盐霉素抗肿瘤作用研究进展

盐霉素(salinomycin)特异性杀伤肿瘤干细胞(cancer stem cell,CSC)作用的发现,引起了国内外学者的广泛关注.最近的研究表明,盐霉素能高选择性杀死小鼠身上的人乳腺癌CSC并且其效力比紫杉醇高100倍.盐霉素这种靶向作用于CSC的能力及较好的成药性,使其具有研发为一种新型的抗癌药物的潜能.通过手术及术后化疗抗癌的传统方法已经难以对抗肿瘤的复发或转移.然而,利用离子型载体抗生素即盐霉素杀伤肿瘤干细胞这一特性,消除肿瘤复发与转移的”根源”,从而达到治愈”癌症”这一顽疾的目的在理论上是可行的.多项研究已证实盐霉素能对抗多种肿瘤干细胞,因此我们认为盐霉素是一种广谱抗肿瘤药物,这些结论将推动临床抗肿瘤研究进入一个崭新的阶段,为防癌治癌工作提供实验依据和新的思路.本文将系统阐述盐霉素抗肿瘤药效学及其作用机制的研究进展,以期为后续临床研发抗癌新化合物提供参考.     

生物标记物与精准医疗研究进展

自2015年精准医疗理念提出后,生物标记物与精准医疗愈加被人们重视。并被广泛应用于病毒、癌症等重大疾病的筛查与治疗研究中。新兴循环生物标记物的应用与开发,在HBV、HPV的检测和肿瘤的靶向药物治疗、细胞治疗、免疫抑制剂、癌症疫苗开发方向上都取得了重大成果。与传统的医疗方法相比,生物标记物为辅助精准医疗的检测治疗模式,无论是在研发还是治疗上都有着显著的优势。因此,综述了生物标记物与精准医疗的应用,并就最近的研究报告重点综述了生物标记物与精准医疗的最新研究进展。     

Salinomycin induces apoptosis and overcomes apoptosis resistance in human cancer cells

Salinomycin is a polyether antibiotic isolated from Streptomyces albus that acts in different biological membranes as a ionophore with a preference for potassium. It is widely used as an anticoccidial drug in poultry and is fed to ruminants to improve nutrient absorption and feed efficiency. Salinomycin has recently been shown to selectively deplete human breast cancer stem cells from tumorspheres and to inhibit breast cancer growth and metastasis in mice. We show here that salinomycin induces massive apoptosis in human cancer cells of different origin, but not in normal cells such as human T lymphocytes. Moreover, salinomycin is able to induce apoptosis in cancer cells that exhibit resistance to apoptosis and anticancer agents by overexpression of Bcl-2, P-glycoprotein or 26S proteasomes with enhanced proteolytic activity. Salinomycin activates a distinct apoptotic pathway that is not accompanied by cell cycle arrest and that is independent of tumor suppressor protein p53, caspase activation, the CD95/CD95L system and the proteasome. Thus, salinomycin should be considered as a novel and effective anticancer agent that overcomes multiple mechanisms of apoptosis resistance in human cancer cells.     

Purification and characterization of a novel anticancer peptide derived from Ruditapes philippinarum

The aim of this study was to purify a novel peptide from Ruditapes philippinarum and investigate its anticancer activities. For the aim, eight proteases were applied for enzymatic hydrolysis. α-Chymotrypsin hydrolyzates, which showed clearly superior cytotoxicity activity on prostate cancer cells, were further purified using a flow filtration system and consecutive chromatographic methods. Finally, a novel anticancer peptide was purified, and the sequence was identified as Ala-Val-Leu-Val-Asp-Lys-Gln-Cys-Pro-Asp at N-terminal. The peptide from R. philippinarum effectively induced apoptosis on prostate, breast and lung cancer cells but not on normal liver cells. This is the first report of an anticancer peptide purified from the hydrolyzates of R. philippinarum.     

