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Hao S, Yao Z, Liu Y. Hsa_circ_0000106 Acts as a Tumor Promoter in Pancreatic Cancer by Targeting the MiR-455-3p/HDAC4. Horm Metab Res 2023; 55:722-732. [PMID: 37553012 DOI: 10.1055/a-2125-7018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/10/2023]
Abstract
Circular RNAs (circRNAs) frequently participate in pancreatic cancer (PC) progression. This study focuses on circ_0000106, a novel circRNA, and its potential function in PC development. Circ_00001106, miR-455-3p, and HDAC4 expression levels in PC were determined using qRT-PCR and immunoblotting. RNA immunoprecipitation and dual-luciferase reporter assays were performed to verify their binding interactions. Loss-of-function assays, including CCK-8, colony formation, and transwell assays, were used to estimate the proliferative and migratory properties of PC cells. A nude mouse model was constructed to assess the influence of circ_0000106 on tumor formation in vivo. A pronounced elevation of circ_0000106 and HDAC4 and a reduction of miR-455-3p in PC were observed. Circ_0000106 was prone to binding to miR-455-3p, and miR-455-3p further targeted HDAC4. Functionally, the proliferative and migratory properties of PC cells were dampened by the loss of circ_0000106 or HDAC4 and could be potentiated by miR-455-3p inhibition. Moreover, the knockdown of circ_0000106 delayed tumor growth in vivo. Additionally, the downregulation of miR-455-3p attenuated the repressive effects of circ_0000106 deficiency on PC cell migration and proliferation. Loss of HDAC4 exerted similar mitigative effects on miR-455-3p downregulation-stimulated PC cells. In conclusion, circ_0000106 promotes tumor migration and growth in PC by targeting the miR-455-3p/HDAC4 axis. These results suggest that the circ_0000106/miR-455-3p/HDAC4 network could be regarded as a latent target for PC treatment.
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Affiliation(s)
- Shunxin Hao
- Department of General Surgery, Wuhan University of Science and Technology Hospital, Wuhan, China
| | - Zhi Yao
- Department of General Surgery, Wuhan University of Science and Technology Hospital, Wuhan, China
| | - Yifeng Liu
- Department of General Surgery, Wuhan University of Science and Technology Hospital, Wuhan, China
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The Class I HDAC Inhibitor Valproic Acid Strongly Potentiates Gemcitabine Efficacy in Pancreatic Cancer by Immune System Activation. Biomedicines 2022; 10:biomedicines10030517. [PMID: 35327319 PMCID: PMC8945828 DOI: 10.3390/biomedicines10030517] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/26/2022] [Accepted: 02/16/2022] [Indexed: 01/01/2023] Open
Abstract
Background: Gemcitabine efficacy in pancreatic cancer is often impaired due to limited intracellular uptake and metabolic activation. Epi-drugs target gene expression patterns and represent a promising approach to reverse chemoresistance. In this study, we investigate the chemosensitizing effect of different epi-drugs when combined with gemcitabine in pancreatic cancer. Methods: Mouse KPC3 cells were used for all experiments. Five different epi-drugs were selected for combination therapy: 5-aza-2′-deoxycytidine, hydralazine, mocetinostat, panobinostat, and valproic acid (VPA). Treatment effects were determined by cell proliferation and colony forming assays. Expression of genes were assessed by real-time quantitative PCR. The most promising epi-drug for combination therapy was studied in immune competent mice. Intratumor changes were defined using NanoString PanCancer panel IO360. Results: All epi-drugs, except hydralazine, potentiated the gemcitabine response in KPC3 cells (range decrease IC50 value 1.7−2-fold; p < 0.001). On colony formation, the cytotoxic effect of 0.5 ng/mL gemcitabine was 1.4 to 6.3 times stronger (p < 0.01). Two out of three drug-transporter genes were strongly upregulated following epi-drug treatment (a range fold increase of 17−124 and 9−60 for Slc28a1 and Slc28a3, respectively; all p < 0.001). VPA combined with gemcitabine significantly reduced tumor size with 74% compared to vehicle-treated mice and upregulated expression of immune-related pathways (range pathway score 0.86−1.3). Conclusions: These results provide a strong rationale for combining gemcitabine with VPA treatment. For the first time, we present intratumor changes and show activation of the immune system. Clinical trials are warranted to assess efficacy and safety of this novel combination in pancreatic cancer patients.
