The integrin-linked kinase-associated phosphatase (ILKAP) is a regulatory hub of ovarian cancer cell susceptibility to platinum drugs

BackgroundPlatinum drugs are the most powerful chemotherapeutic agents in the treatment of ovarian cancer. We demonstrated previously that unexpectedly ovarian cancer cells are sensitised to cisplatin (CDDP) by the hepatocyte growth factor (HGF), usually considered an anti-apoptotic factor.MethodsWe used quantitative polymerase chain reaction and Western blot analysis to evaluate gene and protein expression, immunofluorescence to evaluate protein localisation and functional assays to measure cell viability and apoptosis.ResultsIn ovarian cancer cells, CDDP induced the phosphorylation, i.e. the activation, of the p90RSK. Surprisingly, a 48-h-long cell pre-treatment with HGF reverted this activation. HGF pre-treatment also resulted in the increased expression of the integrin-linked kinase (ILK)-associated phosphatase (ILKAP) that dephosphorylated the p90RSK. Conversely, CDDP down-modulated ILKAP expression. This impaired CDDP efficacy, as ILKAP silencing protected cells from CDDP-induced death. In line, the biochemical inhibition of the p90RSK or the combined silencing of the most expressed RSK isoforms, namely RSK1 and RSK2, increased the efficacy of CDDP. However, p90RSK inhibition was not sufficient to revert cell protection from death after ILKAP suppression, because of the simultaneous increased activity of the anti-apoptotic kinases ILK and ILK substrate AKT, which were both dephosphorylated, i.e. negatively regulated, by ILKAP. Only the combined inhibition of p90RSK and ILK reverted the effect of ILKAP suppression.ConclusionsAs RSKs, ILK and AKT are vital kinases for ovarian cancer onset and progression, data suggest that ILKAP is a regulatory hub of ovarian cancer cell survival by controlling the activation of these kinases.     

铂类抗肿瘤药的进展与临床评价

目的:探讨铂类抗肿瘤药的临床特点及其研究进展,为临床应用提供参考。方法:通过查阅国内外相关文献,系统地了解铂类抗肿瘤药的临床作用及相关不良反应;并检索近年上市、未获批准及正在进行临床研究的铂类药物,以分析其临床发展趋势。结果与结论:在过去的10年间,药物研发转向注重药物运输靶向介质,这些新药在保留传统铂类化合物的活性的同时,在很大程度上减少了传统铂类药物的不良反应。     

以铂类为基础治疗非小细胞肺癌的疗效及与MTHFR C677T基因多态性的相关性分析

目的 探讨以铂类为基础治疗非小细胞肺癌的疗效及其与亚甲基四氢叶酸还原酶(MTHFR)C677T基因多态性的相关性.方法 选取经病理确诊行手术切除后接受以铂类为基础化疗方案的NSCLC患者180例为研究组,另选择同期体检的健康人100名作为健康对照组.通过血液学标本提取的DNA进行MTHFR C677T基因分型.比较MT...     

血清中耐药相关的差异表达蛋白质在诊断卵巢上皮性癌铂类耐药中的临床价值

目的 分析血清耐药相关的差异表达蛋白质在诊断卵巢上皮性癌铂类耐药患者中的价值,为非手术卵巢上皮性癌患者化疗药物方案的制定提供参考.方法 选择川北医学院附属医院妇产科2015年3月至2016年3月收治的经铂类药物治疗无效的卵巢癌患者40例设为观察组,选择同期收治的经铂类药物治疗获得改善的卵巢癌患者40例作为对照组,采集两组受试者静脉血,采用酶联免疫法(ELISA)检测并比较两组患者的血清耐药相关蛋白(SERPINA1、FN1、ORM1、annexinA3、destrin、IDHl))的表达情况,所有患者均行病理穿刺,获取病理组织,采用逆转录一聚合酶链反应(RT-PCR)检测方法对病理组织中的上述耐药相关蛋白进行检测.分析血清标本检测结果和病理组织检测的SERPINA1、FN1、ORM1、destrin、annexinA3、IDHl结果之间的差异性和相关性.结果 观察组患者血清中的SERPINA1、FN1、ORM1、destrin、annexinA3、IDHl水平分别为(753.6±138.6)μg/μL、(223.5±51.5)μg/μL、(72.2±40.9)μg/μL、(331.5±21.8)μg/μL、(344.2±40.6)μg/μL、(44.5±21.3)μg/μL,病理组织中上述指标分别为(38.69±6.7)％、(32.32±6.6)％、(35.48±6.1)％、(29.44±5.4)％、(26.63±4.8)％、(11.37±1.5)％,对照组患者血清中的SERPINA1、FN1、ORM1、destrin、annexinA3、IDHl水平分别为(512.6±113.4)μg/μL、(125.5±41.4)μg/μL、(64.6±41.4)μg/μL、(215.7±21.1)μg/μL、(23.42±5.3)μg/μL、(115.5±21.3)μg/μL,病理组织中上述指标分别为(27.49±5.7)％、(21.38±5.4)％、(23.41±5.2)％、(23.41±5.2)％、(21.22±4.6)％、(29.43±2.3)％.观察组患者血清中SERPINA1、FN1、ORM1、destrin、annexinA3均明显高于对照组,但血清中IDHl水平明显低于对照组,差异均有统计学意义(P<0.05);观察组患者卵巢癌病理组织中的SERPINA1、FN1、ORM1、destrin、annexinA3水平均明显高于对照组,但IDHl水平明显低于对照组,差异均有统计学意义(P<0.05);血清中检测的SERPINA1、FN1、ORM1、destrin、annexinA3、IDHl水平与病理组织中检测的结果的spearman相关性系数分别为0.734、0.683、0.702、0.682、0.593、0.618,均呈正相关(P<0.05).结论 血清中耐药相关的差异表达蛋白质检测结果与病理组织中的检测结果密切相关,对于无法行手术探查或者治疗的患者,采用血清样本检测耐药相关差异蛋白质可为化疗药物方案的制定提供重要的参考,具有较高的临床价值.     

