多药耐药基因的研究现况及应用

<正> 肿瘤细胞对多种细胞毒药物的拮抗性是影响肿瘤化疗的主要障碍。它是以肿瘤细胞对亲脂性细胞毒药物,包括各种植物碱类抗肿瘤药物的交叉拮抗为特征,可分为天然性和获得性耐药,区别在于后者是在化疗过程中诱导的对一种抗肿瘤药物产生耐药后,同时对其他不相关非同类药物亦产生耐药性,即多耐药性(multidrug resistance,MDR)。MDR的产生机制复杂,常见原因是P-糖蛋白(Pgp)的超表达。     

抗肿瘤药培美曲塞的药理实验研究

分析了抗肿瘤药培美曲塞的药理作用以及该种药物的临床疗效。通过查阅资料以及开展药理研究,分析抗肿瘤药培美曲塞的作用机制、药效学、药代动力学、不良反应、耐受性以及耐药机制,通过查阅临床上报道的关于培美曲塞治疗恶性肿瘤的临床研究,分析该种药物的抗肿瘤功效。通过药理实验,得出以下结果:1作用机制:培美曲塞通所具有的叶酸拮抗作用,能够抑制肿瘤细胞复制;2药效学:培美曲塞具有广谱抗肿瘤活性;3药代动力学:培美曲塞的药物代谢符合多室模型,组织内分布有限,经尿液迅速清除,平均半衰期2~3h;4不良反应:培美曲塞常见不良反应包括中线性粒细胞减少、腹泻、黏膜炎、恶心、呕吐;5耐受性:培美曲塞不良反应严重程度低,耐受性较好;6耐药机制:培美曲塞的耐药机制主要为叶酰聚谷氨酸合酶表达的变化。7药物疗效分析发现,培美曲塞能够有效提高肿瘤患者疾病治疗有效率,延长患者生存期。培美曲塞所具有的独特药理作用,能够有效降低肿瘤患者病死率。     

肿瘤细胞多药耐药化学逆转剂研究进展

用MDR的逆转是肿瘤治疗过程中的关键。用化学药物阻断耐药机制,如针对各种耐药蛋白和PKC的逆转剂;反义核酸技术阻断耐药途径,如反义核酸、核酶及小RNA等;细胞因子拮抗耐药过程;物理逆转措施如微波、超声波等等。利用化学逆转剂对肿瘤细胞的耐药的分析。     

用于药物递送的pH敏感聚合物研究进展

本文综述了pH敏感聚合物(pH-sensitive polymer)载体靶向输送抗肿瘤药物的研究进展。肿瘤组织的细胞间质呈弱酸性(pH值7),而肿瘤细胞内的溶酶体和内涵体具有更强的酸性(pH值4~6)。pH敏感聚合物在酸性介质中能发生质子化或化学反应,使其物理或化学性质发生改变。使用pH敏感型聚合物做成的药物载体能够对肿瘤酸性微环境产生响应,实现药物的快速释放、激活载体的靶向传输功能、促进载体的细胞内吞。大量实验表明,pH敏感型药物载体输送抗肿瘤药物可以明显增加药物在作用部位的浓度,从而饱和肿瘤细胞的多种抗药机制,克服肿瘤细胞的耐药性,提高抗癌药物的治疗效果同时减少其毒副作用。     

白蛋白结合蛋白在肿瘤细胞中功能及抗肿瘤药物中应用的研究进展

肿瘤细胞代谢活跃,需消耗大量的能量和营养以支持细胞的快速生长,肿瘤细胞和肿瘤血管上皮细胞中高度表达各种转运蛋白以增加营养的吸收。在恶性肿瘤细胞中,白蛋白结合蛋白（albumin-binding proteins,ABPs）负责白蛋白的摄取、转运、累积或再利用,与肿瘤形成、浸润和转移密切相关,有望作为肿瘤治疗或药物开发的新靶点。目前,在各种组织细胞中已陆续发现了7种ABPs,ABPs在肿瘤细胞中的功能和作用机制也逐渐成为研究热点。因此,本文就ABPs在肿瘤细胞中功能及抗肿瘤药物中应用的研究进展作一综述。     