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Sanaei M, Kavoosi F. Histone Deacetylases and Histone Deacetylase Inhibitors: Molecular Mechanisms of Action in Various Cancers. Adv Biomed Res 2019; 8:63. [PMID: 31737580 PMCID: PMC6839273 DOI: 10.4103/abr.abr_142_19] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 09/22/2019] [Accepted: 09/23/2019] [Indexed: 01/15/2023] Open
Abstract
Epigenetic modifications such as histone modification play an important role in tumorigenesis. There are several evidence that histone deacetylases (HDACs) play a key role in cancer induction and progression by histone deacetylation. Besides, histone acetylation is being accessed as a therapeutic target because of its role in regulating gene expression. HDAC inhibitors (HDACIs) are a family of synthetic and natural compounds that differ in their target specificities and activities. They affect markedly cancer cells, inducing cell differentiation, cell cycle arrest and cell death, reduction of angiogenesis, and modulation of the immune system. Here, we summarize the mechanisms of HDACs and the HDACIs in several cancers. An online search of different sources such as PubMed, ISI, and Scopus was performed to find available data on mechanisms and pathways of HDACs and HDACIs in different cancers. The result indicated that HDACs induce cancer through multiple mechanisms in various tissues. This effect can be inhibited by HDACIs which affect cancer cell by different pathways such as cell differentiation, cell cycle arrest, and cell death. In conclusion, these findings indicate that the HDACs play a major role in carcinogenesis through various pathways, and HDACIs can inhibit HDAC activity by multiple mechanisms resulting in cell cycle arrest, cell growth inhibition, and apoptosis induction.
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Affiliation(s)
- Masumeh Sanaei
- From the Research Center for Noncommunicable Diseases, Jahrom University of Medical Sciences, Jahrom, Iran
| | - Fraidoon Kavoosi
- From the Research Center for Noncommunicable Diseases, Jahrom University of Medical Sciences, Jahrom, Iran
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Zhang F, Chen Z, Shao C, Huang Q. Is level of acetylation directly correlated to radiation sensitivity of cancer cell? Mutat Res 2018; 813:13-19. [PMID: 30576946 DOI: 10.1016/j.mrfmmm.2018.11.001] [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: 08/21/2018] [Revised: 11/01/2018] [Accepted: 11/20/2018] [Indexed: 02/05/2023]
Abstract
It is known that histone deacetylase inhibitors (HDACis) can modify acetylation of tumor cells and affect radiation sensitivity, or, radiosensitivity. While previous studies showed that trichostatin A (TSA, a typical HDACi) could enhance cell acetylation and so be used as radiation-sensitizer in radiotherapy, we questioned if the radiosensitivity is correlated with cellular acetylation directly. So we inspected radiation response of HeLa cells treated with TSA and investigated the time-dependent effect on radiosensitivity. To our surprise, HeLa cells treated with 200 nM TSA for shorter period (6 h) had relatively higher acetylation level but apparently less radiation damage compared to the irradiated cells with same radiation dose treatment of TSA but for longer time (24 h) with lower acetylation level, gainsaying the direct relationship between acetylation and radiosensitivity. We explained that the anti-oxidation activity for the combined treatments with TSA-radiation gave rise to the enhanced radiation protection of the cells at certain period of time. This work has therefore for the first time presented the experimental evidence showing that there is no direct relationship between acetylation and radiation sensitivity, and our results may also provide the guidance for optimized radiotherapy assisted by HDACis in cancer treatment.
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Affiliation(s)
- Fengqiu Zhang
- Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Institute of Technical Biology and Agriculture Engineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China; Henan Key Laboratory of Ion-beam Bioengineering, School of Physical Engineering, Zhengzhou University, Zhengzhou, 450052, China; University of Science &Technology of China, Hefei, 230026, China
| | - Zhu Chen
- Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Institute of Technical Biology and Agriculture Engineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China; University of Science &Technology of China, Hefei, 230026, China
| | - Changsheng Shao
- Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Institute of Technical Biology and Agriculture Engineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China; University of Science &Technology of China, Hefei, 230026, China
| | - Qing Huang
- Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Institute of Technical Biology and Agriculture Engineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China; University of Science &Technology of China, Hefei, 230026, China.
