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Zhang J, Yang XY, Chen J, Zhou Q, Pan G, Wang Y, Luo W, Hou J, Bao H, Xu G, Tang G, Bai H, Yu R. A Poly(amino acid)-Based Nanomedicine Strategy: Telomere-Telomerase Axis Targeting and Magnetic Resonance Imaging in Hepatocellular Carcinoma Treatment. NANO LETTERS 2024; 24:8351-8360. [PMID: 38916238 DOI: 10.1021/acs.nanolett.4c01767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
Targeting telomere maintenance has emerged as a promising strategy for hepatocellular carcinoma (HCC) treatment. However, given the duality of the telomere-telomerase axis in telomere maintenance, a comprehensive strategy is urgently needed. Herein, we develop a poly(amino acid) (D-PAAs)-based strategy for spatiotemporal codelivery of telomerase inhibitor, BIBR1523, and AKT inhibitor, isobavachalcone. By leveraging D-PAAs' modifiability, we synthesize polymer-inhibitor conjugates (PB and PI) and a folic acid-decorated tumor-targeting vector (PF). These building blocks undergo micellization to fabricate a codelivery nanomedicine (P-BI@P-FA) by exploiting D-PAAs' noncovalent assembly. P-BI@P-FA improves the pharmacokinetics, tumor selectivity, and bioavailability of small molecule inhibitors and initiates a dual telomere-specific inhibition by combining telomerase deactivation with telomere disruption. Furthermore, a hybrid tumor-targeting magnetic nanosystem is designed using D-PAAs and manganese dioxide to showcase magnetic resonance imaging capacities. Our D-PAAs-based strategy addresses the pressing need for telomere-specific HCC treatment while allowing for diagnostic application, presenting a promising avenue for nanomedicine design.
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Affiliation(s)
- Jinguo Zhang
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, People's Republic of China
| | - Xiao-Yan Yang
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, People's Republic of China
| | - Jiayi Chen
- Department of Chemistry, Zhejiang University, Hangzhou 310028, People's Republic of China
| | - Qiaomei Zhou
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, People's Republic of China
| | - Guohua Pan
- Department of Chemistry, Zhejiang University, Hangzhou 310028, People's Republic of China
| | - Yining Wang
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, People's Republic of China
| | - Wangping Luo
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, People's Republic of China
| | - Jue Hou
- Department of Chemistry, Zhejiang University, Hangzhou 310028, People's Republic of China
| | - Hanxiao Bao
- Department of Chemistry, Zhejiang University, Hangzhou 310028, People's Republic of China
| | - Guoqiao Xu
- Department of Chemistry, Zhejiang University, Hangzhou 310028, People's Republic of China
| | - Guping Tang
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, People's Republic of China
- Department of Chemistry, Zhejiang University, Hangzhou 310028, People's Republic of China
| | - Hongzhen Bai
- Department of Chemistry, Zhejiang University, Hangzhou 310028, People's Republic of China
| | - Risheng Yu
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, People's Republic of China
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Ouyang R, Liu J, Wang S, Zhang W, Feng K, Liu C, Liu B, Miao Y, Zhou S. Virtual Screening-Based Study of Novel Anti-Cancer Drugs Targeting G-Quadruplex. Pharmaceutics 2023; 15:pharmaceutics15051414. [PMID: 37242656 DOI: 10.3390/pharmaceutics15051414] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 04/19/2023] [Accepted: 04/25/2023] [Indexed: 05/28/2023] Open
Abstract
In order to develop new anti-cancer drugs more efficiently and reduce side effects based on active drug targets, the virtual drug screening was carried out through the target of G-quadruplexes and 23 hit compounds were, thus, screened out as potential anticancer drugs. Six classical G-quadruplex complexes were introduced as query molecules, and the three-dimensional similarity of molecules was calculated by shape feature similarity (SHAFTS) method so as to reduce the range of potential compounds. Afterwards, the molecular docking technology was utilized to perform the final screening followed by the exploration of the binding between each compound and four different structures of G-quadruplex. In order to verify the anticancer activity of the selected compounds, compounds 1, 6 and 7 were chosen to treat A549 cells in vitro, the lung cancer epithelial cells, for further exploring their anticancer activity. These three compounds were found to be of good characteristics in the treatment of cancer, which revealed the great application prospect of the virtual screening method in developing new drugs.
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Affiliation(s)
- Ruizhuo Ouyang
- Institute of Bismuth and Rhenium Science, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Jinyao Liu
- Institute of Bismuth and Rhenium Science, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Shen Wang
- Institute of Bismuth and Rhenium Science, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Weilun Zhang
- Institute of Bismuth and Rhenium Science, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Kai Feng
- Institute of Bismuth and Rhenium Science, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Conghao Liu
- Institute of Bismuth and Rhenium Science, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Baolin Liu
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Yuqing Miao
- Institute of Bismuth and Rhenium Science, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Shuang Zhou
- Cancer Institute, Tongji University School of Medicine, Shanghai 200092, China
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3
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Morshedi K, Borran S, Ebrahimi MS, Masoud Khooy MJ, Seyedi ZS, Amiri A, Abbasi-Kolli M, Fallah M, Khan H, Sahebkar A, Mirzaei H. Therapeutic effect of curcumin in gastrointestinal cancers: A comprehensive review. Phytother Res 2021; 35:4834-4897. [PMID: 34173992 DOI: 10.1002/ptr.7119] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/18/2021] [Accepted: 03/26/2021] [Indexed: 12/11/2022]
Abstract
Gastrointestinal (GI) cancers with a high global prevalence are a leading cause of morbidity and mortality. Accordingly, there is a great need to develop efficient therapeutic approaches. Curcumin, a naturally occurring agent, is a promising compound with documented safety and anticancer activities. Recent studies have demonstrated the activity of curcumin in the prevention and treatment of different cancers. According to systematic studies on curcumin use in various diseases, it can be particularly effective in GI cancers because of its high bioavailability in the gastrointestinal tract. Nevertheless, the clinical applications of curcumin are largely limited because of its low solubility and low chemical stability in water. These limitations may be addressed by the use of relevant analogues or novel delivery systems. Herein, we summarize the pharmacological effects of curcumin against GI cancers. Moreover, we highlight the application of curcumin's analogues and novel delivery systems in the treatment of GI cancers.
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Affiliation(s)
- Korosh Morshedi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Sarina Borran
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | | | - Zeynab Sadat Seyedi
- Department of Cell and Molecular Biology, Faculty of Chemistry, University of Kashan, Kashan, Iran
| | - Atefeh Amiri
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Abbasi-Kolli
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Maryam Fallah
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan, Pakistan
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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Wu Y, Zhong D, Li Y, Wu H, Xu X, Yang J, Gu Z. Tumor-Oriented Telomerase-Terminated Nanoplatform as Versatile Strategy for Multidrug Resistance Reversal in Cancer Treatment. Adv Healthc Mater 2020; 9:e1901739. [PMID: 32125789 DOI: 10.1002/adhm.201901739] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 02/08/2020] [Accepted: 02/10/2020] [Indexed: 02/05/2023]
Abstract
Multidrug resistance is one of the major problems in chemotherapy, and exploiting impactful targets to reverse drug resistance of most tumors remains a difficult problem. In this study, the tumor-oriented nanoparticle, BIBR1532-loaded peptide dendrimeric prodrug nanoassembly (B-PDPN), is used to assist telomerase inhibition for multidrug resistance reversal. B-PDPN possesses the characteristics of an acid-activated histidine to promote cellular uptake, a redox-sensitive poly(ethylene glycol) (PEG) layer to actualize endosomal escape and telomerase inhibitor release, and an acid sensitive chemical bond to facilitate chemotherapeutic drug release. Telomerase termination weakens the protective effect of hTERT protein on mitochondria and enhances reactive oxygen species (ROS) production, which increases DNA damage and apoptosis. The tumor-oriented nanoparticle B-PDPN achieves a broad-spectrum telomerase inhibition to combat multidrug resistance. In vivo experiments support the evidence that B-PDPN accumulates in the tumor site and reduces the expression of hTERT in tumor tissues to inhibit drug resistant tumor growth. This work introduces an innovative strategy of utilizing features of tumor-activated nanoplatform to assist telomerase termination. The nanoplatform enhances intracellular drug concentration and nucleus delivery of doxorubicin (DOX), and promotes DNA damage to combat multidrug resistance.
