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51.
Shang-jun Tang Li-kun Chen Fang Wang Yun-kai Zhang Zhen-cong Huang Kenneth Kin Wah To Xiao-kun Wang Tanaji T. Talele Zhe-sheng Chen Wei-qiang Chen Li-wu Fu 《Biochemical pharmacology》2014
The overexpression of ATP-binding cassette (ABC) transporters often leads to the development of multidrug resistance (MDR), which is the major factor contributing to the failure of chemotherapy. The objective of this study was to investigate the enhancement of CEP-33779, a small-molecule inhibitor of Janus kinase 2 (JAK2), on the efficacy of conventional chemotherapeutic agents in MDR cells with overexpression of P-glycoprotein (ABCB1), multidrug resistance-associated protein 1 (ABCC1) and breast cancer resistance protein (ABCG2). Our results showed that CEP-33779, at nontoxic concentrations, significantly sensitized ABCB1 overexpressing MDR cells to its anticancer substrates. CEP-33779 significantly increased intracellular accumulation and decreased the efflux of doxorubicin by inhibiting the ABCB1 transport function. Furthermore, CEP-33779 did not alter the expression of ABCB1 both at protein and mRNA levels but did stimulate the activity of ABCB1 ATPase. CEP-33779 was predicted to bind within the large hydrophobic cavity of homology modeled ABCB1. In addition, the down-regulation of JAK2 by shRNA altered neither the expression of ABCB1 nor the cytotoxic effect of chemotherapeutic agents in ABCB1-overexpressing cells. Significantly, CEP-33779 enhanced the efficacy of vincristine against the ABCB1-overexpressing and drug resistant KBv200 cell xenograft in nude mice. In conclusion, we conclude that CEP-33779 enhances the efficacy of substrate drugs in ABCB1-overexpressing cells by directly inhibiting ABCB1 transport function. The findings encouraged to further study on the combination therapy of CEP-33779 with conventional chemotherapeutic agents in ABCB1 mediated-MDR cancer patients. 相似文献
52.
Objective: Colon cancer is one of the most common human malignancies. Cancer stem cells (CSCs), despite being only a small subset of cancer cells, have the capability to self-renew and sustain the tumor. They also have the ability to proliferate. Multiple CSCs-associated markers have been identified in colon cancer including CD133, ALDH1 and β-catenin. The aim of the work was to study the prognostic value of CSCs markers (CD133, ALDH 1 and β-catenin), as well as their rela- tionship to clinicopathological features of colon cancer. Methods: CD133, ALDH1 and β-catenin proteins expression was as- sessed immunohistochemically in a series of colon cancers and their prognostic significance was evaluated. Results: CD133 expression showed significant relationship to tumor stage and lymph node metastasis (P-value 0.004 & 〈 0.001 respectively), and near significant relationship to liver metastasis (P-value 0.092). ALDH1 was significantly associated with tumor grade, stage and nodal metastasis (P-value 0.021,0.001 and 0.026 respectively), but its relationship to liver metastasis was near sig- nificant (P-value 0.068). Nuclear β-catenin was significantly related to tumor grade, stage, nodal and liver metastasis (P-value 0.001, 〈 0.001, 〈 0.001 and 0.008 respectively). Overall survival (OS) was associated inversely with CD133, ALDH1 positivity, and directly with nuclear 13-catenin posiUvity (P-value 〈 0.001,0.0001 and 〈 0.001 respectively). Also recurrence free survival (RFS) was associated inversely with CD133, ALDH1 and directly with nuclearβ-catenin positivity (P-value 0.0001,0.001 and 〈 0.001 respectively). Conclusion: CD133, ALDH1 and β-catenin expressions of tumor cells have significant impact upon malignant progression of colon cancer and thus patient survival and tumor recurrence. Hence they can be used to predict outcome of colon cancer patients. 相似文献
53.