Mechanisms of autophagy and apoptosis: Recent developments in breast cancer cells

Autophagy,the pathway whereby cell components are degraded by lysosomes,is involved in the cell response to environmental stresses,such as nutrient deprivation,hypoxia or exposition to chemotherapeutic agents.Under these conditions,which are reminiscent of certain phases of tumor development,autophagy either promotes cell survival or induces cell death. This strengthens the possibility that autophagy could be an important target in cancer therapy,as has been proposed.Here,we describe the regulation of survival and death by autophagy and apoptosis,especially in cultured breast cancer cells.In particular,we discuss whether autophagy represents an apoptosis-independent process and/or if they share common pathways. We believe that understanding in detail the molecular mechanisms that underlie the relationships between autophagy and apoptosis in breast cancer cells could improve the available treatments for this disease.     

肿瘤相关间充质干细胞及其靶向治疗的研究进展

间充质干细胞（MSCs）存在于许多组织中,在组织出现损伤时会迁移到受伤部位进行修复。而癌症可以被看作是\"永远不会愈合的伤口\",在肿瘤微环境中MSCs会被持续募集成为肿瘤微环境的一部分。最近出现了一种肿瘤相关间充质干细胞（TA-MSCs）,它可以激活肿瘤的发生,促进肿瘤的发展与转移。本文讨论了MSCs与TA-MSCs之间的关系;探讨对TA-MSCs的最新认识及其调节癌细胞生存、增殖、迁移与耐药能力。而且,讨论了把TA-MSCs作为癌症治疗上游或者下游的靶点或者用MSCs做载体来传递癌症因子将会发展为癌症治疗的新手段。     

Cancer stem cell hypothesis: a brief summary and two proposals

The investigation and development of the cancer stem cell (CSC) model has received much focus during these years. CSC is characterized as a small fraction of cancer cells that have an indefinite ability for self-renewal and pluripotency and are responsible for initiating and sustaining of the bulk of cancer. So, whether current treatment strategies, most of which target the rapid division of cancer cells, could interfere with the slow-cycling CSCs is broadly questioned. Meanwhile, however, the new understanding of tumorigenesis has led to the development of new drug screening strategies. Both stem cells and mesenchymal stem cells have been vigorously used in pre-clinical studies of their anti-tumor potential, mainly due to their inherent tumoritropic migratory properties and their ability to carry anti-tumor transgenes. Here, based on the tumorigenic and tumoritropic characteristics of CSCs, we proposed two hypotheses exploring possible usage of CSCs as novel anti-tumor agents and potential sources for tissue regeneration. Further experimental validation of these hypotheses may unravel some new research topics.     

Thoughts about cancer stem cells in solid tumors

Cancer chemotherapy efficacy is frequently impaired by either intrinsic or acquired tumor resistance.A fundamental problem in cancer research is identifying the cell type that is capable of sustaining neoplastic growth and its origin from normal tissue cells.In recent years,the cancer stem cell(CSC) theory has changed the classical view of tumor growth and therefore the therapeutic perspective.Overcoming intrinsic and acquired resistance of cancer stem/progenitor cells to current clinical treatments represents a major challenge in treating and curing the most aggressive and metastatic cancers.On the other hand,the identification of CSCs in vivo and in vitro relies on specific surface markers that should allow the sorting cancer cells into phenotypically distinct subpopulations.In the present review,recent papers published on CSCs in solid tumors(breast,prostate,brain and melanoma) are discussed,highlighting critical points such as the choice of markers to sort CSCs and mouse models to demonstrate that CSCs are able to replicate the original tumor.A discussion of the possible role of aldehyde dehydrogenase and CXCR6 biomarkers as signaling molecules in CSCs and normal stem cells is also discussed.The author believes that efforts have to be made to investigate the functional and biological properties of putative CSCs in cancer.Developing diagnostic/prognostic tools to follow cancer development is also a challenge.In this connection it would be useful to develop a multidisciplinary approach combining mathematics,physics and biology which merges experimental approaches and theory.Biological models alone are probably unable to resolve the problem completely.     