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Affiliation(s)
- Yahui Wu
- Huaxi MR Research Center (HMRRC)Department of RadiologyFunctional and Molecular Imaging Key Laboratory of Sichuan ProvinceWest China Hospital, and National Engineering Research Center for BiomaterialsSichuan University Chengdu 610041 P. R. China
- College of Life SciencesSichuan University Chengdu 610064 P. R. China
| | - Dan Zhong
- Huaxi MR Research Center (HMRRC)Department of RadiologyFunctional and Molecular Imaging Key Laboratory of Sichuan ProvinceWest China Hospital, and National Engineering Research Center for BiomaterialsSichuan University Chengdu 610041 P. R. China
| | - Yachao Li
- Huaxi MR Research Center (HMRRC)Department of RadiologyFunctional and Molecular Imaging Key Laboratory of Sichuan ProvinceWest China Hospital, and National Engineering Research Center for BiomaterialsSichuan University Chengdu 610041 P. R. China
| | - Huayu Wu
- Huaxi MR Research Center (HMRRC)Department of RadiologyFunctional and Molecular Imaging Key Laboratory of Sichuan ProvinceWest China Hospital, and National Engineering Research Center for BiomaterialsSichuan University Chengdu 610041 P. R. China
| | - Xianghui Xu
- College of Materials Science and EngineeringNanjing Tech University Nanjing 211816 P. R. China
| | - Jun Yang
- The Key Laboratory of Bioactive MaterialsMinistry of EducationCollege of Life ScienceNankai University Tianjin 300071 P. R. China
| | - Zhongwei Gu
- Huaxi MR Research Center (HMRRC)Department of RadiologyFunctional and Molecular Imaging Key Laboratory of Sichuan ProvinceWest China Hospital, and National Engineering Research Center for BiomaterialsSichuan University Chengdu 610041 P. R. China
- College of Materials Science and EngineeringNanjing Tech University Nanjing 211816 P. R. China
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Garg C, Sharma AK, Gupta A, Kumar P. Anisamido-Polyethylenimines as Efficient Nonviral Vectors for the Transport of Plasmid DNA to Sigma Receptor-Bearing Cells In Vitro. J Pharm Sci 2018; 108:1552-1558. [PMID: 30513318 DOI: 10.1016/j.xphs.2018.11.037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Revised: 10/24/2018] [Accepted: 11/27/2018] [Indexed: 01/31/2023]
Abstract
Site-specific delivery of therapeutics promises better outcomes in the treatment of diseases. A small ligand, anisamide, has been shown to specifically bind sigma receptors highly overexpressed on prostate cancer cells, one of the leading cancers causing deaths worldwide. Here, anisamide-tethered polyethylenimine polymers (AP) have been synthesized and evaluated for their capability to transport nucleic acid across the cell membrane. A series of modified polymers (AP-1 to AP-4) was synthesized, physicochemically characterized, and evaluated for their transfection efficiency and cytotoxicity. Postconjugation, there was a marginal decrease in the buffering capacity; however, it did not diminish the ultimate objective of the study rather improved the transfection efficiency and decreased the cytotoxicity making these polymers as efficient and safe vectors for nucleic acid delivery. All the modified polymers displayed enhanced capability to deliver DNA inside the cells. Among the series, the modified polymer, AP-4 (10% attempted substitution), exhibited the highest transfection in HEK293 cells having abundant sigma receptors with minimal cytotoxicity. The projected polymer also showed complete protection of bound DNA against enzymatic degradation. Altogether, the results demonstrated targeting ability of the proposed polymers to deliver nucleic acid to sigma receptor-bearing cells in vitro.
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Affiliation(s)
- Charu Garg
- Nucleic Acids Research Laboratory, CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi 110007, India; Department of Chemistry, Dyal Singh College, University of Delhi, Lodhi Road, New Delhi 110003, India
| | - Ashwani Kumar Sharma
- Nucleic Acids Research Laboratory, CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi 110007, India
| | - Alka Gupta
- Department of Chemistry, Dyal Singh College, University of Delhi, Lodhi Road, New Delhi 110003, India.
| | - Pradeep Kumar
- Nucleic Acids Research Laboratory, CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi 110007, India.
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Shariati M, Hajigholami S, Malekshahi ZV, Entezari M, Bodaghabadi N, Sadeghizadeh M. Nanocurcumin-Mediated Down-Regulation of Telomerase Via Stimulating TGFβ1 Signaling Pathway in Hepatocellular Carcinoma Cells. IRANIAN BIOMEDICAL JOURNAL 2018; 22:171-179. [PMID: 28992682 PMCID: PMC5889502 DOI: 10.22034/ibj.22.3.171] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Revised: 08/09/2017] [Accepted: 09/10/2017] [Indexed: 01/30/2023]
Abstract
BACKGROUND Curcumin, extracted from turmeric, represents enormous potential to serve as an anticancer agent. Telomerase is viewed as a prominent molecular target of curcumin, and Transforming growth factor-β1 (TGFβ1) has proven to be a major inhibitory signaling pathway for telomerase activity. In the current study, we aimed to explore suppressive effects of nanocurcumin on telomerase expression through TGFβ1 pathway in a hepatocellular carcinoma cell line (Huh7). METHODS MTT assay was used to determine the effect of nonocurcumin on viability of Huh7 cells. RT-PCR was used to analyze the gene expression patterns. RESULTS MTT assay revealed that nanocurcumin acts in a dose- and time-dependent manner to diminish the cell viability. RT-PCR analysis indicated that nanocurcumin results in augmentation of TGFβ1 72 hours post treatment and leads to the reduction of telomerase expression 48 and 72 hours post exposure. Also, up-regulation of Smad3 and E2F1 and down-regulation of Smad7 confirmed the effect of nanocurcumin on intermediate components of TGFβ1 pathway. Furthermore, transfection of the proximal promoter of telomerase triggered a significant reduction in luciferase activity. CONCLUSION The data from the present study lead us to develop a deeper understanding of the mechanisms underlying nanocurcumin-mediated regulation of telomerase expression, thereby presenting a new perspective to the landscape of using nanocurcumin as a cancer-oriented therapeutic agent.
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Affiliation(s)
- Molood Shariati
- Department of Molecular Genetics, School of Biological Sciences, Tarbiat Modares University, P.O. Box 14115-154, Tehran, Iran
| | - Samira Hajigholami
- Department of Molecular Genetics, School of Biological Sciences, Tarbiat Modares University, P.O. Box 14115-154, Tehran, Iran
| | - Ziba Veisi Malekshahi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Maliheh Entezari
- Department of Biology, Islamic Azad University, Tehran Medical Sciences Branch, Tehran, Iran
| | - Narges Bodaghabadi
- Department of Molecular Genetics, School of Biological Sciences, Tarbiat Modares University, P.O. Box 14115-154, Tehran, Iran
| | - Majid Sadeghizadeh
- Department of Molecular Genetics, School of Biological Sciences, Tarbiat Modares University, P.O. Box 14115-154, Tehran, Iran
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Blasco V, Cuñat AC, Sanz-Cervera JF, Marco JA, Falomir E, Murga J, Carda M. Arylureas derived from colchicine: Enhancement of colchicine oncogene downregulation activity. Eur J Med Chem 2018; 150:817-828. [DOI: 10.1016/j.ejmech.2018.03.039] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 03/01/2018] [Accepted: 03/13/2018] [Indexed: 02/07/2023]
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Genetic variants in TERT are associated with risk of gastric cancer in a Chinese Han population. Oncotarget 2018; 7:82727-82732. [PMID: 27825130 PMCID: PMC5347727 DOI: 10.18632/oncotarget.13102] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2016] [Accepted: 09/16/2016] [Indexed: 01/15/2023] Open
Abstract
Telomerase reverse transcriptase (TERT) is a gene within the cancer susceptibility region located at Chr5p15.33, which is associated with multiple cancer types. In this study, we validated the association between TERT polymorphisms and gastric cancer (GC) risk with a case-control study in a Chinese Han population. A total of 302 GC patients and 300 control individuals were recruited. We identified three single nucleotide polymorphisms (SNPs) in TERT that were associated with GC. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in logistic regression models after adjusting for age and gender to assess the association. The minor alleles of three SNPs were associated with increased GC risk inallelic model analysis. For two of the SNPs, rs10069690 and rs2853676,, the dominant and additive model frequencies were higher in GC cases compared to controls. Further haplotype analysis revealed a protective effect of haplotype “CG” of the TERT gene, while the haplotype “TA” increased GC risk.Our resultsprovide new evidence for the association between TERT and GC susceptibility in the Chinese Han population.