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Pegoraro NS, Mattiazzi J, da Silveira EF, Azambuja JH, Braganhol E, Cruz L. Improved photostability and cytotoxic effect of coenzyme Q10 by its association with vitamin E acetate in polymeric nanocapsules. Pharm Dev Technol 2017; 23:400-406. [PMID: 28521578 DOI: 10.1080/10837450.2017.1332641] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The present study showed the development of nanocapsules containing the association of the coenzyme Q10 and vitamin E acetate and the evaluation of their effect on in vitro cells culture of malignant glioma and melanoma. In order to investigate if nanocapsules are able to protect coenzyme Q10 from degradation under UVC radiation, a photostability study was carried out. For this, three concentrations of vitamin E acetate were evaluated (1%, 2%, or 3%). Nanocapsules presented suitable physicochemical characteristics and were able to protect coenzyme Q10 from photodegradation. In addition, this protection was influenced by higher vitamin E acetate concentrations, attributing to this oil an important role on coenzyme Q10 photostabilization. Regarding to in vitro citotoxicity assay, nanocapsules containing coenzyme Q10 and 2% vitamin E significantly reduced glioma and melanoma cell viability in 61% and 66%, respectively. In this sense, these formulations represent interesting platforms for the delivery of coenzyme Q10 and vitamin E acetate, presenting effect on the reduction of malignant cells viability.
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Affiliation(s)
- Natháli S Pegoraro
- a Programa de Pós-Graduação em Ciências Farmacêuticas, Centro de Ciências da Saúde , Universidade Federal de Santa Maria , Santa Maria , Brasil
| | - Juliane Mattiazzi
- a Programa de Pós-Graduação em Ciências Farmacêuticas, Centro de Ciências da Saúde , Universidade Federal de Santa Maria , Santa Maria , Brasil
| | - Elita F da Silveira
- b Programa de Pós-Graduação em Bioquímica e Bioprospecção, Centro de Ciências Químicas, Farmacêuticas e de Alimentos , Universidade Federal de Pelotas , Pelotas , Brasil
| | - Juliana H Azambuja
- b Programa de Pós-Graduação em Bioquímica e Bioprospecção, Centro de Ciências Químicas, Farmacêuticas e de Alimentos , Universidade Federal de Pelotas , Pelotas , Brasil.,c Programa de Pós-Graduação em Biociências , Universidade Federal de Ciências da Saúde , Porto Alegre , Brasil
| | - Elizandra Braganhol
- b Programa de Pós-Graduação em Bioquímica e Bioprospecção, Centro de Ciências Químicas, Farmacêuticas e de Alimentos , Universidade Federal de Pelotas , Pelotas , Brasil.,c Programa de Pós-Graduação em Biociências , Universidade Federal de Ciências da Saúde , Porto Alegre , Brasil
| | - Letícia Cruz
- a Programa de Pós-Graduação em Ciências Farmacêuticas, Centro de Ciências da Saúde , Universidade Federal de Santa Maria , Santa Maria , Brasil.,d Departamento de Farmácia Industrial , Universidade Federal de Santa Maria , Santa Maria , Brasil
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Yar Saglam AS, Yilmaz A, Onen HI, Alp E, Kayhan H, Ekmekci A. HDAC inhibitors, MS-275 and salermide, potentiates the anticancer effect of EF24 in human pancreatic cancer cells. EXCLI JOURNAL 2016; 15:246-55. [PMID: 27330528 PMCID: PMC4908665 DOI: 10.17179/excli2016-186] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 03/07/2016] [Indexed: 02/06/2023]
Abstract
Histone deacetylases (HDACs) play a major role in the regulation of chromatin structure and gene expression by changing acetylation status of histone and non-histone proteins. MS-275 (entinostat, MS) is a well-known benzamide-based HDACI and Salermide (SAL), a reverse amide compound HDACI, have antiproliferative effects on several human cancer cells. In this study, we aimed to investigate the effects of HDACIs (MS and SAL) alone and/or combined use with EF24 (EF), a novel synthetic curcumin analog, on human pancreatic cancer cell line (BxPC-3). In vitro, BxPC-3 cells were exposed to varying concentrations of MS, SAL with or without EF, and their effects on cell viability, acetylated Histone H3 and H4 levels, cytotoxicity, and cleaved caspase 3 levels, and cell cycle distribution were measured. The viability of BxPC-3 cells decreased significantly after treatment with EF, MS and SAL treatments. MS and SAL treatment increased the acetylation of histone H3 and H4 in a dose dependent manner. MS and SAL alone or combined with EF were increased the number of cells in G1 phase. In addition, treatment with agents significantly decreased the ratio of cell in G2/M phase. There were significant dose-dependent increases at cleaved Caspase 3 levels after MS treatment but not after SAL treatment. Our results showed that HDAC inhibitors (MS and SAL), when combined with EF, may effectively reduce pancreatic cancer cell (BxPC-3) progression and stop the cell cycle at G1 phase. Further molecular analyses are needed to understand the fundamental molecular consequences of HDAC inhibition in pancreas cancer cells.