Yong Zhong Kaopeng Guan Chunxia Zhou Wenbo Ma Dongmei Wang Youhui Zhang Shuren Zhang 《Cancer letters》2010
Cancer stem cell (CSC) is generally believed to be a very small proportion of tumor cells capable of initiating and sustaining growth of the tumor. Its existence is usually demonstrated by xenotransplanting human cancer cells in immunodeficient mice. In this paper, we report that the growth of B16-F10 melanoma cells in syngeneic mice could be maintained by a relatively larger proportion (>10%) of tumor cells. The result of this study does not seem to support the current view that cancer stem cells (CSCs) responsible for the sustainable growth of tumor are rare. 相似文献
54.
Identification and characterization of tumorigenic liver cancer stem/progenitor cells 总被引:28,自引:0,他引:28
BACKGROUND & AIMS: Recent efforts in stem cell biology suggest that tumors are organized in a hierarchy of heterogeneous cell populations and that the capability to maintain tumor formation/growth specifically resides in a small population of cells called cancer stem cells (CSCs). The aim of this study is to identify, isolate, and characterize the CSC population that drives and maintains hepatocellular carcinoma (HCC) growth and metastasis. METHODS: Normal stem cells involved in liver regeneration were identified using a severe partial hepatectomy model. Purified HCC cells, with or without expression of the identified normal stem cell phenotype, were evaluated, based on their tumorigenic potential and exhibition of defined stem/progenitor cell-like properties, to determine whether liver CSCs can be or partly be identified by this surface marker. RESULTS: We report the identification and isolation of a population of CSCs expressing a CD133 surface phenotype from human liver cell lines. CD133(+) cells possess a greater colony-forming efficiency, higher proliferative output, and greater ability to form tumor in vivo. These cells are endowed with characteristics similar to those of progenitor cells including the expression of "stemness" genes, the ability to self-renew, and the ability to differentiate into nonhepatocyte-like lineages. Furthermore, CD133 is found to represent only a minority of the tumor cell population in human HCC specimens. CONCLUSIONS: We report the identification of a CSC population in HCC characterized by their CD133 phenotype. The identification of tumorigenic liver CSCs could provide new insight into the HCC tumorigenic process and possibly bear great therapeutic implications. 相似文献
55.
Suicide gene therapy is based on the introduction into tumor cells of a viral or a bacterial gene, which allows the conversion of a non-toxic compound into a lethal drug. Although suicide gene therapy has been successfully used in a large number of in vitro and in vivo studies, its application to cancer patients has not reached the desirable clinical significance. However, recent reports on pre-clinical cancer models demonstrate the huge potential of this strategy when used in combination with new therapeutic approaches. In this review, we summarize the different suicide gene systems and gene delivery vectors addressed to cancer, with particular emphasis on recently developed systems and associated bystander effects. In addition, we review the different strategies that have been used in combination with suicide gene therapy and provide some insights into the future directions of this approach, particularly towards cancer stem cell eradication. 相似文献
56.
NF‐κB‐regulated miR‐155, via repression of QKI,contributes to the acquisition of CSC‐like phenotype during the neoplastic transformation of hepatic cells induced by arsenite 下载免费PDF全文
57.