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9
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Rajczak E, Pecoraro VL, Juskowiak B. Sm(iii)[12-MCGa(III)shi-4] as a luminescent probe for G-quadruplex structures. Metallomics 2017; 9:1735-1744. [DOI: 10.1039/c7mt00232g] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The luminescent anionic metallacrown Sm12-MC-4 exhibits similarity in shape and size to the guanine tetrad and is able to form complexes with G-quadruplex assembly.
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Affiliation(s)
- Ewa Rajczak
- Faculty of Chemistry
- Adam Mickiewicz University in Poznan
- 61-614 Poznan
- Poland
| | | | - Bernard Juskowiak
- Faculty of Chemistry
- Adam Mickiewicz University in Poznan
- 61-614 Poznan
- Poland
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10
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Sneider A, VanDyke D, Paliwal S, Rai P. Remotely Triggered Nano-Theranostics For Cancer Applications. Nanotheranostics 2017; 1:1-22. [PMID: 28191450 PMCID: PMC5298883 DOI: 10.7150/ntno.17109] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 10/16/2016] [Indexed: 01/02/2023] Open
Abstract
Nanotechnology has enabled the development of smart theranostic platforms that can concurrently diagnose disease, start primary treatment, monitor response, and, if required, initiate secondary treatments. Recent in vivo experiments demonstrate the promise of using theranostics in the clinic. In this paper, we review the use of remotely triggered theranostic nanoparticles for cancer applications, focusing heavily on advances in the past five years. Remote triggering mechanisms covered include photodynamic, photothermal, phototriggered chemotherapeutic release, ultrasound, electro-thermal, magneto-thermal, X-ray, and radiofrequency therapies. Each section includes a brief overview of the triggering mechanism and summarizes the variety of nanoparticles employed in each method. Emphasis in each category is placed on nano-theranostics with in vivo success. Some of the nanotheranostic platforms highlighted include photoactivatable multi-inhibitor nanoliposomes, plasmonic nanobubbles, reduced graphene oxide-iron oxide nanoparticles, photoswitching nanoparticles, multispectral optoacoustic tomography using indocyanine green, low temperature sensitive liposomes, and receptor-targeted iron oxide nanoparticles loaded with gemcitabine. The studies reviewed here provide strong evidence that the field of nanotheranostics is rapidly evolving. Such nanoplatforms may soon enable unique advances in the clinical management of cancer. However, reproducibility in the synthesis procedures of such "smart" platforms that lend themselves to easy scale-up in their manufacturing, as well as the development of new and improved models of cancer that are more predictive of human responses, need to happen soon for this field to make a rapid clinical impact.
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Affiliation(s)
| | | | | | - Prakash Rai
- ✉ Corresponding author: Prakash Rai, Phone 978-934-4971,
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Merghoub N, El Btaouri H, Benbacer L, Gmouh S, Trentesaux C, Brassart B, Attaleb M, Madoulet C, Wenner T, Amzazi S, Morjani H, El Mzibri M. Tomentosin Induces Telomere Shortening and Caspase-Dependant Apoptosis in Cervical Cancer Cells. J Cell Biochem 2016; 118:1689-1698. [PMID: 27922187 DOI: 10.1002/jcb.25826] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Accepted: 11/30/2016] [Indexed: 12/23/2022]
Abstract
Tomentosin, a natural sesquiterpene lactone purified from of Inula viscosa L., was investigated for its anti-proliferative, telomere shortening, and apoptotic effects on human cervical cancer HeLa and SiHa cell lines. Tomentosin was found to inhibit the growth of SiHa and HeLa cell lines in dose and time-dependent manner (IC50 values of 7.10 ± 0.78 μM and 5.87 ± 0.36 μM, respectively after 96 h of treatment). As evidenced by TTAGGG telomere length assay, tomentosin target specifically the telomeric overhang lengthening. This was confirmed by the evaluation of the cytotoxic effects of tomentosin in the foetal fibroblast Wi38 and JW10 cells which were derived from Wi38 and express hTERT, the telomerase catalytic subunit. We found that JW10 cells are 4.7-fold more sensitive to tomentosin which argues for telomere as its specific target. Furthermore, we found that tomentosin mediate this cytotoxic effect by inducing apoptosis and cell cycle arrest at G2/M phase. Morphological features of treated cells, as evidenced by Hoechst 33324 staining, revealed that the cytotoxic effect was due to induction of apoptosis. This was accompanied by pro-caspase-3 cleavage, an increase in caspase-3 activity and a cleavage of poly (ADP-ribose) polymerase (PARP). Moreover, tomentosin induced a decrease in mitochondrial membrane potential (ΔΨm) and an increase in reactive oxygen species (ROS), accompanied by a decrease in Bcl-2 expression. This indicates that tomentosin-induced apoptosis may involve a mitochondria-mediated signaling pathway. This study provides the first evidence that tomentosin targets telomere machinery and induces apoptosis in cervical cancer cells. The molecular mechanism underlying tomentosin-induced apoptosis may involve a mitochondria-mediated signaling pathway. J. Cell. Biochem. 118: 1689-1698, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Nawel Merghoub
- Laboratoire de Biochimie-Immunologie, Faculté des Sciences de Rabat, Agdal, Morocco.,Unité Biologie & Recherche Médicale CNESTEN, Rabat, Morocco.,MEDyC CNRS UMR7369, UFR Sciences, UFR Médecine et UFR Pharmacie, Reims, France.,Green Biotechnology Center, MAScIR (Moroccan foundation for Advanced Science, Innovation and Research), Rabat, Morocco
| | - Hassan El Btaouri
- MEDyC CNRS UMR7369, UFR Sciences, UFR Médecine et UFR Pharmacie, Reims, France
| | - Laila Benbacer
- Unité Biologie & Recherche Médicale CNESTEN, Rabat, Morocco
| | - Saïd Gmouh
- Centre National Pour la Recherche Scientifique et Technique, Rabat, Morocco
| | - Chantal Trentesaux
- University of Reims and MNHN, INSERM U565, CNRS UMR 7196, 75005, Paris, France
| | - Bertrand Brassart
- MEDyC CNRS UMR7369, UFR Sciences, UFR Médecine et UFR Pharmacie, Reims, France
| | | | - Claudie Madoulet
- MEDyC CNRS UMR7369, UFR Sciences, UFR Médecine et UFR Pharmacie, Reims, France
| | - Thomas Wenner
- Laboratoire de Pathologie de la cellule B Indolente, UMR CNRS 5239, Faculté de Médecine Lyon Sud, France
| | - Saaid Amzazi
- Laboratoire de Biochimie-Immunologie, Faculté des Sciences de Rabat, Agdal, Morocco
| | - Hamid Morjani
- MEDyC CNRS UMR7369, UFR Sciences, UFR Médecine et UFR Pharmacie, Reims, France
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Li Y, Zhang H, Zhai GX. Intelligent polymeric micelles: development and application as drug delivery for docetaxel. J Drug Target 2016; 25:285-295. [PMID: 27701892 DOI: 10.1080/1061186x.2016.1245309] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Recent years, docetaxel (DTX)-loaded intelligent polymeric micelles have been regarded as a promising vehicle for DTX for the reason that compared with conventional DTX-loaded micelles, DTX-loaded intelligent micelles not only preserve the basic functions of micelles such as DTX solubilization, enhanced accumulation in tumor tissue, and improved bioavailability and biocompatibility of DTX, but also possess other new properties, for instance, tumor-specific DTX delivery and series of responses to endogenous or exogenous stimulations. In this paper, basic theories and action mechanism of intelligent polymeric micelles are discussed in detail, especially the related theories of DTX-loaded stimuli-responsive micelles. The relevant examples of stimuli-responsive DTX-loaded micelles are also provided in this paper to sufficiently illustrate the advantages of relevant technology for the clinical application of anticancer drug, especially for the medical application of DTX.