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Affiliation(s)
- Atiye Seda Yar Saglam
- Department of Medical Biology and Genetics, Faculty of Medicine, Gazi University, Besevler, Ankara, Turkey
| | - Akin Yilmaz
- Department of Medical Biology, Faculty of Medicine, Hitit University, Çorum, Turkey
| | - Hacer Ilke Onen
- Department of Medical Biology and Genetics, Faculty of Medicine, Gazi University, Besevler, Ankara, Turkey
| | - Ebru Alp
- Department of Medical Biology, Faculty of Medicine, Giresun University, Giresun, Turkey
| | - Handan Kayhan
- Department of Adult Heamatology, Faculty of Medicine, Gazi University, Besevler, Ankara, Turkey
| | - Abdullah Ekmekci
- Department of Medical Biology and Genetics, Faculty of Medicine, Gazi University, Besevler, Ankara, Turkey
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Chiorean EG, Coveler AL. Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies. Drug Des Devel Ther 2015; 9:3529-45. [PMID: 26185420 PMCID: PMC4500614 DOI: 10.2147/dddt.s60328] [Citation(s) in RCA: 134] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Pancreatic cancer is the fourth leading cause of cancer death in the US and is expected to become the second leading cause of cancer-related deaths in the next decade. Despite 5-fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel significantly improving outcomes for metastatic cancer, refractory disease still poses significant challenges. Difficulties with early detection and the inherent chemo- and radio-resistant nature of this malignancy led to attempts to define the sequential biology of pancreatic cancer in order to improve survival outcomes. Pancreatic adenocarcinoma is characterized by several germline or acquired genetic mutations, the most common being KRAS (90%), CDK2NA (90%), TP53 (75%-90%), DPC4/SMAD4 (50%). In addition, the tumor microenvironment, chemoresistant cancer stem cells, and the desmoplastic stroma have been the target of some promising clinical investigations. Among the core pathways reproducibly shown to lead the development and progression of this disease, DNA repair, apoptosis, G1/S cell cycle transition, KRAS, Wnt, Notch, Hedgehog, TGF-beta, and other cell invasion pathways, have been the target of "precision therapeutics". No single molecularly targeted therapeutic though has been uniformly successful, probably due to the tumor heterogeneity, but biomarker research is evolving and it hopes to select more patients likely to benefit. Recent reports note activity with immunotherapies such as CD40 agonists, CCR2 inhibitors, cancer vaccines, and novel combinations against the immunosuppressive tumor milieu are ongoing. While many obstacles still exist, clearly we are making progress in deciphering the heterogeneity within pancreatic cancers. Integrating conventional and immunological targeting will be the key to effective treatment of this deadly disease.
