PI3K/Akt信号通路在肝癌中相关机制及药物研究进展

肝癌在我国的死亡率逐年提升,发病年龄也日趋年轻化,发现时大多已处于中、晚期,失去了最佳手术时机.随着近年来高通量测序技术水平的不断提高,多条信号通路的调控机制对肝癌的辅助治疗成为研究热点,对肝癌的靶点进行分子靶向治疗成为一项有效的手段.多条信号通路在肝癌的发病过程中发挥作用;其中,磷脂酰肌醇3-激酶(PI3K)/Akt...     

异常甲基化的原钙黏蛋白7对雄激素非依赖性前列腺癌细胞生长的影响

目的探讨异常甲基化的原钙黏蛋白7(PCDH7)对雄激素非依赖性前列腺癌(AIPC)细胞生长的影响。方法培养AIPC细胞系LNCaP-AI,采用甲基化酶抑制剂5-氮杂-2′-脱氧胞苷(AZA)处理细胞24 h,RT-PCR和Western blot法检测PCDH7 mRNA和蛋白的表达水平,CCK-8法检测细胞生长情况,流式细胞术检测细胞凋亡,Transwell法检测细胞侵袭能力。结果加入AZA后,PCDH7基因启动子片段1甲基化水平为0.00486±0.00144,低于对照组的0.00956±0.00594,片段2甲基化水平为0.00610±0.00171,低于对照组的0.00858±0.00180(P<0.05),且PCDH7 mRNA和蛋白表达均上调(P<0.01)。加入DNA甲基化转移酶1后PCDH7 mRNA和蛋白表达下调(P<0.05)。加入AZA后,细胞生长抑制率和细胞凋亡率增加[(15.3%vs.0%)和(5.06%vs.3.44%)](P<0.01),侵袭细胞数下降(P<0.01)。结论异常甲基化的PCDH7在AIPC细胞中表达上调,能够抑...     

抑制PI3K信号通路的抗肿瘤天然药物研究进展

磷脂酰肌醇3-激酶(PI3K)信号通路是正常细胞生理代谢的重要信号转导途径,也是肿瘤细胞发生和发展的关键信号通路。人类肿瘤基因组学研究表明,PI3K信号通路可将癌基因和多种受体与许多细胞功能联系在一起,该通路也是肿瘤中最常被激活的通路,抑制该信号通路,可抑制肿瘤的生长与转移。概述了PI3K及其信号通路与肿瘤发生、发展和转移的关系以及PI3K信号通路的主要抑制途径,综述近年来抗肿瘤天然药物抑制PI3K信号通路的研究进展。     

PI3K/Akt信号通路与阿尔茨海默病关系的研究进展

神经系统活动的基础是神经元以及它们之间的联系。在生长发育过程中,如果这些结构出现变化就会导致相应的疾病发生,如轻度认知障碍(mild cognitive impairment,MIC)、阿尔茨海默病(Alzheimer′s disease,AD)、帕金森病(Parkinson disease,PD)等老化疾病。导致这些疾病发生的机制很多,包括基因水平改变、细胞内外部环境变化等。目前认为磷脂酰肌醇-3-激酶/丝/苏氨酸激酶(phosphatidylinositol-3-kinases/serine threonine kinase,PI3K/Akt)信号通路与细胞生存、细胞代谢以及细胞凋亡等机制密切相关。因     

甲状腺癌相关信号通路的研究进展

甲状腺癌是内分泌系统最常见的恶性肿瘤,其发生发展与多个信号转导通路有关.其中丝裂原活化蛋白激酶/细胞外信号调节激酶(MAPK/ERK)信号通路经BRAFV600E突变和RET/PTC重排等所导致的通路效应可促进甲状腺乳头状癌的细胞增殖和分化,磷脂酰肌醇-3激酶/蛋白激酶B(PI3K/AKT)通路可由多因素激活后与甲状腺...     