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Affiliation(s)
- Yimu Li
- a Department of Pharmaceutics , College of Pharmacy, Shandong University , Jinan , China
| | - Hui Zhang
- a Department of Pharmaceutics , College of Pharmacy, Shandong University , Jinan , China
| | - Guang-Xi Zhai
- a Department of Pharmaceutics , College of Pharmacy, Shandong University , Jinan , China
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13
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Shahbazi R, Ozpolat B, Ulubayram K. Oligonucleotide-based theranostic nanoparticles in cancer therapy. Nanomedicine (Lond) 2016; 11:1287-308. [PMID: 27102380 DOI: 10.2217/nnm-2016-0035] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Theranostic approaches, combining the functionality of both therapy and imaging, have shown potential in cancer nanomedicine. Oligonucleotides such as small interfering RNA and microRNA, which are powerful therapeutic agents, have been effectively employed in theranostic systems against various cancers. Nanoparticles are used to deliver oligonucleotides into tumors by passive or active targeting while protecting the oligonucleotides from nucleases in the extracellular environment. The use of quantum dots, iron oxide nanoparticles and gold nanoparticles and tagging with contrast agents, like fluorescent dyes, optical or magnetic agents and various radioisotopes, has facilitated early detection of tumors and evaluation of therapeutic efficacy. In this article, we review the advantages of theranostic applications in cancer therapy and imaging, with special attention to oligonucleotide-based therapeutics.
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Affiliation(s)
- Reza Shahbazi
- Department of Nanotechnology & Nanomedicine, Institute for Graduate Studies in Science & Engineering, Hacettepe University, Ankara 06532, Turkey
| | - Bulent Ozpolat
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kezban Ulubayram
- Department of Nanotechnology & Nanomedicine, Institute for Graduate Studies in Science & Engineering, Hacettepe University, Ankara 06532, Turkey.,Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Hacettepe University, Ankara 06100, Turkey.,Department of Bioengineering, Institute for Graduate Studies in Science & Engineering, Hacettepe University, Ankara 06532, Turkey
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14
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Interaction of metallacrown complexes with G-quadruplex DNA. J Inorg Biochem 2016; 155:105-14. [DOI: 10.1016/j.jinorgbio.2015.11.025] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Revised: 11/06/2015] [Accepted: 11/30/2015] [Indexed: 11/19/2022]
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15
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Moradi Binabaj M, Hosseini SA, Khoshbin Khoshnazar A, Asadi J. The Simultaneous Effect of Valproic Acid and Gamma Radiation on Telomerase Activity and Bax and Bcl-2 Protein Levels in MCF-7 Breast Cancer Cell Line. Jundishapur J Nat Pharm Prod 2015. [DOI: 10.17795/jjnpp-22818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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16
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Søndergaard S, Aznauryan M, Haustrup EK, Schiøtt B, Birkedal V, Corry B. Dynamics of fluorescent dyes attached to G-quadruplex DNA and their effect on FRET experiments. Chemphyschem 2015; 16:2562-70. [PMID: 26174803 DOI: 10.1002/cphc.201500271] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 06/05/2015] [Indexed: 11/08/2022]
Abstract
FRET spectroscopy is a promising approach for investigating the dynamics of G-quadruplex DNA folds and improving the targeting of G-quadruplexes by potential anticancer compounds. To better interpret such experiments, classical and replica-exchange molecular dynamics simulations and fluorescence-lifetime measurements are used to understand the behavior of a range of Cy3-based dyes attached to the 3' end of G-quadruplex DNA. The simulations revealed that the dyes interact extensively with the G-quadruplex. Identification of preferred dye positions relative to the G-quadruplex in the simulations allows the impact of dye-DNA interactions on FRET results to be determined. All the dyes show significant deviations from the common approximation of being freely rotating and not interacting with the host, but one of the Cy3 dye analogues is slightly closer to this case.
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Affiliation(s)
- Siri Søndergaard
- Department of Chemistry, Aarhus University, Langelandsgade 140, 8000 Aarhus C (Denmark).,Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds vej 14, 8000 Aarhus C (Denmark)
| | - Mikayel Aznauryan
- Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds vej 14, 8000 Aarhus C (Denmark)
| | - Emil K Haustrup
- Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds vej 14, 8000 Aarhus C (Denmark)
| | - Birgit Schiøtt
- Department of Chemistry, Aarhus University, Langelandsgade 140, 8000 Aarhus C (Denmark).,Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds vej 14, 8000 Aarhus C (Denmark)
| | - Victoria Birkedal
- Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds vej 14, 8000 Aarhus C (Denmark).
| | - Ben Corry
- Research School of Biology, Australian National University, Linnaeus Way, Canberra ACT 2601 (Australia).
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17
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Majidi S, Zeinali Sehrig F, Samiei M, Milani M, Abbasi E, Dadashzadeh K, Akbarzadeh A. Magnetic nanoparticles: Applications in gene delivery and gene therapy. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2015; 44:1186-93. [DOI: 10.3109/21691401.2015.1014093] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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18
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Noureini SK, Wink M. Dose-dependent cytotoxic effects of boldine in HepG-2 cells-telomerase inhibition and apoptosis induction. Molecules 2015; 20:3730-43. [PMID: 25719742 PMCID: PMC6272231 DOI: 10.3390/molecules20033730] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Revised: 02/11/2015] [Accepted: 02/12/2015] [Indexed: 01/14/2023] Open
Abstract
Plant metabolites are valuable sources of novel therapeutic compounds. In an anti-telomerase screening study of plant secondary metabolites, the aporphine alkaloid boldine (1,10-dimethoxy-2,9-dihydroxyaporphine) exhibited a dose and time dependent cytotoxicity against hepatocarcinoma HepG-2 cells. Here we focus on the modes and mechanisms of the growth-limiting effects of this compound. Telomerase activity and expression level of some related genes were estimated by real-time PCR. Modes of cell death also were examined by microscopic inspection, staining methods and by evaluating the expression level of some critically relevant genes. The growth inhibition was correlated with down-regulation of the catalytic subunit of telomerase (hTERT) gene (p < 0.01) and the corresponding reduction of telomerase activity in sub-cytotoxic concentrations of boldine (p < 0.002). However, various modes of cell death were stimulated, depending on the concentration of boldine. Very low concentrations of boldine over a few passages resulted in an accumulation of senescent cells so that HepG-2 cells lost their immortality. Moreover, boldine induced apoptosis concomitantly with increasing the expression of bax/bcl2 (p < 0.02) and p21 (p < 0.01) genes. Boldine might thus be an interesting candidate as a potential natural compound that suppresses telomerase activity in non-toxic concentrations.
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Affiliation(s)
- Sakineh Kazemi Noureini
- Deptartment of Biology, Faculty of Basic Sciences, Hakim Sabzevari University, P.O. Box 397, Sabzevar, 9617966376 Iran.
| | - Michael Wink
- Department of Biology, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, INF 364, 69120, Heidelberg, Germany.
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Guan GG, Wang WB, Lei BX, Wang QL, Wu L, Fu ZM, Zhou FX, Zhou YF. UBE2D3 is a positive prognostic factor and is negatively correlated with hTERT expression in esophageal cancer. Oncol Lett 2015; 9:1567-1574. [PMID: 25789002 PMCID: PMC4356423 DOI: 10.3892/ol.2015.2926] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 01/13/2015] [Indexed: 12/20/2022] Open
Abstract
Human telomerase reverse transcriptase (hTERT) is a critical factor in unlimited cell proliferation and immortalization, with numerous studies demonstrating that high expression of hTERT is a poor prognostic factor in various types of cancer. Ubiquitin-conjugating enzyme E2D 3 (UBE2D3) is a member of the E2 family, and participates in the ubiquitin proteasome pathway to regulate basic cellular activities, such as cell cycle control, the DNA damage response, apoptosis, and tumorigenesis. Our previous study initially determined that downregulation of UBE2D3 expression increases hTERT expression and cell proliferation, however, the association between the expression of these two proteins and their functions in cancer tissues remains unknown. Therefore, the protein expression levels of hTERT and UBE2D3 were evaluated in 150 esophageal cancer and 30 adjacent healthy tissue samples by performing immunohistochemical analysis. Concurrently, the clinicopathological data of the enrolled patients were obtained to allow correlation analysis. It was identified that the expression of hTERT in the esophageal cancer tissues was significantly higher compared with that of the adjacent tissues (P=0.015), however, the expression of UBE2D3 was significantly lower in esophageal cancer tissues than the adjacent tissues (P=0.001). Additionally, the study demonstrated that hTERT was significantly upregulated in poorly-differentiated, advanced tumor-node-metastasis (TNM) stage cancer tissues (P<0.05 for all), however, UBE2D3 expression was downregulated in poorly-differentiated, lymph node invaded cancer tissues and recurrent cases. It was also identified that traditional factors, including tumor location, T stage, lymph node status, TNM stage, and molecular factors of hTERT and UBE2D3, were significantly associated with overall survival time (P<0.05 for all). Furthermore, UBE2D3, lymph node status and tumor location were independent prognostic factors for esophageal cancer in multivariate analysis. Most notably, hTERT and UBE2D3 expression were negatively correlated with each other. In conclusion, the findings of the present study indicated that hTERT and UBE2D3 proteins appear to be involved in the development of esophageal cancer, that UBE2D3 may a positive prognostic factor for esophageal cancer, and that UBE2D3 and hTERT expression levels are inversely correlated.