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Affiliation(s)
| | - Andrew L Coveler
- Department of Medicine, Division of Oncology, University of Washington, Seattle, WA, USA
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Tang SC, Chen YC. Novel therapeutic targets for pancreatic cancer. World J Gastroenterol 2014; 20:10825-10844. [PMID: 25152585 PMCID: PMC4138462 DOI: 10.3748/wjg.v20.i31.10825] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 02/13/2014] [Accepted: 04/09/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer has become the fourth leading cause of cancer death in the last two decades. Only 3%-15% of patients diagnosed with pancreatic cancer had 5 year survival rate. Drug resistance, high metastasis, poor prognosis and tumour relapse contributed to the malignancies and difficulties in treating pancreatic cancer. The current standard chemotherapy for pancreatic cancer is gemcitabine, however its efficacy is far from satisfactory, one of the reasons is due to the complex tumour microenvironment which decreases effective drug delivery to target cancer cell. Studies of the molecular pathology of pancreatic cancer have revealed that activation of KRAS, overexpression of cyclooxygenase-2, inactivation of p16INK4A and loss of p53 activities occurred in pancreatic cancer. Co-administration of gemcitabine and targeting the molecular pathological events happened in pancreatic cancer has brought an enhanced therapeutic effectiveness of gemcitabine. Therefore, studies looking for novel targets in hindering pancreatic tumour growth are emerging rapidly. In order to give a better understanding of the current findings and to seek the direction in future pancreatic cancer research; in this review we will focus on targets suppressing tumour metastatsis and progression, KRAS activated downstream effectors, the relationship of Notch signaling and Nodal/Activin signaling with pancreatic cancer cells, the current findings of non-coding RNAs in inhibiting pancreatic cancer cell proliferation, brief discussion in transcription remodeling by epigenetic modifiers (e.g., HDAC, BMI1, EZH2) and the plausible therapeutic applications of cancer stem cell and hyaluronan in tumour environment.
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Jafary H, Ahmadian S, Soleimani M. Synergistic anticancer activity of valproate combined with nicotinamide enhances anti-proliferation response and apoptosis in MIAPaca2 cells. Mol Biol Rep 2014; 41:3801-3812. [PMID: 24595447 DOI: 10.1007/s11033-014-3246-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2013] [Accepted: 02/07/2014] [Indexed: 01/01/2023]
Abstract
Histone deacetylase is strongly associated with epigenetic regulation and carcinogenesis, and its inhibitors can induce cell cycle arrest and apoptosis of the cancer cells. In this study we aimed to examine the antiproliferative effects a combination of the valproate with nicotinamide in MIAPaca2 cell line. We revealed that valproate acted in a synergistic/additive with nicotinamide to inhibit the proliferation and induction of apoptosis in MIAPaca2 cancer cell line. MIAPaca2 was treated with various concentrations of valproate. The MTT assay and colony formation in soft agar indicated that valproate at 0.5 mM, when used alone weakly, suppressed proliferation of cells (37 ± 3.02%) whereas the combination treatment of valproate + nicotinamide significantly suppressed cell proliferation (58 ± 3.5%). The effect of nicotinamide at 25 mM on cell proliferation and cell colonization induced 50% apoptosis of MIAPaca2 cells. To identify the anti-proliferation and apoptotic effects of valproate and nicotinamide we performed flow cytometric and microscopic analyses. The results indicated significant apoptosis induction and nuclear morphological alterations greater than when valproate was used alone. Furthermore, western blot analyses was performed to study the role of acetyl-histone H3 levels, and quantitative RNA expression analyses were performed on expression of thrombospondin (TSP) and maspin genes in MIAPaca2. We found that the combination treatment of valproate + nicotinamide enhanced the expression of maspin and TSP genes and the biological response of the cell line was correlated with the increase of histone H3 acetylation after nicotinamide and valproate application. Together our findings indicate that valproate which act as inhibitor of cell proliferation and inducer of apoptosis in human cancer MIAPaca2 cells when used in combination with nicotinamide makes it a potentially good candidate for new anticancer drug development.