PI3K/Akt信号通路在肿瘤发展和治疗中的作用

目前发现有多条信号网络通路参与调控肿瘤生成、增殖、凋亡等分子机制,PI3K/Akt是其中比较重要的一条信号传导途径,该通路与肿瘤的发生发展密切相关。该文就PI3K/Akt信号通路的结构组成与调控肿瘤机制进行阐述,并介绍了其在临床中的应用与前景。     

去势抵抗前列腺癌中的非激素信号通路作用机制及其相关药物研究进展

前列腺癌是男性泌尿生殖系统常见的恶性肿瘤之一,近十年来我国前列腺癌的发病率呈明显上升的趋势。目前,以雄激素阻断为主的内分泌治疗是除根治手术和放疗或化疗之外临床上比较主流的前列腺癌治疗方案,虽然在治疗前期能获得良好的临床收益,但近九成的患者仍会进入去势抵抗阶段,且其中又有近九成的患者会发生骨转移,患者的生活质量随着疾病进程急剧降低。有研究表明在形成去势抵抗的过程中,除雄激素信号通路外还涉及了多种其他分子信号的变化,包括经典的致癌信号通路和免疫炎症致癌信号通路等。了解这些独立于雄激素信号通路的其他信号通路在去势抵抗形成中的作用机制,将有助于了解雄激素阻断治疗在去势抵抗中的脱靶效应以及引入新的治疗靶点和治疗策略,推动去势抵抗摆脱临床"无药可用"的困境。     

肝细胞胰岛素信号传导通路与胰岛素抵抗

肝脏在人体的葡萄糖代谢中有着重要作用,从胰岛素与其受体(InsR)结合开始,肝脏糖代谢构成了一个复杂的传导通路,起到稳定血糖的生理作用。对这一信号通路的深入研究将有利于进一步阐明糖尿病的发病机制并为糖尿病的治疗提供思路。基于此原因,本文综述了肝细胞胰岛素信号传导通路的传导机制及其意义。     

PI3K／Akt/mTOR信号通路在甲状腺癌中的研究进展

甲状腺癌是最常见的内分泌系统恶性肿瘤,特别是严重危害了女性健康。近年来,我国甲状腺癌的发病率呈明显上升趋势,以沿海城市为甚,超过了其他恶性肿瘤的增长速度。因为癌症带给社会、家庭和个人巨大的负担,寻找甲状腺癌诊疗的新方法变得尤为重要。近年来,磷酸酰肌醇-3激酶,     

神经降压素在雄激素非依赖性前列腺肿瘤动物模型中的表达

【摘要】目的观察神经降压素（NT）在原位前列腺肿瘤动物模型中的表达。方法利用原位种植包埋法和外科手术去势技术对Balbc-nu裸鼠分别构建雄激素依赖、去势3d和雄激素非依赖性原位前列腺肿瘤动物模型;Af? fymetrix基因芯片技术检测NT在3组肿瘤组织中mRNA的表达差异,运用荧光实时定量聚合酶链反应（qRT-PCR）验证结果;HE染色在光镜下观察肿瘤组织病理学改变;ELISA法测定裸鼠血清前列腺特异性抗原（PSA）浓度;免疫组织化学法检测3组肿瘤组织中NT的蛋白相对表达量。结果与雄激素依赖组比较,雄激素非依赖组和去势3d 组NTmRNA表达分别上调5.10和下调0.33;用RT-PCR和qRT-PCR验证其结果,雄激素非依赖组的表达水平较雄激素依赖组分别上调1.41和7.27（P＜0.01）,去势3d组的表达水平分别下调0.78和0.46（P＜0.05）;肿瘤组织HE 染色可见明显的核异型性和瘤节结构;雄激素依赖组PSA和NT结果均分别为（0.48±0.03）μg/L和0.031±0.008,去势3d组均分别为（0.17±0.03）μg/L和0.021±0.004,雄激素非依赖组均分别为（0.87±0.02）μg/L和0.042±0.010;与雄激素依赖组比较,去势3d组表达降低,雄激素非依赖组表达升高（P＜0.01）。结论NT在前列腺肿瘤由雄激素依赖向雄激素非依赖这一变化过程中起着一定的作用,可以作为雄激素非依赖性前列腺肿瘤治疗靶点和特异性诊断指标。     

Signaling inhibitors in the treatment of prostate cancer

Inhibiting androgen receptor (AR) activation through medical or surgicalcastration and blockade of AR-androgen binding is the cornerstone oftreatment for advanced prostate cancer. However, in most cases tumorgrowth eventually becomes androgen independent. Alternative mechanisms ofAR activation, some of which involve growth factor receptor signaling,have been demonstrated in prostate cancer models, and it is likely that anumber of autocrine and paracrine growth factor ligand-receptorinteractions such as those of epidermal growth factors, fibroblast growthfactors, and insulin-like growth factors contribute to the androgenindependent phenotype by promoting cell proliferation and survival.Blocking activation through growth factor receptors and upstream signalingproteins has emerged as a credible approach to cancer treatment.Successful application of this approach in prostate cancer using a growingarray of small molecule kinase inhibitors, antibodies, and antisenseoligonucleotides will be greatly accelerated by elucidation of the keysignaling pathways that maintain the androgen independent phenotype.     