Komal N. Padhariya Maithili Athavale Sangeeta Srivastava Prashant S. Kharkar 《Drug development research》2021,82(1):68-85
An alarming increase in global death toll resulting from cancer incidents, particularly due to multidrug resistance and reduced efficacy as a consequence of target mutations, has compelled us to look for novel anticancer agents. Cancer stem cells (CSCs), contributing majorly to the chemoresistance and tumor relapse, seem to the main culprits. In the present investigation, new chemical entities (NCEs) belonging to four novel chemical series ( A : 4′‐allyl‐2′‐methoxyphenoxymethyl‐1,2,3‐triazoles; B : 4′‐acetamidophenoxymethyl‐1,2,3‐triazoles; C : naphthalene‐1′‐yloxymethyl‐1,2,3‐triazoles, and D : naphthalene‐2′‐yloxymethyl‐1,2,3‐triazoles) were synthesized via Copper (I)‐catalyzed alkyne‐azide cycloaddition reaction and evaluated for in vitro anticancer activity. A total of 30 NCEs ( 39–68 ) were screened at 10 μM concentration in cell viability assay against cancer cell lines such as breast (MDA‐MB‐231), prostate (PC‐3), glioma (U87 MG), along with cervical (SiHa) and lung (A549). The NCEs from Series C ( 56–60 ) and D ( 61–68 ) were more potent than those in Series A ( 39‐45 ) and Series B ( 46–55 ) at the tested concentration. Furthermore, NCEs with >80% inhibition at 10 μM were evaluated for dose response. A total of five NCEs, 48 , 56 , 61 , 65 and 66 , were further assessed in soft‐agar assay and found to be relatively potent (IC50 < 10 μM). Finally, the hits were screened in sphere assay to identify potential CSC inhibitors against mammospheres (MDA‐MB‐231) and prostatospheres (PC‐3). More so, the hits were also evaluated to understand in vitro cytotoxicity against normal cells using mouse embryonic fibroblast cell line (NIH/3T3) and human peripheral blood mononuclear cells (hPBMCs). Overall, hits 56 and 61 exhibited potent anticancer as well as CSC inhibitory activities with notably less toxicity toward NIH/3T3 and hPBMCs. On the whole, our arduous study led to the identification of potential hits with anticancer and CSC inhibitory activities, with minimal or no toxicity to normal cells. 相似文献
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59.
Shakti Ranjan Satapathy Anmada Nayak Sumit Siddharth Sarita Das Deepika Nayak Chanakya Nath Kundu 《Nanomedicine : nanotechnology, biology, and medicine》2018,14(3):883-896
Complete eradication of aggressive oral cancer remains a challenge due to the presence of CSCs. They resist conventional chemotherapeutic agents due to their self-renewal, drug efflux, and efficient DNA repair capacity. Here, we formulated a hybrid-nanoparticle (QAuNP) using quinacrine and gold and characterized/investigated its anti-angiogenic and anti-metastatic effect on OSCC-CSCs. QAuNP significantly inhibited cellular proliferation, caused apoptosis in vitro, and disrupted angiogenesis in vivo and tumor regression in xenograft mice model. It not only inhibited crucial angiogenic markers Ang-1, Ang-2 and VEGF but also depleted MMP-2 in H-357-PEMT cells in a p53 and p21-dependent manner. QAuNP also increased the ROS and NO generation in OSCC-CSCs and reduced the mitochondrial membrane potential. It altered the level of inflammatory cytokines IL-6, IL-1β, TNF-α and metastasis-associated markers (CD-44, CD-133) in H-357-PEMT and CM-treated endothelial cells (HUVEC) in p53/p21-dependent manner. Therefore, QAuNP will be a useful therapeutic agent against metastatic OSCC. 相似文献
60.
Yang F Jin C Subedi S Lee CL Wang Q Jiang Y Li J Di Y Fu D 《Cancer treatment reviews》2012,38(6):566-579
Pancreatic cancer is a devastating disease with incidence increasing at an alarming rate and survival not improved substantially during the past three decades. Although enormous efforts have been made in early detection and comprehensive treatment for this disease, little or no survival improvement was obtained, which necessitates the development of novel strategies. Emerging inorganic nanomaterials, such as carbon nanotubes, quantum dots, mesoporous silica/gold/supermagnetic nanoparticles, have been widely used in biomedical research with great optimism for cancer diagnosis and therapy. Such nanoparticles possess unique optical, electrical, magnetic and/or electrochemical properties. With such properties along with their impressive nano-size, these particles can be targeted to cancer cells, tissues, and ligands efficiently and monitored with extreme precision in real-time. In additional to liposome, dendrimer, and polymeric nanoparticles, they are considered the most promising nanomaterials with the capability of both cancer detection and multimodality treatment. Emerging approaches to harness nanotechnology to optimize the existing diagnostic and therapeutic tools for pancreatic cancer have been extensively explored during the recent years. Future options for early detection, individual therapy and monitoring responses of pancreatic cancer are focused on multifunctional nanomedicine. In this review, we present the recent development of clinically applicable inorganic nanoparticles, with focus on the diagnosis and treatment of pancreatic cancer. Furthermore, their advantages in theranostic nanomedicine, and challenges of translation to clinical practice, are discussed. 相似文献