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Affiliation(s)
- Hanieh Jafary
- Department of Biochemistry, Institute of Biochemistry and Biophysics, University of Tehran, P.O. Box 13145-1384, Tehran, Iran
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Ouaïssi M, Turrini O, Hubert C, Louis G, Gigot JF, Mabrut JY. Vascular resection during radical resection of pancreatic adenocarcinomas: evolution over the past 15 years. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2014; 21:623-38. [PMID: 24890182 DOI: 10.1002/jhbp.122] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
This literature review aimed to critically analyze oncological results of vascular resection during pancreatectomy for adenocarcinoma in the light of the concept evolution of locally advanced tumors and microscopic complete resection. The literature search was conducted in PubMed and Medline for the period June 1994 to December 2012, retaining English as the language of publication. The review of 12 publications indicated that mortality and morbidity rates were not significantly different for pancreatectomy with or without venous resection (VR). Six comparative studies showed worse long-term survival in the VR group, though one meta-analysis, albeit with a significant population heterogeneity, demonstrated that the overall survival between VR and the control group was similar (12% vs. 17%). The compilation of 13 comparative studies showed a significantly lower rate of complete microscopic resection in the VR patient group compared to controls (63% vs. 77%; P = 0.001). Concerning pancreatectomy combined to arterial resection, the literature review indicated a significantly greater mortality and morbidity rate and a lower survival rate compared to pancreatic resection alone. Conflicting results concerning the long-term outcome of VR was due to the heterogeneity of the patient population. Since the only chance to cure patients of pancreatic adenocarcinoma is to obtain free resection margins, VR is a valid therapeutic option. But combined arterial resection to pancreatic resection does not appear to be recommended.
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Affiliation(s)
- Mehdi Ouaïssi
- Department of Digestive Surgery, Timone Hospital, Marseille, France
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Wightman F, Lu HK, Solomon AE, Saleh S, Harman AN, Cunningham AL, Gray L, Churchill M, Cameron PU, Dear AE, Lewin SR. Entinostat is a histone deacetylase inhibitor selective for class 1 histone deacetylases and activates HIV production from latently infected primary T cells. AIDS 2013; 27:2853-62. [PMID: 24189584 DOI: 10.1097/qad.0000000000000067] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVES To compare the potency, toxicity and mechanism of action of multiple histone deacetylase inhibitors (HDACi) in activating HIV production from latency. DESIGN In-vitro analysis of HDACi in a primary T-cell model of HIV latency and latently infected cell lines. METHODS Latently infected chemokine ligand 19 (CCL19)-treated CD4⁺ T cells and the latently infected cell lines ACH2 and J-Lat were treated with a panel of HDACi, including entinostat, vorinostat, panonbinostat and MCT3. Viral production and cell viability were compared. Expression of cellular HDACs was measured by western blot and PCR. Association of HDACs with the HIV long-terminal repeat (LTR) using latently infected CCL19-treated primary CD4⁺ T cells in the presence and absence of specific HDACi was determined by chromatin immunoprecipitation (ChIP). RESULTS We demonstrated considerable variation in the potency and toxicity of HDACi in latently infected primary CD4⁺ T cells and cell lines. All HDACi tested activated HIV production in latently infected primary T cells with greatest potency demonstrated with entinostat and vorinostat and greatest toxicity with panobinostat. Following the addition of HDACi in vitro, there were no changes in markers of T-cell activation or expression of the HIV coreceptors chemokine (C-X-C motif) receptor 4 (CXCR4) or chemokine (C-C motif) receptor type 5 (CCR5). ChIP analysis of latently infected CCL19-treated primary CD4⁺ T cells showed binding by HDAC1, HDAC2 and HDAC3 to the LTR with removal of HDAC1 and HDAC2 following treatment with the HDACi vorinostat and HDAC1 only following treatment with entinostat. CONCLUSION The HDACi entinostat, selective for inhibition of class I HDACs, induced virus expression in latently infected primary CD4⁺ T cells making this compound an attractive novel option for future clinical trials.
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The anti-tumor effect of HDAC inhibition in a human pancreas cancer model is significantly improved by the simultaneous inhibition of cyclooxygenase 2. PLoS One 2013; 8:e75102. [PMID: 24040391 PMCID: PMC3770617 DOI: 10.1371/journal.pone.0075102] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2013] [Accepted: 08/12/2013] [Indexed: 12/30/2022] Open
Abstract
Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer death worldwide, with no satisfactory treatment to date. In this study, we tested whether the combined inhibition of cyclooxygenase-2 (COX-2) and class I histone deacetylase (HDAC) may results in a better control of pancreatic ductal adenocarcinoma. The impact of the concomitant HDAC and COX-2 inhibition on cell growth, apoptosis and cell cycle was assessed first in vitro on human pancreas BxPC-3, PANC-1 or CFPAC-1 cells treated with chemical inhibitors (SAHA, MS-275 and celecoxib) or HDAC1/2/3/7 siRNA. To test the potential antitumoral activity of this combination in vivo, we have developed and characterized, a refined chick chorioallantoic membrane tumor model that histologically and proteomically mimics human pancreatic ductal adenocarcinoma. The combination of HDAC1/3 and COX-2 inhibition significantly impaired proliferation of BxPC-3 cells in vitro and stalled entirely the BxPC-3 cells tumor growth onto the chorioallantoic membrane in vivo. The combination was more effective than either drug used alone. Consistently, we showed that both HDAC1 and HDAC3 inhibition induced the expression of COX-2 via the NF-kB pathway. Our data demonstrate, for the first time in a Pancreatic Ductal Adenocarcinoma (PDAC) model, a significant action of HDAC and COX-2 inhibitors on cancer cell growth, which sets the basis for the development of potentially effective new combinatory therapies for pancreatic ductal adenocarcinoma patients.
