randomized, controlled trials (RCTs) are still being carried out to obtain statistically reliable results.

Objective

The aim of this meta-analysis was to review long-term, prospective RCTs investigating the effect of NSAIDs on the relative risk (RR) for developing ≥1 new colorectal polyp or adenoma in a high-risk population.

Methods

We conducted a comprehensive search of MEDLINE, PubMed, and other electronic databases (including Inter-Science, Science Direct, Ebsco, Synergy, and Proquest) (key terms: nonsteroidal anti-inflammatory drugs, aspirin, colorectal, and polyps; years: 1974-2004) for English-language articles. Eligible studies were analyzed in terms of demographic data, adverse effects, and effect of NSAIDs on the RRs.

Results

Four long-term, prospective RCTs were used in the statistical analysis. A total of 2069 high-risk patients were enrolled; 1880 patients completed the studies, and 1127 were in active-treatment groups (aspirin 81-325 mg/d or sulindac 150-300 mg/d). Our meta-analysis of these studies revealed that the overall RR for developing ≥ 1 new colorectal polyp or adenoma was significantly reduced by using aspirin or other NSAIDs (RR = 0.809; 95% CI, 0.718-0.912).

Conclusions

The results of this meta-analysis suggest that regular use of aspirin 81 to 325 mg/d or sulindac 150 to 300 mg/d for ≥1 year was associated with a decrease in the RR for developing ≥ 1 new colorectal polyp or adenoma to 0.80 (95% CI, 0.718-0.912) in patients at high risk.     

奥沙利铂为基础的方案治疗老年晚期结直肠癌的临床观察

目的探讨奥沙利铂为基础的方案治疗老年晚期结直肠癌的疗效及安全性。方法选择经病理学确诊的46例老年晚期结直肠癌患者,均采用奥沙利铂为基础的方案化疗,其中包括FOLFOX方案18例,XELOX方案25例,另有3例为奥沙利铂联合氟尿嘧啶方案。所有患者至少完成2个周期的化疗,观察客观有效率(RR)、疾病控制率(DCR)、中位疾病进展时间(TTP)、总生存时间(OS)和化疗相关不良反应。结果 46例患者中,RR及DCR分别为39.1%和80.4%,TTP和OS分别为7.0月和24.0月。化疗相关不良反应可以耐受,Ⅰ~Ⅱ度不良反应主要包括中性粒细胞减少、血小板减少、贫血等,Ⅲ~Ⅳ度不良反应少见,主要为中性粒细胞减少和腹泻。结论奥沙利铂为基础的方案治疗老年晚期结直肠癌安全有效,值得在老年人群中进一步研究推广。     

沉默RAGE对人卵巢癌细胞株增殖、凋亡能力及周期分布的影响

目的 研究沉默晚期糖基化终产物受体(receptor for advanced glycosylation end products,RAGE)对人卵巢癌细胞株增殖、凋亡能力及周期分布的影响.方法 人上皮性卵巢癌SKOV-3细胞经过慢病毒载体构建,分为空白组、过表达组和沉默组.进行细胞增殖、细胞凋亡、细胞周期实验,We...     

虫草素调节非小细胞肺癌细胞株细胞周期、凋亡及相关抑癌基因的实验研究

目的 研究虫草素对非小细胞肺癌细胞株H358细胞周期、凋亡及相关抑癌基因的调节作用。方法 培养非小细胞肺癌细胞株H358并分组,空白对照组用不含药物的DMEM处理,虫草素组用含有50μmol/L、100μmol/L、200μmol/L虫草素的DMEM处理,处理24 h后测定细胞周期分布、细胞凋亡率、抑癌基因表达水平。结果 不同剂量虫草素处理后,H358细胞的S期比率、凋亡率及PTEN、p53、p16及Caspase-3、Caspase-8、Caspase-9的mRNA表达水平明显高于空白对照组,G2/M期比率明显低于对照组(P <0. 05),且200μmol/L虫草素处理后,H358细胞的S期比率、凋亡率及PTEN、p53、p16及Caspase-3、Caspase-8、Caspase-9的mRNA表达水平明显高于其他浓度虫草素处理的细胞,G2/M期比率明显低于其他浓度虫草素处理的细胞(P <0. 05)。结论 虫草素处理非小细胞肺癌细胞株能够使细胞周期停滞、细胞凋亡加剧,增加抑癌基因表达是虫草素发挥以上调节作用的分子途径,并呈剂量依赖性。     