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Affiliation(s)
- Ge Ge Guan
- Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Wen Bo Wang
- Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan University, Wuhan, Hubei 430071, P.R. China ; Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Bing Xin Lei
- Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Qiao Li Wang
- Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Lin Wu
- Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Zhen Ming Fu
- Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan University, Wuhan, Hubei 430071, P.R. China ; Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Fu Xiang Zhou
- Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan University, Wuhan, Hubei 430071, P.R. China ; Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Yun Feng Zhou
- Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan University, Wuhan, Hubei 430071, P.R. China ; Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430071, P.R. China
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20
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Rodríguez L, Villalobos X, Solé A, Lliberós C, Ciudad CJ, Noé V. Improved design of PPRHs for gene silencing. Mol Pharm 2015; 12:867-77. [PMID: 25615267 DOI: 10.1021/mp5007008] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Nowadays, the modulation of gene expression by nucleic acids has become a routine tool in biomedical research for target validation and it is also used to develop new therapeutic approaches. Recently, we developed the so-called polypurine reverse Hoogsteen hairpins (PPRHs) that show high stability and a low immunogenic profile and we demonstrated their efficacy both in vitro and in vivo. In this work, we explored different characteristics of PPRHs to improve their usage as a tool for gene silencing. We studied the role of PPRH length in the range from 20 to 30 nucleotides. We also proved their higher affinity of binding and efficacy on cell viability compared to nonmodified TFOs. To overcome possible off-target effects, we tested wild-type PPRHs, which proved to be capable of binding to their target sequence with more affinity, displaying a higher stability of binding and a higher effect in terms of cell viability. Moreover, we developed a brand new molecule called Wedge-PPRH with the ability to lock the ds-DNA into the displaced structure and proved its efficacy in prostate and breast cancer cell lines.
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Affiliation(s)
- Laura Rodríguez
- Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona , 08028 Barcelona, Spain
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21
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Kalathiya U, Padariya M, Baginski M. Molecular Modeling and Evaluation of Novel Dibenzopyrrole Derivatives as Telomerase Inhibitors and Potential Drug for Cancer Therapy. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2014; 11:1196-1207. [PMID: 26357055 DOI: 10.1109/tcbb.2014.2326860] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
During previous years, many studies on synthesis, as well as on anti-tumor, anti-inflammatory and anti-bacterial activities of the pyrazole derivatives have been described. Certain pyrazole derivatives exhibit important pharmacological activities and have proved to be useful template in drug research. Considering importance of pyrazole template, in current work the series of novel inhibitors were designed by replacing central ring of acridine with pyrazole ring. These heterocyclic compounds were proposed as a new potential base for telomerase inhibitors. Obtained dibenzopyrrole structure was used as a novel scaffold structure and extension of inhibitors was done by different functional groups. Docking of newly designed compounds in the telomerase active site (telomerase catalytic subunit TERT) was carried out. All dibenzopyrrole derivatives were evaluated by three docking programs: CDOCKER, Ligandfit docking (Scoring Functions) and AutoDock. Compound C_9g, C_9k and C_9l performed best in comparison to all designed inhibitors during the docking in all methods and in interaction analysis. Introduction of pyrazole and extension of dibenzopyrrole in compounds confirm that such compound may act as potential telomerase inhibitors.
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Abstract
In recent years, hundreds of genes have been linked to a variety of human diseases, and the field of gene therapy has emerged as a way to treat this wide range of diseases. The main goal of gene therapy is to find a gene delivery vehicle that can successfully target diseased cells and deliver therapeutic genes directly to their cellular compartment. The two main types of gene delivery vectors currently being investigated in clinical trials are recombinant viral vectors and synthetic nonviral vectors. Recombinant viral vectors take advantage of the evolutionarily optimized viral mechanisms to deliver genes, but they can be hard to specifically target in vivo and are also associated with serious side effects. Synthetic nonviral vectors are made out of highly biocompatible lipids or polymers, but they are much less efficient at delivering their genetic payload due to the lack of any active delivery mechanism. This mini review will introduce the current state of gene delivery in clinical trials, and discuss the specific challenges associated with each of these vectors. It will also highlight some specific gaps in knowledge that are limiting the advancement of this field and touch on the current areas of research being explored to overcome them.
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Affiliation(s)
- Yarong Liu
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California, USA
| | - Jennifer Rohrs
- Department of Biomedical Engineering, University of Southern California, Los Angeles, California, USA
| | - Pin Wang
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California, USA
- Department of Biomedical Engineering, University of Southern California, Los Angeles, California, USA
- Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, California, USA
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23
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Li D, Tang X, Pulli B, Lin C, Zhao P, Cheng J, Lv Z, Yuan X, Luo Q, Cai H, Ye M. Theranostic nanoparticles based on bioreducible polyethylenimine-coated iron oxide for reduction-responsive gene delivery and magnetic resonance imaging. Int J Nanomedicine 2014; 9:3347-61. [PMID: 25045265 PMCID: PMC4099417 DOI: 10.2147/ijn.s61463] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Theranostic nanoparticles based on superparamagnetic iron oxide (SPIO) have a great promise for tumor diagnosis and gene therapy. However, the availability of theranostic nanoparticles with efficient gene transfection and minimal toxicity remains a big challenge. In this study, we construct an intelligent SPIO-based nanoparticle comprising a SPIO inner core and a disulfide-containing polyethylenimine (SSPEI) outer layer, which is referred to as a SSPEI-SPIO nanoparticle, for redox-triggered gene release in response to an intracellular reducing environment. We reveal that SSPEI-SPIO nanoparticles are capable of binding genes to form nano-complexes and mediating a facilitated gene release in the presence of dithiothreitol (5–20 mM), thereby leading to high transfection efficiency against different cancer cells. The SSPEI-SPIO nanoparticles are also able to deliver small interfering RNA (siRNA) for the silencing of human telomerase reverse transcriptase genes in HepG2 cells, causing their apoptosis and growth inhibition. Further, the nanoparticles are applicable as T2-negative contrast agents for magnetic resonance (MR) imaging of a tumor xenografted in a nude mouse. Importantly, SSPEI-SPIO nanoparticles have relatively low cytotoxicity in vitro at a high concentration of 100 μg/mL. The results of this study demonstrate the utility of a disulfide-containing cationic polymer-decorated SPIO nanoparticle as highly potent and low-toxic theranostic nano-system for specific nucleic acid delivery inside cancer cells.