氨基酸在抗肿瘤药物修饰研究中的设计合成及其活性研究

氨基酸是生命活动中最基本的物质,是生命代谢的物质基础,肿瘤细胞对氨基酸的需求远大于正常组织.将氨基酸引人抗肿瘤药物分子中,可以提高其对肿瘤细胞的选择性,增强药物的脂溶性、缓解药物对细胞的毒性等.越来越多的药学工作者相继用氨基酸对各抗肿瘤药物进行结构修饰,并对其活性进行研究,以求寻找到更有利于癌症患者的高效、低毒的抗肿瘤药物.     

苦参碱和氧化苦参碱抗肿瘤作用机制研究进展

苦参碱和氧化苦参碱是一类生物碱,具有多方面药理活性。目前国内外关于苦参碱和氧化苦参碱抗肿瘤作用的研究表明:苦参碱和氧化苦参碱通过抑制肿瘤细胞DNA的合成、影响肿瘤细胞的正常周期来抑制肿瘤细胞的增殖;通过影响与肿瘤细胞相关基因的表达、抑制相关酶的活性等诱导肿瘤细胞发生凋亡。因此,这种生物碱对抗肿瘤作用的研究受到了极大的关注。就近年来对苦参碱和氧化苦参碱抗肿瘤作用的研究作一简要综述,概括其对各种癌细胞的抗肿瘤作用机制。     

线粒体靶向抗肿瘤药物及其分类

线粒体是真核细胞重要的细胞器,在细胞代谢中发挥主要作用。线粒体与疾病的发生、发展、治疗密切相关,线粒体靶向抗肿瘤药物分子的设计和研究已成为药学、化学和生命科学等领域的关注热点。分别简述了8类线粒体靶向抗肿瘤药物的作用机制和特征,介绍了2类新型多功能线粒体靶向抗肿瘤药物,并展望了抗肿瘤药物未来的发展方向。     

pH响应的二氧化硅纳米粒子载运阿霉素进行癌症化疗

对所制备的二氧化硅纳米粒子(MS NPs)的载药性能、生物相容性和pH响应的药物释放性能进行了系统研究。实验结果显示,该MS NPs对化疗药物阿霉素(Dox)的负载量可达30μg·mg~(-1),具有很好的药物载运能力。此外,这种MS NPs具有pH响应性,能够对肿瘤微环境发生响应并精准释放药物对肿瘤细胞进行治疗。细胞MTT实验结果表明,所制得的MS NPs具有良好的生物相容性以及载药后很好的抗肿瘤能力,72h后可杀灭约82%的肿瘤细胞。因此,所制备的MS NPs在抗肿瘤领域有着巨大的应用潜力。     

pH敏感聚合物胶束类型及释药机制的概述

肿瘤细胞增殖速度快,肿瘤组织的供氧不足,肿瘤细胞代谢产生大量乳酸,导致肿瘤组织与体内正常组织器官相比pH值偏低。因此,利用不同组织中pH值的差异设计具有pH敏感的聚合物胶束载药系统,从而提高抗肿瘤药物的靶向性和治疗效果。本文主要从pH敏感聚合物胶束的类型和及其释药机制等方面概述了pH敏感聚合物胶束纳米给药系统的研究进展。     

The Role of Exosomes and Their Applications in Cancer

Exosomes are very small extracellular vesicles secreted by multiple cell types and are extensively distributed in various biological fluids. Recent research indicated that exosomes can participate in regulating the tumor microenvironment and impacting tumor proliferation and progression. Due to the extensive enrollment in cancer development, exosomes have become a focus of the search for a new therapeutic method for cancer. Exosomes can be utilized for the therapeutic delivery of small molecules, proteins and RNAs to target cancer cells with a high efficiency. Exosome-carried proteins, lipids and nucleic acids are being tested as promising biomarkers for cancer diagnosis and prognosis, even as potential treatment targets for cancer. Moreover, different sources of exosomes exhibit multiple performances in cancer applications. In this review, we elaborate on the specific mechanism by which exosomes affect the communication between tumors and the microenvironment and state the therapeutic and diagnostic applications of exosomes in cancers.     