健脾复方对人大肠癌移植瘤裸小鼠肿瘤细胞凋亡的影响

目的研究健脾复方对人大肠癌移植瘤裸小鼠肿瘤细胞凋亡的影响。方法将50只BALB/C裸小鼠建立人大肠癌原位移植瘤模型,并按1∶1∶1∶1∶1随机分入健脾复方组、塞来昔布组、氟尿嘧啶(5-Fu)组、模型对照组和空白对照组,分别治疗8周。采用免疫组化法检测凋亡相关的因子信号转导与转录激活因子-3(Stat-3)、B细胞淋巴瘤因子-2(Bcl-2)、存活素(Survivin)、半胱氨酸蛋白酶(Caspase)-3、Caspase-8和Caspase-9的表达。结果大肠癌肿瘤组织中Stat-3、Bcl-2、Caspase-9和Caspase-3的表达均存在异常。健脾复方能下调Stat-3、Bcl-2的表达,上调Caspase-9、Caspase-8、Caspase-3的表达,但对于Survivin的调节作用有待进一步确定。结论健脾复方能够调控大肠癌裸小鼠移植瘤的细胞凋亡,是其抑制大肠癌发生发展的可能机制。     

结直肠癌术后患者应用奥沙利铂联合卡培他滨方案化疗对外周血淋巴细胞亚群的影响

目的 观察ⅡB期～ⅢC期结直肠癌术后患者应用奥沙利铂联合卡培他滨方案化疗前后外周血淋巴细胞亚群水平变化,探讨奥沙利铂联合卡培他滨方案化疗对外周血淋巴细胞亚群的影响.方法 ⅡB～ⅢC期结直肠癌术后患者62例为结直肠癌组,体检健康者84例为对照组.结直肠癌患者术后给予奥沙利铂130 mg/m2,静脉滴注,2 h滴注完毕,第...     

紫杉醇联合三氧化二砷作用人结肠腺癌LS-174T细胞增殖及凋亡的实验研究

目的以人结肠腺癌LS-174T细胞系作为体外模型,研究紫杉醇与三氧化二砷联合作用抑制肿瘤细胞增殖及凋亡双重作用的机理。方法采用不同浓度的紫杉醇与三氧化二砷联合作用于体外培养的人结肠腺癌LS-174T细胞,以MTT比色法和形态学观察检测其对人结肠腺癌LS-174T细胞的抑制作用。以TUNEL法和Annexin V-Fife、PI染色、共聚焦显微镜检测其对人结肠腺癌LS-174T细胞系的凋亡诱导作用。结果不同浓度的紫杉醇与三氧化二砷联合组对人结肠腺癌LS-174T细胞增殖的抑制作用均强于紫杉醇或三氧化二砷单用药组。联合用药组从形态学观察及应用TUNEL法和Annexin V-FITC、PI染色结果显示联合用药组可检测到大量凋亡结肠腺癌细胞,明显多于单用药组。结论紫杉醇与三氧化二砷联合应用于人结肠腺癌LS-174T细胞可协同抑制其增殖,并可明显诱导肿瘤细胞凋亡发生。     

腹腔镜结直肠癌根治术对结直肠癌患者细胞免疫功能、胃肠激素及预后的影响*

目的探讨腹腔镜结直肠癌根治术对结直肠癌患者细胞免疫功能、胃肠激素及预后的影响。方法选择2016年7月-2017年10月收治的结直肠癌患者86例为研究对象,采用随机数字表法分为观察组和对照组各43例。对照组给予开腹结直肠癌根治术,观察组给予腹腔镜结直肠癌根治术,比较两组手术相关指标、细胞免疫功能、胃肠激素的变化和不良反应等情况。结果观察组手术时间明显长于对照组,排便时间、排气时间、住院时间明显短于对照组,术中出血量明显少于对照组(t=10.67,11.22,13.58,8.56,19.52;P 0.05);T淋巴细胞CD3~+、CD4~+、CD8~+和CD4~+/CD8~+减少值均明显少于对照组(t=10.99,17.76,10.46,10.49;P 0.05);血清胃泌素(GAS)、胃动素(MTL)减少值均明显低于对照组(t=10.31,13.73;P 0.05);并发症发生率11.63%明显低于对照组30.23%(χ2=4.50,P 0.05)。结论腹腔镜结直肠癌根治术有助于促进患者术后康复,降低术后并发症的发生,可能与对机体细胞免疫功能和胃肠激素影响较小等因素有关。     