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Affiliation(s)
- Dan Li
- Department of Nuclear Medicine, Shanghai 10th People's Hospital, Tongji University School of Medicine, Tongji University, People's Republic of China
| | - Xin Tang
- Shanghai East Hospital, The Institute for Biomedical Engineering and Nanoscience, Tongji University School of Medicine, Tongji University, People's Republic of China
| | - Benjamin Pulli
- Department of Nuclear Medicine, Shanghai 10th People's Hospital, Tongji University School of Medicine, Tongji University, People's Republic of China
| | - Chao Lin
- Shanghai East Hospital, The Institute for Biomedical Engineering and Nanoscience, Tongji University School of Medicine, Tongji University, People's Republic of China
| | - Peng Zhao
- Shanghai East Hospital, The Institute for Biomedical Engineering and Nanoscience, Tongji University School of Medicine, Tongji University, People's Republic of China
| | - Jian Cheng
- Shanghai East Hospital, The Institute for Biomedical Engineering and Nanoscience, Tongji University School of Medicine, Tongji University, People's Republic of China
| | - Zhongwei Lv
- Department of Nuclear Medicine, Shanghai 10th People's Hospital, Tongji University School of Medicine, Tongji University, People's Republic of China
| | - Xueyu Yuan
- Department of Nuclear Medicine, Shanghai 10th People's Hospital, Tongji University School of Medicine, Tongji University, People's Republic of China
| | - Qiong Luo
- Department of Nuclear Medicine, Shanghai 10th People's Hospital, Tongji University School of Medicine, Tongji University, People's Republic of China
| | - Haidong Cai
- Department of Nuclear Medicine, Shanghai 10th People's Hospital, Tongji University School of Medicine, Tongji University, People's Republic of China
| | - Meng Ye
- Department of Nuclear Medicine, Shanghai 10th People's Hospital, Tongji University School of Medicine, Tongji University, People's Republic of China
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Cheng YB, Guo LP, Yao P, Ning XY, Aerken G, Fang DC. Telomerase and hTERT: Can they serve as markers for gastric cancer diagnosis? World J Gastroenterol 2014; 20:6615-6619. [PMID: 24914385 PMCID: PMC4047349 DOI: 10.3748/wjg.v20.i21.6615] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2013] [Revised: 02/15/2014] [Accepted: 03/05/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate telomerase activity and human telomerase reverse transcriptase (hTERT) expression in normal human gastric mucosal epithelial cells (nhGMECs) and fibroblasts (nhGMFs).
METHODS: nhGMECs and nhGMFs were isolated and cultured from specimens obtained during routine surgery for bleeding peptic ulcer. Telomerase activity in nhGMFs, nhGMECs, and the tumor cell lines BGC-823, SGC-7901 and MKN-28 cells was analyzed using the telomeric repeat amplification protocol assay. hTERT protein was determined in nhGMECs, nhGMFs, BGC-823, SGC-7901 and MKN-28 cells by indirect immunofluorescence.
RESULTS: A similar level of telomerase activity was observed in nhGMECs, nhGMFs and BGC-823, SGC-7901, MKN-28 cell lines. Positive hTERT immunostaining was detected in nhGMECs, nhGMFs, BGC-823, SGC-7901 and MKN-28 cell lines.
CONCLUSION: The use of telomerase or hTERT as diagnostic markers for gastric cancer may require further studies.
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Qin Y, Guo H, Tang B, Yang SM. The non-reverse transcriptase activity of the human telomerase reverse transcriptase promotes tumor progression (review). Int J Oncol 2014; 45:525-31. [PMID: 24888567 DOI: 10.3892/ijo.2014.2470] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Accepted: 04/17/2014] [Indexed: 11/05/2022] Open
Abstract
In human cancer, high expression of telomerase is correlated with tumor aggressiveness and metastatic potential. Human telomerase reverse transcriptase (hTERT), which regulates telomere length, can promote tumor development. Most research on hTERT has been focused on its crucial function of telomere maintenance. However, there are many phenomena that cannot be explained by its reverse transcriptase activity. Accumulating evidence suggests that hTERT has functions independent of its protective function at the telomere ends, such as increasing the anti-apoptotic capacity of cells, enhancing DNA repair, maintaining stem cells and regulating gene expression. This review will provide an update on the non-reverse transcriptase activity of hTERT and its contribution to tumor formation, metastasis and cancer stem cell maintenance. Repression of the non-reverse transcriptase activity of hTERT may be a new strategy for tumor therapy.
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Affiliation(s)
- Yong Qin
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
| | - Hong Guo
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
| | - Bo Tang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
| | - Shi-Ming Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
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Dizaj SM, Jafari S, Khosroushahi AY. A sight on the current nanoparticle-based gene delivery vectors. NANOSCALE RESEARCH LETTERS 2014; 9:252. [PMID: 24936161 PMCID: PMC4046008 DOI: 10.1186/1556-276x-9-252] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Accepted: 04/25/2014] [Indexed: 05/17/2023]
Abstract
Nowadays, gene delivery for therapeutic objects is considered one of the most promising strategies to cure both the genetic and acquired diseases of human. The design of efficient gene delivery vectors possessing the high transfection efficiencies and low cytotoxicity is considered the major challenge for delivering a target gene to specific tissues or cells. On this base, the investigations on non-viral gene vectors with the ability to overcome physiological barriers are increasing. Among the non-viral vectors, nanoparticles showed remarkable properties regarding gene delivery such as the ability to target the specific tissue or cells, protect target gene against nuclease degradation, improve DNA stability, and increase the transformation efficiency or safety. This review attempts to represent a current nanoparticle based on its lipid, polymer, hybrid, and inorganic properties. Among them, hybrids, as efficient vectors, are utilized in gene delivery in terms of materials (synthetic or natural), design, and in vitro/in vivo transformation efficiency.
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Affiliation(s)
- Solmaz Maleki Dizaj
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Samira Jafari
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahmad Yari Khosroushahi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Pharmacognosy, Faculty of Pharmacy, Tabriz University of Medical Sciences, Daneshgah Street, P.O.Box 51664, 14766 Tabriz, Iran
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Synthesis, biological evaluation, and molecular docking studies of pyrazolyl-acylhydrazone derivatives as novel anticancer agents. Med Chem Res 2014. [DOI: 10.1007/s00044-014-0909-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Luo Y, Zhou Y, Fu J, Zhu HL. 4,5-Dihydropyrazole derivatives containing oxygen-bearing heterocycles as potential telomerase inhibitors with anticancer activity. RSC Adv 2014. [DOI: 10.1039/c4ra02200a] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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29
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Torijano-Gutiérrez S, Díaz-Oltra S, Falomir E, Murga J, Carda M, Marco JA. Synthesis of combretastatin A-4 O-alkyl derivatives and evaluation of their cytotoxic, antiangiogenic and antitelomerase activity. Bioorg Med Chem 2013; 21:7267-74. [DOI: 10.1016/j.bmc.2013.09.064] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2013] [Revised: 09/22/2013] [Accepted: 09/26/2013] [Indexed: 11/26/2022]
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30
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Wilson KA, Chateau ML, Porteus MH. Design and Development of Artificial Zinc Finger Transcription Factors and Zinc Finger Nucleases to the hTERT Locus. MOLECULAR THERAPY. NUCLEIC ACIDS 2013; 2:e87. [PMID: 23612114 PMCID: PMC3650244 DOI: 10.1038/mtna.2013.12] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2012] [Accepted: 02/05/2013] [Indexed: 01/07/2023]
Abstract
The ability to direct human telomerase reverse transcriptase (hTERT) expression through either genetic control or tunable regulatory factors would advance not only our understanding of the transcriptional regulation of this gene, but also potentially produce new strategies for addressing telomerase-associated disease. In this work, we describe the engineering of artificial zinc finger transcription factors (ZFTFs) and ZF nucleases (ZFNs) to target sequences within the hTERT promoter and exon-1. We were able to identify several active ZFTFs that demonstrate a broadly tunable response when screened by a cell-based transcriptional reporter assay. Using the same DNA-binding domains, we generated ZFNs that were screened in combinatorial pairs in cell-based extrachromosomal single-strand annealing (SSA) assays and in gene-targeting assays using stably integrated constructs. Selected ZFN pairs were tested for the ability to induce sequence changes in a Cel1 assay and we observed frequencies of genomic modification up to 18.7% at the endogenous hTERT locus. These screening strategies have pinpointed several ZFN pairs that may be useful in gene editing of the hTERT locus. Our work provides a foundation for using engineered ZF proteins (ZFPs) for modulation of the hTERT locus.Molecular Therapy - Nucleic Acids (2013) 2, e87; doi:10.1038/mtna.2013.12; published online 23 April 2013.