Tumor Escape Phenotype in Bladder Cancer Is Associated with Loss of HLA Class I Expression,T-Cell Exclusion and Stromal Changes

Cancer eradication and clinical outcome of immunotherapy depend on tumor cell immunogenicity, including HLA class I (HLA-I) and PD-L1 expression on malignant cells, and on the characteristics of the tumor microenvironment, such as tumor immune infiltration and stromal reaction. Loss of tumor HLA-I is a common mechanism of immune escape from cytotoxic T lymphocytes and is linked to cancer progression and resistance to immunotherapy with the inhibitors of PD-L1/PD-1 signaling. Here we observed that HLA-I loss in bladder tumors is associated with T cell exclusion and tumor encapsulation with stromal elements rich in FAP-positive cells. In addition, PD-L1 upregulation in HLA-I negative tumors demonstrated a correlation with high tumor grade and worse overall- and cancer-specific survival of the patients. These changes define common immuno-morphological signatures compatible with cancer immune escape and acquired resistance to therapeutic interventions across different types of malignancy. They also may contribute to the search of new targets for cancer treatment, such as FAP-expressing cancer-associated fibroblasts, in refractory bladder tumors.     

Cell Survival and Apoptosis Signaling as Therapeutic Target for Cancer: Marine Bioactive Compounds

Inhibition of apoptosis leads to activation of cell survival factors (e.g., AKT) causes continuous cell proliferation in cancer. Apoptosis, the major form of cellular suicide, is central to various physiological processes and the maintenance of homeostasis in multicellular organisms. A number of discoveries have clarified the molecular mechanism of apoptosis, thus clarifying the link between apoptosis and cell survival factors, which has a therapeutic outcome. Induction of apoptosis and inhibition of cell survival by anticancer agents has been shown to correlate with tumor response. Cellular damage induces growth arrest and tumor suppression by inducing apoptosis, necrosis and senescence; the mechanism of cell death depends on the magnitude of DNA damage following exposure to various anticancer agents. Apoptosis is mainly regulated by cell survival and proliferating signaling molecules. As a new therapeutic strategy, alternative types of cell death might be exploited to control and eradicate cancer cells. This review discusses the signaling of apoptosis and cell survival, as well as the potential contribution of marine bioactive compounds, suggesting that new therapeutic strategies might follow.     

Differentiation of Cancer Stem Cells by Using Synthetic Small Molecules: Toward New Therapeutic Strategies against Therapy Resistance

Despite the existing arsenal of anti-cancer drugs, 10 million people die each year worldwide due to cancers; this highlights the need to discover new therapies based on innovative modes of action against these pathologies. Current chemotherapies are based on the use of cytotoxic agents, targeted drugs, monoclonal antibodies or immunotherapies that are able to reduce or stop the proliferation of cancer cells. However, tumor eradication is often hampered by the presence of resistant cells called cancer stem-like cells or cancer stem cells (CSCs). Several strategies have been proposed to specifically target CSCs such as the use of CSC-specific antibodies, small molecules able to target CSC signaling pathways or drugs able to induce CSC differentiation rendering them sensitive to classical chemotherapy. These latter compounds are the focus of the present review, which aims to report recent advances in anticancer-differentiation strategies. This therapeutic approach was shown to be particularly promising for eradicating tumors in which CSCs are the main reason for therapeutic failure. This general view of the chemistry and mechanism of action of compounds inducing the differentiation of CSCs could be particularly useful for a broad range of researchers working in the field of anticancer therapies as the combination of compounds that induce differentiation with classical chemotherapy could represent a successful approach for future therapeutic applications.     