肿瘤中与survivin有关的信号通路及分子以及靶向survivin的治疗前景

Survivin在细胞内环境稳定和肿瘤的形成中起重要的作用,在肿瘤的治疗中,survivivin的靶向治疗调节与一些典型的信号通路和一系列生长因子有关。众所周知,survivin是一个小的凋亡蛋白抑制因子,也是一个主要的抗癌靶标,与细胞分裂和凋亡抑制有关,它在大部分正常组织中缺失但在大部分癌组织中过表达。Survivin是一个与众多细胞信号通路有关的节点蛋白,这些通路协调各种细胞因子、转录网络和修饰基因,通过调节癌细胞内环境稳定直接或间接促进细胞增殖。临床前研究数据表明,survivin的抑制可以降低细胞增殖促进凋亡,增加细胞对细胞毒药物和放疗的敏感性,其过表达与不良预后和治疗耐受有关。因此对于癌症治疗,survivin是一个潜在的靶标。     

DNA-PKcs: A promising therapeutic target in human hepatocellular carcinoma?

Hepatocellular carcinoma (HCC) is a frequent and deadly disease worldwide. The absence of effective therapies when the tumor is surgically unresectable leads to an extremely poor outcome of HCC patients. Thus, it is mandatory to elucidate the molecular pathogenesis of HCC in order to develop novel therapeutic strategies against this pernicious tumor. Mounting evidence indicates that suppression of the DNA damage response machinery might be deleterious for the survival and growth of the tumor cells. In particular, DNA dependent protein kinase catalytic subunit (DNA-PKcs), a major player in the non-homologous end-joining (NHEJ) repair process, seems to represent a valuable target for innovative anti-neoplastic therapies in cancer. DNA-PKcs levels are strongly upregulated and associated with a poor clinical outcome in various tumor types, including HCC. Importantly, DNA-PKcs not only protects tumor cells from harmful DNA insults coming either from the microenvironment or chemotherapeutic drug treatments, but also possesses additional properties, independent from its DNA repair activity, that provide growth advantages to cancer cells. These properties (metabolic and gene reprogramming, invasiveness and metastasis, resistance to apoptosis, etc.) have started to be elucidated. In the present review, we summarize the physiologic and oncogenic roles of DNA-PKcs, with a special emphasis on liver cancer. In particular, this work focuses on the molecular mechanism whereby DNA-PKcs exerts its pro-tumorigenic activity in cancer cells. In addition, the upstream regulator of DNA-PKcs activation as well as its downstream effectors thus far identified are illustrated. Furthermore, the potential therapeutic strategies aimed at inhibiting DNA-PKcs activity in HCC are discussed.     

Ovarian cancer stem cells: Can targeted therapy lead to improved progression-free survival?

Despite significant effort and research funds, epithelial ovarian cancer remains a very deadly disease. There are no effective screening methods that discover early stage disease; the majority of patients are diagnosed with advanced disease. Treatment modalities consist primarily of radical debulking surgery followed by taxane and platinum-based chemotherapy. Newer therapies including limited targeted agents and intraperitoneal delivery of chemotherapeutic drugs have improved disease-free intervals, but failed to yield longlasting cures in most patients. Chemotherapeutic resistance, particularly in the recurrent setting, plagues the disease. Targeting the pathways and mechanisms behind the development of chemoresistance in ovarian cancer could lead to significant improvement in patient outcomes. In many malignancies, including blood and other solid tumors, there is a subgroup of tumor cells, separate from the bulk population, called cancer stem cells(CSCs). These CSCs are thought to be the cause of metastasis, recurrence and resistance. However, todate, ovarian CSCs have been difficult to identify, isolate, and target. It is felt by many investigators that finding a putative ovarian CSC and a chemotherapeutic agent to target it could be the key to a cure for this deadly disease. This review will focus on recent advances in this arena and discuss some of the controversies surrounding the concept.