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Affiliation(s)
- Kimberly A Wilson
- Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
- Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
| | - Morgan L Chateau
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Matthew H Porteus
- Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
- Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
- Department of Pediatrics, Stanford University, Stanford, California, USA
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Kesarwani K, Gupta R. Bioavailability enhancers of herbal origin: an overview. Asian Pac J Trop Biomed 2013; 3:253-66. [PMID: 23620848 PMCID: PMC3634921 DOI: 10.1016/s2221-1691(13)60060-x] [Citation(s) in RCA: 218] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Accepted: 03/07/2013] [Indexed: 01/08/2023] Open
Abstract
Recently, the use of herbal medicines has been increased all over the world due to their therapeutic effects and fewer adverse effects as compared to the modern medicines. However, many herbal drugs and herbal extracts despite of their impressive in-vitro findings demonstrates less or negligible in-vivo activity due to their poor lipid solubility or improper molecular size, resulting in poor absorption and hence poor bioavailability. Nowadays with the advancement in the technology, novel drug delivery systems open the door towards the development of enhancing bioavailability of herbal drug delivery systems. For last one decade many novel carriers such as liposomes, microspheres, nanoparticles, transferosomes, ethosomes, lipid based systems etc. have been reported for successful modified delivery of various herbal drugs. Many herbal compounds including quercetin, genistein, naringin, sinomenine, piperine, glycyrrhizin and nitrile glycoside have demonstrated capability to enhance the bioavailability. The objective of this review is to summarize various available novel drug delivery technologies which have been developed for delivery of drugs (herbal), and to achieve better therapeutic response. An attempt has also been made to compile a profile on bioavailability enhancers of herbal origin with the mechanism of action (wherever reported) and studies on improvement in drug bioavailability, exhibited particularly by natural compounds.
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Affiliation(s)
| | - Rajiv Gupta
- *Corresponding author: Rajiv Gupta, Professor & Dean, School of Pharmacy, BBD University, Lucknow. U.P., India. Tel: 9839278227 E-mail:
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Xu W, Tan Q, Yu M, Sun Q, Kong H, Lægsgaard E, Stensgaard I, Kjems J, Wang JG, Wang C, Besenbacher F. Atomic-scale structures and interactions between the guanine quartet and potassium. Chem Commun (Camb) 2013; 49:7210-2. [DOI: 10.1039/c3cc43302a] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Huang G, Geng J, Wang R, Chen L. Identification of a New Cytotoxic T-Cell Epitope p675 of Human Telomerase Reverse Transcriptase. Cancer Biother Radiopharm 2012; 27:600-5. [PMID: 22917214 DOI: 10.1089/cbr.2012.1193] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Affiliation(s)
- Guichun Huang
- Medical Oncology Department of Jinling Hospital, Medical School of Nanjing University, Nanjing, People's Republic of China
| | - Jian Geng
- Medical Oncology Department of Jinling Hospital, Medical School of Nanjing University, Nanjing, People's Republic of China
| | - Rui Wang
- Medical Oncology Department of Jinling Hospital, Medical School of Nanjing University, Nanjing, People's Republic of China
| | - Longbang Chen
- Medical Oncology Department of Jinling Hospital, Medical School of Nanjing University, Nanjing, People's Republic of China
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Zhang YB, Wang XL, Liu W, Yang YS, Tang JF, Zhu HL. Design, synthesis and biological evaluation of heterocyclic azoles derivatives containing pyrazine moiety as potential telomerase inhibitors. Bioorg Med Chem 2012; 20:6356-65. [PMID: 23018096 DOI: 10.1016/j.bmc.2012.08.059] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2012] [Revised: 08/30/2012] [Accepted: 08/31/2012] [Indexed: 02/02/2023]
Abstract
Three series of novel heterocyclic azoles derivatives containing pyrazine (5a-5k, 8a-8k and 11a-11k) have been designed, synthesized, structurally determined, and their biological activities were evaluated as potential telomerase inhibitors. Among the oxadiazole derivatives, compound 5c showed the most potent biological activity against SW1116 cancer cell line (IC(50)=2.46 μM against SW1116 and IC(50)=3.55 μM for telomerase). Compound 8h performed the best in the thiadiazole derivatives (IC(50)=0.78 μM against HEPG2 and IC(50)=1.24 μM for telomerase), which was comparable to the positive control. While compound 11f showed the most potent biological activity (IC(50)=4.12 μM against SW1116 and IC(50)=15.03 μM for telomerase) among the triazole derivatives. Docking simulation by positioning compounds 5c, 8h and 11f into the telomerase structure active site was performed to explore the possible binding model. The results of apoptosis demonstrated that compound 8h possessed good antitumor activity against HEPG2 cancer cell line. Therefore, compound 8h with potent inhibitory activity in tumor growth inhibition may be a potential antitumor agent against HEPG2 cancer cell. Therefore, the introduction of oxadiazole, thiadiazole and triazole structures reinforced the combination of our compounds and the receptor, resulting in progress of bioactivity.
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Affiliation(s)
- Yan-Bin Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China
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Dong M, Mürdter TE, Philippi C, Loretz B, Schaefer UF, Lehr CM, Schwab M, Ammon-Treiber S. Pulmonary delivery and tissue distribution of aerosolized antisense 2'-O-Methyl RNA containing nanoplexes in the isolated perfused and ventilated rat lung. Eur J Pharm Biopharm 2012; 81:478-85. [PMID: 22565122 DOI: 10.1016/j.ejpb.2012.04.022] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2012] [Revised: 04/25/2012] [Accepted: 04/27/2012] [Indexed: 12/31/2022]
Abstract
Pulmonary delivery of drugs, particularly in the treatment of lung cancer, is an attractive strategy for future targeted therapy. In this context, inhalation of nanoplexes might offer a new mode for drug delivery in gene therapy. However, limited data are currently available demonstrating pulmonary delivery, cellular uptake as well as local tolerability in lung tissue. The aim of this study was to elucidate the pulmonary delivery, tissue distribution and local tolerability of aerosolized chitosan-coated poly(lactide-co-glycolide) based nanoplexes containing antisense 2'-O-Methyl RNA (OMR). Therefore, an aerosol of OMR-nanoplexes or OMR alone was administered intra-tracheally using the model of the isolated perfused and ventilated rat lung. Localization of OMR in rat lung tissue was examined by immunohistochemistry. Administration of the OMR-nanoplex formulation resulted in significantly higher cellular OMR uptake of the respiratory epithelium in contrast to the administration of OMR alone, indicating that drug administration via aerosolized nanoplexes is able to target lung tissue. No prominent changes in lung physiology parameters were observed following inhalation, suggesting good local tolerability of OMR-nanoplex formulation.
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Affiliation(s)
- M Dong
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart and University of Tuebingen, Germany
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Fernández-Marcelo T, Morán A, de Juan C, Pascua I, Head J, Gómez A, Hernando F, López-Asenjo JA, Hernández S, Sánchez-Pernaute A, Torres AJ, Benito M, Iniesta P. Differential expression of senescence and cell death factors in non-small cell lung and colorectal tumors showing telomere attrition. Oncology 2012; 82:153-64. [PMID: 22433385 DOI: 10.1159/000335678] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2011] [Accepted: 12/06/2011] [Indexed: 12/22/2022]
Abstract
OBJECTIVE The main aim of this work is to investigate the expression of factors related to senescence and cell death pathways in non-small cell lung cancers (NSCLCs) and colorectal cancers (CRCs) in relation to telomere status. METHODS We analyzed 158 tissue samples, 36 NSCLCs, 43 CRCs, and their corresponding control tissues obtained from patients submitted to surgery. Telomere function was evaluated by determining telomerase activity and telomere length. Expression of factors related to senescence, cell death pathways, transformation and tumorigenesis was investigated using arrays. Results were validated by real-time quantitative PCR. RESULTS Considering tumors with telomere shortening, expression for BNIP3, DAPK1, NDRG1, EGFR, and CDKN2A was significantly higher in NSCLC than in CRC, whereas TP53 was overexpressed in CRC with respect to NSCLC. Moreover, compared to nontumor samples, DAPK1, GADD45A, SHC1, and TP53 were downregulated in the group of NSCLCs with telomere shortening, and no significant differences were found in CRC. CONCLUSIONS In NSCLC, the failure of pathways which involve factors such as DAPK1, GADD45A, SHC1, and TP53, in response to short telomeres, could promote tumor progression. In CRC, the viability of these pathways in response to short telomeres could contribute to limiting tumorigenesis.