Pt(IV) Prodrugs with NSAIDs as Axial Ligands

A chemo-anti-inflammatory strategy is of interest for the treatment of aggressive cancers. The platinum (IV) prodrug with non-steroidal anti-inflammatory drugs (NSAIDs) as axial ligands is designed to efficiently enter tumor cells due to high lipophilicity and release the cytotoxic metabolite and NSAID intracellularly, thereby reducing side effects and increasing the therapeutic efficacy of platinum chemotherapy. Over the last 7 years, a number of publications have been devoted to the design of such Pt(IV) prodrugs in combination with anti-inflammatory chemotherapy, with high therapeutic efficacy in vitro and In vivo. In this review, we summarize the studies devoted to the development of Pt(IV) prodrugs with NSAIDs as axial ligands, the study of the mechanism of their cytotoxic action and anti-inflammatory activity, the structure–activity ratio, and therapeutic efficacy.     

Vasopressin Receptor Type-2 Mediated Signaling in Renal Cell Carcinoma Stimulates Stromal Fibroblast Activation

Vasopressin type-2 receptor (V2R) is ectopically expressed and plays a pathogenic role in clear cell renal cell carcinoma (ccRCC) tumor cells. Here we examined how V2R signaling within human ccRCC tumor cells (Caki1 cells) stimulates stromal cancer-associated fibroblasts (CAFs). We found that cell culture conditioned media from Caki1 cells increased activation, migration, and proliferation of fibroblasts in vitro, which was inhibited by V2R gene silencing in Caki1 cells. Analysis of the conditioned media and mRNA of the V2R gene silenced and control Caki1 cells showed that V2R regulates the production of CAF-activating factors. Some of these factors were also found to be regulated by YAP in these Caki1 cells. YAP expression colocalized and correlated with V2R expression in ccRCC tumor tissue. V2R gene silencing or V2R antagonist significantly reduced YAP in Caki1 cells. Moreover, the V2R antagonist reduced YAP expression and myofibroblasts in mouse xenograft tumors. These results suggest that V2R plays an important role in secreting pro-fibrotic factors that stimulate fibroblast activation by a YAP-dependent mechanism in ccRCC tumors. Our results demonstrate a novel role for the V2R-YAP axis in the regulation of myofibroblasts in ccRCC and a potential therapeutic target.     

Inhibition of the FGF/FGFR System Induces Apoptosis in Lung Cancer Cells via c-Myc Downregulation and Oxidative Stress

Lung cancer represents an extremely diffused neoplastic disorder with different histological/molecular features. Among the different lung tumors, non-small-cell lung cancer (NSCLC) is the most represented histotype, characterized by various molecular markers, including the expression/overexpression of the fibroblast growth factor receptor-1 (FGFR1). Thus, FGF/FGFR blockade by tyrosine kinase inhibitors (TKi) or FGF-ligand inhibitors may represent a promising therapeutic approach in lung cancers. In this study we demonstrate the potential therapeutic benefit of targeting the FGF/FGFR system in FGF-dependent lung tumor cells using FGF trapping (NSC12) or TKi (erdafitinib) approaches. The results show that inhibition of FGF/FGFR by NSC12 or erdafitinib induces apoptosis in FGF-dependent human squamous cell carcinoma NCI-H1581 and NCI-H520 cells. Induction of oxidative stress is the main mechanism responsible for the therapeutic/pro-apoptotic effect exerted by both NSC12 and erdafitinib, with apoptosis being abolished by antioxidant treatments. Finally, reduction of c-Myc protein levels appears to strictly determine the onset of oxidative stress and the therapeutic response to FGF/FGFR inhibition, indicating c-Myc as a key downstream effector of FGF/FGFR signaling in FGF-dependent lung cancers.