高水溶性铂类抗肿瘤药物的设计与合成

目的设计与合成具有高水溶性的铂类抗肿瘤药物。方法通过在丙二酸铂结构中偶联糖分子设计出目标化合物并合成取得水溶性抗肿瘤药物。结果得到了迄今水溶性最好的金属铂类抗肿瘤化合物,其动物模型抗肿瘤活性和安全性均优于顺铂和卡铂。结论通过糖分子偶联设计取得的新型铂类抗肿瘤药物能够解决一般铂类药物的低水溶性问题,经初步动物模型抗肿瘤药效实验证明该类药物具有理想的抗肿瘤效果。     

A Multimodal Approach in Coil Embolization of a Bile Leak Following Cholecystectomy

Bile leak is a well-known complication of cholecystectomy. Endoscopic drainage and decompression of the biliary system including temporary insertion of a biliary stent is generally considered the treatment of choice. We report the successful obliteration of a bile leak using fibered platinum coils placed under fluoroscopic guidance after stent treatment had failed.     

Nature of M–Bi bonds in dihalobismuth complexes of nickel,palladium and platinum trans-[X(PMe3)2M(BiX2] (M = Ni,Pd, Pt; X = Cl,Br, I): A theoretical study

Geometry, electronic structure and bonding energy analysis of the terminal neutral dihalobismuth complexes of nickel, palladium and platinum trans-[X(PMe₃)₂M(BiX₂)] (M = Ni, Pd, Pt; X = Cl, Br, I) were investigated at the BP86/TZ2P/ZORA level of theory. The calculated geometrical parameters of platinum complex trans-[Cl(PMe₃)₂Pt(BiCl₂)] are in excellent agreement with structurally characterized platinum complex trans-[Cl(PCy₃)₂Pt(BiCl₂)]. The variations in the M–Bi bond distances show that the trans effect of halides is relatively greater than the effects of halides bonded to the Bi atom. Hence, the strength of the M–Bi bond decreases on going from X = Cl to X = I in the complexes trans-[X(PMe₃)₂M(BiX₂)]. From the perspective of covalent bonding, however π-symmetry contributions are, in all complexes, significantly smaller than the corresponding σ bonding contribution. Thus, in these complexes, the [BiX₂] behaves predominantly as a σ donor. The natural population analysis (NPA) charge distributions indicate the bismuth atom carries a significant positive charge in all cases. The contributions of the electrostatic interactions ΔE_elstat are significantly larger in all bismuth complexes (I–IX) than the covalent bonding ΔE_orb. The interaction energy increases in the order Ni < Pd < Pt, and the absolute values of the ΔE_Pauli, ΔE_int and ΔE_elstat contributions to the M–Bi bonds decrease according to X = Cl > Br > I.     

Photon activation therapy and brachytherapy

PurposeIn photon activation therapy (PAT), energy deposition at critical sites within a tumor can be increased by complexing the DNA with higher Z atoms, and provoking the emission of Auger electrons after inducing a photoelectric effect. This in vivo study evaluates the hypothesis using X-rays from palladium-103 seeds to excite the L-edge of platinum (Pt) atoms bound to the DNA of cancerous cells.Methods and MaterialsPt (II) tetrakis(N-methyl-4-pyridyl) porphyrin chloride was used to locate Pt atoms adjacent to the DNA of the KHJJ murine mammary carcinoma; a 2.3-mCi palladium-103 seed was implanted in the tumor.ResultsThe tumor periphery received subtherapeutic doses. The rate of tumor growth in mice treated with PAT was slower than in mice treated with brachytherapy only.ConclusionsThe tumor growth delay for PAT-treated mice is attributed to Auger emission from Pt atoms that produced substantial local damage. However, other co-existing mechanisms cannot be ruled out.