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Affiliation(s)
- Tamara Fernández-Marcelo
- Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Madrid, España
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Kim GY, Kim WJ, Choi YH. Pectenotoxin-2 from marine sponges: a potential anti-cancer agent-a review. Mar Drugs 2011; 9:2176-2187. [PMID: 22163180 PMCID: PMC3229229 DOI: 10.3390/md9112176] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2011] [Revised: 10/09/2011] [Accepted: 10/19/2011] [Indexed: 11/27/2022] Open
Abstract
Pectenotoxin-2 (PTX-2), which was first identified as a cytotoxic entity in marine sponges, has been reported to display significant cytotoxicity to human cancer cells where it inhibits mitotic separation and cytokinesis through the depolymerization of actin filaments. In the late stage of endoreduplication, the effects of PTX-2 on different cancer cells involves: (i) down-regulation of anti-apoptotic Bcl-2 members and IAP family proteins; (ii) up-regulation of pro-apoptotic Bax protein and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-receptor 1/receptor 2 (DR4/DR5); and (iii) mitochondrial dysfunction. In addition, PTX-2 induces apoptotic effects through suppression of the nuclear factor κB (NF-κB) signaling pathway in several cancer cells. Analysis of cell cycle regulatory proteins showed that PTX-2 increases phosphorylation of Cdc25c and decreases protein levels of Cdc2 and cyclin B1. Cyclin-dependent kinase (Cdk) inhibitor p21 and Cdk2, which are associated with the induction of endoreduplication, were upregulated. Furthermore, it was found that PTX-2 suppressed telomerase activity through the transcriptional and post-translational suppression of hTERT. The purpose of this review was to provide an update regarding the anti-cancer mechanism of PTX-2, with a special focus on its effects on different cellular signaling cascades.
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Affiliation(s)
- Gi-Young Kim
- Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Jeju 690-756, Korea; E-Mail:
| | - Wun-Jae Kim
- Department of Urology, Chungbuk National University College of Medicine, Cheongju 361-763, Korea; E-Mail:
| | - Yung Hyun Choi
- Department of Biochemistry, College of Oriental Medicine, Dongeui University, Busan 614-052, Korea
- Department of Biomaterial Control (BK21 program), Graduate School, and Blue-Bio Industry RIC, Dongeui University, Busan 614-052, Korea
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +82-51-850-7413; Fax: +82-51-853-4036
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Tissue slice model of human lung cancer to investigate telomerase inhibition by nanoparticle delivery of antisense 2′-O-methyl-RNA. Int J Pharm 2011; 419:33-42. [DOI: 10.1016/j.ijpharm.2011.07.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2011] [Revised: 07/05/2011] [Accepted: 07/06/2011] [Indexed: 01/08/2023]
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Serrano D, Bleau AM, Fernandez-Garcia I, Fernandez-Marcelo T, Iniesta P, Ortiz-de-Solorzano C, Calvo A. Inhibition of telomerase activity preferentially targets aldehyde dehydrogenase-positive cancer stem-like cells in lung cancer. Mol Cancer 2011; 10:96. [PMID: 21827695 PMCID: PMC3199900 DOI: 10.1186/1476-4598-10-96] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2011] [Accepted: 08/09/2011] [Indexed: 01/08/2023] Open
Abstract
Background Mortality rates for advanced lung cancer have not declined for decades, even with the implementation of novel chemotherapeutic regimens or the use of tyrosine kinase inhibitors. Cancer Stem Cells (CSCs) are thought to be responsible for resistance to chemo/radiotherapy. Therefore, targeting CSCs with novel compounds may be an effective approach to reduce lung tumor growth and metastasis. We have isolated and characterized CSCs from non-small cell lung cancer (NSCLC) cell lines and measured their telomerase activity, telomere length, and sensitivity to the novel telomerase inhibitor MST312. Results The aldehyde dehydrogenase (ALDH) positive lung cancer cell fraction is enriched in markers of stemness and endowed with stem cell properties. ALDH+ CSCs display longer telomeres than the non-CSC population. Interestingly, MST312 has a strong antiproliferative effect on lung CSCs and induces p21, p27 and apoptosis in the whole tumor population. MST312 acts through activation of the ATM/pH2AX DNA damage pathway (short-term effect) and through decrease in telomere length (long-term effect). Administration of this telomerase inhibitor (40 mg/kg) in the H460 xenograft model results in significant tumor shrinkage (70% reduction, compared to controls). Combination therapy consisting of irradiation (10Gy) plus administration of MST312 did not improve the therapeutic efficacy of the telomerase inhibitor alone. Treatment with MST312 reduces significantly the number of ALDH+ CSCs and their telomeric length in vivo. Conclusions We conclude that antitelomeric therapy using MST312 mainly targets lung CSCs and may represent a novel approach for effective treatment of lung cancer.
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Affiliation(s)
- Diego Serrano
- Laboratory of Novel Therapeutic Targets, Oncology Division, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
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Yu LL, Zhao JM, Jiang WW. Portal vein infusion of recombinant vascular endothelial growth factor 165 mitigates liver fibrosis in cirrhotic rats. Shijie Huaren Xiaohua Zazhi 2011; 19:2214-2219. [DOI: 10.11569/wcjd.v19.i21.2214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the effect of portal vein infusion of recombinant vascular endothelial growth factor (VEGF) 165 on liver fibrosis in rats with cirrhosis.
METHODS: Fifty male SD rats were randomly divided into normal group (n = 10) and model group (n = 40). The model group was used to induce cirrhosis using the thioacetamide approach. After 10 wk, 25 cirrhotic rats were randomly divided into experimental group (n = 15) and model control group (n = 10). The experimental group was intubated for implantation of an Alzet osmotic pump, which was used to infuse recombinant VEGF165 via the portal vein for 2 wk. The normal group and model control group underwent sham operation. All rats were killed after 2 wk, and HE staining was used to observe the pathological changes in liver tissue. Serum hyaluronic acid and laminin were measured using radioimmunoassay method. Immunohistochemistry was used to detect the expression of type I and type IV collagen in the liver.
RESULTS: Degeneration and necrosis of liver cells, diffuse proliferation of fibrous connective tissue and formation of pseudo lobules occurred in the model control group. In the experimental group, degeneration and necrosis of liver cells were milder and the rate of liver fibrosis was improved significantly compared to the model control group (P < 0.01). Compared to the normal group, serum hyaluronic acid and laminin concentrations increased significantly in the model control group (P < 0.01). However, serum concentrations of hyaluronic acid and laminin was significantly lower in the experimental group than in the model control group (412.63 μg/L ± 85.18 μg/L vs 741.60 μg/L ± 72.83 μg/L; 58.87 μg/L ± 5.46 μg/L vs 92.80 μg/L ± 8.41 μg/L; both P < 0.01). The expression levels of type I and type IV collagen in the liver was significantly lower in the experimental group than in the model control group (6.84 ± 0.96, 8.25 ± 0.82 vs 18.38 ± 1.86, 20.86 ± 2.48, all P < 0.01).
CONCLUSION: Portal vein infusion of VEGF165 can relieve liver fibrosis in rats with cirrhosis.
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Identification of small molecule inhibitors of telomerase activity through transcriptional regulation of hTERT and calcium induction pathway in human lung adenocarcinoma A549 cells. Bioorg Med Chem 2010; 18:6987-94. [PMID: 20813535 DOI: 10.1016/j.bmc.2010.08.021] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2010] [Revised: 08/09/2010] [Accepted: 08/10/2010] [Indexed: 12/27/2022]
Abstract
High telomerase activity (TA) is detected in most cancer cells; and thus, TA inhibition by drug or dietary food components is a new strategy for cancer prevention. In this report, we examined the effects of fourteen natural or synthetic compounds on TA in human lung adenocarcinoma A549 cells. The results demonstrated that some of the tested compounds inhibited TA, being 2'-hydroxy-2,3,4',6'-tetramethoxychalcone (HTMC) was the most potent among tested. In A549 cells, HTMC also inhibited the cell proliferation, decreased the expression of human telomerase reverse transcriptase (hTERT) and sequentially reduced the hTERT promoter. In soft agar assay HTMC treatment reduced the colony formation of A549 cells. Cellular fractionation and immunofluorescence assay demonstrated that there was no translocation of hTERT from nuclei to cytoplasm. Further studies revealed that the release of Ca(2+) was the underlying mechanism of suppressed TA and hTERT transcription in A549 cells exposed to HTMC. These in vitro data support the development of HTMC as a therapeutic agent for cancer complications.
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