替吉奥联合亚叶酸钙及奥沙利铂治疗晚期结直肠癌病人的观察与护理

[目的]总结替吉奥联合亚叶酸钙及奥沙利铂治疗晚期结直肠癌病人的观察与护理。[方法]对25例无法手术切除的晚期结直肠癌病人采用替吉奥胶囊联合亚叶酸钙、奥沙利铂方案进行治疗,同时加强心理护理、毒副反应的观察与护理等。[结果]治疗过程中出现Ⅰ级和Ⅱ级神经毒性8例,恶心、呕吐、食欲下降12例,骨髓抑制5例,变态反应1例,经处理后均好转;1例病人死亡,其余病人均顺利进行治疗。[结论]加强替吉奥联合亚叶酸钙及奥沙利铂治疗晚期结直肠癌病人的护理,可保证治疗的顺利进行。     

奥沙利铂联合卡培他滨治疗晚期或复发性结直肠癌的护理

[目的]总结奥沙利铂联合卡培他滨治疗晚期或复发性结直肠癌的护理措施。[方法]回顾性分析38例晚期或复发性结直肠癌病人行奥沙利铂联合卡培他滨治疗的临床资料。[结果]本组病人化疗过程均顺利,无一例因副反应而停止化疗。[结论]加强晚期或复发性结直肠癌病人行奥沙利铂联合卡培他滨治疗护理是化疗计划顺利进行的保证。     

结直肠癌患者团体心理护理的实践与效果

目的探讨团体心理护理对结直肠癌患者的心理调适作用。方法采用团体心理护理方式对84例结直肠癌患者在常规治疗基础上给予团体心理护理,观察期为4～10d,并记录患者在团体护理前后的心理痛苦、心理压力及睡眠质量的变化。结果患者心理压力总分及焦虑、抑郁、人际维度得分和心理痛苦、睡眠质量得分均下降（P〈0．01或P〈0．05）。结论团体心理护理能够减轻结直肠癌患者的心理痛苦程度以及心理压力水平,提高了住院期间患者的睡眠质量,增强了结直肠癌患者的治疗信心。     

超级增强子长链非编码RNA LINC01232在大肠癌组织中的表达及其对癌细胞生物学行为的影响

目的 探讨超级增强子长链非编码RNA(SE-LncRNA)LINC01232在大肠癌组织中的表达水平及其对大肠癌细胞生物学行为的影响.方法 通过基因芯片筛选4对大肠癌患者组织(癌组织和癌旁组织)中差异表达的SE-LncRNA,发现LINC01232在癌组织中显著高表达(Fold Change=2.6569,P=0.02...     

奥沙利铂联合卡培他滨治疗晚期或复发性结直肠癌的护理

[目的]总结奥沙利铂联合卡培他滨治疗晚期或复发性结直肠癌的护理措施。[方法]回顾性分析38例晚期或复发性结直肠癌病人行奥沙利铂联合卡培他滨治疗的临床资料。[结果]本组病人化疗过程均顺利,无一例因副反应而停止化疗。[结论]加强晚期或复发性结直肠癌病人行奥沙利铂联合卡培他滨治疗护理是化疗计划顺利进行的保证。     

Recent developments in targeting genes and pathways by RNAi‐based approaches in colorectal cancer

A wide spectrum of genetic and epigenetic variations together with environmental factors has made colorectal cancer (CRC), which involves the colon and rectum, a challenging and heterogeneous cancer. CRC cannot be effectively overcomed by common conventional therapies including surgery, chemotherapy, targeted therapy, and hormone replacement which highlights the need for a rational design of novel anticancer therapy. Accumulating evidence indicates that RNA interference (RNAi) could be an important avenue to generate great therapeutic efficacy for CRC by targeting genes that are responsible for the viability, cell cycle, proliferation, apoptosis, differentiation, metastasis, and invasion of CRC cells. In this review, we underline the documented benefits of small interfering RNAs and short hairpin RNAs to target genes and signaling pathways related to CRC tumorigenesis. We address the synergistic effects of RNAi‐mediated gene knockdown and inhibitors/chemotherapy agents to increase the sensitivity of CRC cells to common therapies. Finally, this review points new delivery systems/materials for improving the cellular uptake efficiency and reducing off‐target effects of RNAi.     