Advancing therapies in metastatic castration-resistant prostate cancer

ABSTRACT

Introduction: Prostate cancer is the second most common cause of cancer worldwide and is the most frequently detected cancer in the European Union in men over 50 years of age. Androgen deprivation therapy remains the cornerstone of treatment for recurrent or metastatic disease. Unfortunately, nearly all patients will develop resistance to androgen blockade leading to castration-resistant prostate cancer (CRPC). Over the last 10 years, new treatments have dramatically improved overall survival of men with mCRPC. Current therapies are based on AR-axis inhibitors and taxane-based chemotherapies, as well as radiopharmaceuticals and Sipuleucel T.

Areas covered: The authors provide a review of the current field of systemic therapy in metastatic CRPC. This is followed by an in-depth analysis of recent developments in treatment, and the biological rationale behind these therapies.

Expert opinion: Since several trials with docetaxel or novel hormonal agents showed improvement in overall survival in metastatic castration-sensitive prostate cancer, as well as in non-metastatic castration-resistant patients, it is expected that a growing subgroup of patients will be exposed earlier to chemotherapy and to AR targeted agents. It becomes then fundamental to find novel strategies to overcome drug resistance and further improve survival.     

EGFR和PI3K在进展期胃癌中的表达及临床意义研究

目的探讨进展期胃癌组织中EGFR和PI3K蛋白表达与临床病理参数的相关性及其临床意义。方法采用免疫组织化学染色方法检测68例胃癌组织及15例正常胃黏膜组织中EGFR和PI3K蛋白的表达。结果在68例进展期胃癌组织标本中,EGFR和PI3K蛋白的阳性表达率分别为58.82%和76.47%,在正常胃黏膜中均未见其阳性表达。EGFR阳性表达与淋巴结转移、远处转移及临床TNM分期有关（P〈0.05）;PI3K阳性表达与肿瘤浸润深度、淋巴结转移、远处转移及临床TNM分期有关（P〈0.05）。结论联合检测EGFR和PI3K蛋白表达有助于阐释进展期胃癌发生发展、浸润转移的机制,并可作为评估胃癌恶性生物学行为及预后的参考指标。     

PI3K/Akt/mTOR信号传导通路与前列腺癌关系的研究进展

前列腺癌是威胁中老年男性健康的常见肿瘤,成为男性癌症死因的第二位。 PI3K/Akt/mTOR信号通路能够通过维持细胞生存、抑制细胞凋亡、促进细胞周期运行及血管生成等促进前列腺癌病程发展。本文综合国内外文献,阐述PI3K/Akt/mTOR信号通路在前列腺癌发生发展中的作用以及和通路相关的药物治疗进展。     

Darolutamide (ODM-201) for the treatment of prostate cancer

Introduction: Androgen deprivation therapy (ADT) is a mainstay initial treatment for advanced hormone-sensitive prostate cancer (HSPC), but disease progression to castration-resistant prostate cancer (CRPC) invariably occurs when patients do not succumb to another disease or comorbidity. Recognition that the androgen receptor (AR) axis continues to drive disease progression has led to the development of several AR-directed approved agents, including abiraterone acetate and enzalutamide. An investigational agent, darolutamide (ODM-201, BAY-1841788), has completed early-phase clinical trials, and two global phase III trials are currently accruing patients.

Areas covered: The unmet clinical need, pharmacokinetics, preclinical development, and clinical efficacy and safety of darolutamide for the treatment of advanced prostate cancer are reviewed. The design of two ongoing phase III trials (ARAMIS and ARASENS) of darolutamide in men with non-metastatic CRPC and metastatic HSPC, respectively, are also discussed.