The effects of acetylsalicylic acid on proliferation,apoptosis, and invasion of cyclooxygenase-2 negative colon cancer cells

BACKGROUND: Acetylsalicylic acid (ASA, aspirin), the most common nonsteroidal anti-inflammatory drug (NSAID), has been shown to have a protective effect against the incidence and mortality of colorectal cancer. However, the mechanism of its anticancer function remains unclear. The aim of this study was to determine the effects of acetylsalicylic acid on proliferation, apoptosis, and invasion in human cyclooxygenase-2 (COX-2) negative colorectal cancer cell lines. MATERIALS AND METHODS: After treatment with various concentrations of ASA, cell proliferation was measured in the human colon cancer cell line SW480. Apoptotic cells were identified by transmission electron microscopy, acridine orange staining, and flow cytometry. The invasive potential of SW480 cells was detected using an in vitro invasion assay. The production of carcinoembryonic antigen was measured by microparticle enzyme immunoassay. Expression of Bcl2, Bax, CD44v6, and nm23 were evaluated by immunocytochemistry. RESULTS: ASA significantly inhibited the proliferation of SW480 cells and stimulated apoptosis. Production of carcinoembryonic antigen and the invasive potential of SW480 cells were also inhibited by ASA. After treatment with ASA, down-regulation of Bcl2 and CD44v6 expression and up-regulation of nm23 expression were observed in SW480 cells. No obvious effect of ASA was found on Bax expression. CONCLUSION: Our findings reveal that ASA inhibits the proliferation and promotes apoptosis in the human colon cancer cell line SW480. Down-regulation of Bcl2 expression might represent a potential mechanism by which ASA induces apoptosis in this COX-2 negative colon cancer cell line. Our results also suggest that ASA decreases the invasive potential of these colon cancer cells. Decreased CEA content and CD44v6 expression and elevated nm23 expression may contribute to the effect of ASA on invasive potential of SW480 colon cancer cells.     

Distinct effects of methylseleninic acid versus selenite on apoptosis,cell cycle,and protein kinase pathways in DU145 human prostate cancer cells

Selenium has been implicated as a promising chemopreventive agent for prostate cancer. Whereas the anticancer mechanisms have not been clearly defined, one hypothesis relates to selenium metabolites, especially the monomethyl selenium pool, generated under supranutritional selenium supplementation. To explore potential molecular targets for mediating the chemopreventive activity, we contrasted the effects of methylseleninic acid (MSeA), a novel precursor of methylselenol, versus sodium selenite, a representative of the hydrogen selenide metabolite pool, on apoptosis execution, cell cycle distribution, and selected protein kinases in DU145 human prostate cancer cells. Exposure of DU145 cells to 3 microM MSeA led to a profound G1 arrest at 24 h, and exposure to greater concentrations led to not only G1 arrest, but also to DNA fragmentation and caspase-mediated cleavage of poly(ADP-ribose) polymerase (PARP), two biochemical hallmarks of apoptosis. Immunobiot analyses indicated that G1 arrest induced by the subapoptogenic doses of MSeA was associated with increased expression of p27kip1 and p21cip1, but apoptosis was accompanied by dose-dependent decreases of phosphorylation of protein kinase AKT and extracellular signal-regulated kinase (ERK1/2) in the absence of any phosphorylation change in p38 mitogen-activated protein kinase (p38MAPK) and c-Jun NH2-terminal kinase (JNK1/2). In contrast, selenite exposure caused S-phase arrest and caspase-independent apoptotic DNA fragmentation, which were associated with decreased expression of p27kip1 and p21cip1 and increased phosphorylation of AKT, JNK1/2, and p38MAPK. Although apoptosis induction by MSeA exposure was not sensitive to superoxide dismutase added into the cell culture medium, cell detachment and DNA nucleosomal fragmentation induced by selenite exposure were greatly attenuated by this enzyme, supporting a chemical mediator role of superoxide for these processes. Despite a temporal relationship of AKT and ERK1/2 de-phosphorylation changes before the onset of PARP cleavage in MSeA-exposed cells, experiments with phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 did not show an enhancing effect of specific blocking of AKT on MSeA-induction of PARP cleavage. Taken together, exposure of DU145 cells to MSeA versus selenite induced differential patterns of cell cycle arrest and apoptosis execution as well as distinct patterns of effects on AKT, ERK1/2, JNK1/2, and p38MAPK phosphorylation and p27kip1 and p21cip1 expression. Multiple molecular pathways are likely differentially targeted by selenium metabolite pools to mediate cancer chemoprevention.