Expert opinion: Darolutamide is an oral, investigational, high-affinity AR antagonist which has activity against known AR mutants that confer resistance to other second-generation antiandrogens, has minimal blood–brain barrier penetration, and does not significantly increase serum testosterone. These features may offer potential advantages over the second-generation antiandrogens. In the phase I/II ARADES trial, darolutamide demonstrated promising antitumor activity and a favorable safety profile in men with metastatic CRPC.     

Involvement of microRNA-21 in mediating chemoresistance to docetaxel in androgen-independent prostate cancer PC3 cells

Aim:

To investigate whether microRNA-21 was involved in mediating the chemoresistance of prostate cancer cells to docetaxel.

Methods:

A microarray technique was used to determine the miRNA profile in docetaxel-resistant PC3 cells. Real-time PCR was used to confirm the array results. miR-21 mimics and inhibitors were synthesized and introduced to cells using Lipofectamine 2000. Cell proliferation was examined with the CCK-8 assay. Luciferase reporter containing PDCD 3′UTR was constructed and the activity was detected by a dual luciferase assay. PDCD4 protein expression was evaluated using Western blot.

Results:

A docetaxel-resistant prostate cancer PC3 cell line (PC3R) was established . Using microarrays, miR-21 was found to be up-regulated in PC3R cells. Ectopic expression of miR-21 increased the resistance to docetaxel in PC3 wild type cells. In contrast, silencing of miR-21 in PC3R cells sensitized the cells to docetaxel. The IC₅₀ values for miR-21-silencing cells and control cells were 28.31 and 35.89 nmol/L, respectively. PDCD4, a direct target gene of miR-21, could mediate chemoresistance to docetaxel in PC3 cells.

Conclusion:

Our findings suggest that miR-21 contributed to the resistance of PC3 cells to docetaxel, and that targeting miR-21 may offer a promising therapeutic approach in sensitizing prostate cancer to docetaxel treatment.     

Phase II trial of pyrazine diazohydroxide in androgen-independent prostate cancer

No effective therapy has been demonstrated for hormone refractory prostate cancer (HRPC). Pyrazine diazohydroxide (PZDH) is a novel antineoplastic agent with a broad range of activity in preclinical studies and a moderate toxicity profile in Phase I trials. We undertook a Phase II study of PZDH in HRPC utilizing decline in PSA as the primary end point. Fifteen patients were enrolled, median age of 70 (55–86), median pretherapy PSA 206 ng/ml (range 42–10,000). Four patients were African American. Sites of disease: bone only 7, soft tissue only 2, both 6. All were evaluable for toxicity and response. PZDH was administered at 250 mg/m2 IV every three weeks. The median number of cycles administered was two (range 1–6). Toxicity was mild, with only one patient manifesting serious (grade 3–4) toxicity. Unfortunately, activity was minimal with only a single patient demonstrating a >75% decline in PSA. As this patient's PSA began to rise almost immediately the response was considered transient and not felt to justify pursuing a second stage of the trial. Supporting this conclusion was the disappointing median survival of 220 days. In summary, we conclude that PZDH, while well tolerated at this dose and schedule has only minimal activity in HRPC.     

Androgen deprivation therapy for the treatment of prostate cancer: a focus on pharmacokinetics

Introduction: Medical therapy has undergone many changes as our understanding of prostate cancer cell biology has improved. Androgen deprivation therapy (ADT) remains the mainstay of therapy for metastatic disease. Metastatic castrate-resistant prostate cancer (CRPC) is an important concern since we are unable to stop progression with currently available agents.

Areas covered: Pharmacologic ADT is the most commonly used treatment for metastatic prostate cancer. Multiple agents are available for both first-line and second-line use: antiandrogens, estrogens, luteinizing hormone-releasing hormone agonists/antagonists, and CYP17 inhibitors. With adoption of these drugs, it is important to consider their pharmacokinetic and pharmacodynamic properties. Many undergo metabolism through cytochrome P450. Levels may be altered with co-administration of drugs acting as enzyme inhibitors or inducers. Understanding mechanism of action, metabolism, and excretion of these drugs allows clinicians to provide the best therapeutic care while minimizing adverse events.

Expert opinion: Many men with metastatic prostate cancer will progress to castration resistance. An understanding of resistance mechanisms at the cellular level has revealed new drug targets with hopes of halting or reversing progression of metastatic disease. Second-line agents, traditionally reserved for CRPC, are being studied in metastatic castrate-sensitive prostate cancer, and may offer practice-changing evidence supporting their use.