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Zou Y, Howell GM, Humphrey LE, Wang J, Brattain MG. Ron knockdown and Ron monoclonal antibody IMC-RON8 sensitize pancreatic cancer to histone deacetylase inhibitors (HDACi). PLoS One 2013; 8:e69992. [PMID: 23922886 PMCID: PMC3726703 DOI: 10.1371/journal.pone.0069992] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2013] [Accepted: 06/13/2013] [Indexed: 02/06/2023] Open
Abstract
Recepteur d'origine nantais (Ron) is overexpressed in a panel of pancreatic cancer cells and tissue samples from pancreatic cancer patients. Ron can be activated by its ligand macrophage stimulating protein (MSP), thereby activating oncogenic signaling pathways. Crosstalk between Ron and EGFR, c-Met, or IGF-1R may provide a mechanism underlying drug resistance. Thus, targeting Ron may represent a novel therapeutic strategy. IMC-RON8 is the first Ron monoclonal antibody (mAb) entering clinical trial for targeting Ron overexpression. Our studies show IMC-RON8 downmodulated Ron expression in pancreatic cancer cells and significantly blocked MSP-stimulated Ron activation, downstream Akt and ERK phosphorylation, and survivin mRNA expression. IMC-RON8 hindered MSP-induced cell migration and reduced cell transformation. Histone deacetylase inhibitors (HDACi) are reported to target expression of various genes through modification of nucleosome histones and non-histone proteins. Our work shows HDACi TSA and Panobinostat (PS) decreased Ron mRNA and protein expression in pancreatic cancer cells. PS also reduced downstream signaling of pAkt, survivin, and XIAP, as well as enhanced cell apoptosis. Interestingly, PS reduced colony formation in Ron knockdown cells to a greater extent than Ron scramble control cells in colony formation and soft agarose assays. IMC-RON8 could also sensitize pancreatic cancer cells to PS, as reflected by reduced colony numbers and size in combination treatment with IMC-RON8 and PS compared to single treatment alone. The co-treatment further reduced Ron expression and pAkt, and increased PARP cleavage compared to either treatment alone. This study suggests the potential for a novel combination approach which may ultimately be of value in treatment of pancreatic cancer.
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Affiliation(s)
- Yi Zou
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Gillian M. Howell
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Lisa E. Humphrey
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Jing Wang
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Michael G. Brattain
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
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Koutsounas I, Giaginis C, Patsouris E, Theocharis S. Current evidence for histone deacetylase inhibitors in pancreatic cancer. World J Gastroenterol 2013; 19:813-28. [PMID: 23430136 PMCID: PMC3574878 DOI: 10.3748/wjg.v19.i6.813] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Revised: 10/18/2011] [Accepted: 01/05/2013] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most aggressive human cancers, with more than 200 000 deaths worldwide every year. Despite recent efforts, conventional treatment approaches, such as surgery and classic chemotherapy, have only slightly improved patient outcomes. More effective and well-tolerated therapies are required to reverse the current poor prognosis of this type of neoplasm. Among new agents, histone deacetylase inhibitors (HDACIs) are now being tested. HDACIs have multiple biological effects related to acetylation of histones and many non-histone proteins that are involved in regulation of gene expression, apoptosis, cell cycle progression and angiogenesis. HDACIs induce cell cycle arrest and can activate the extrinsic and intrinsic pathways of apoptosis in different cancer cell lines. In the present review, the main mechanisms by which HDACIs act in pancreatic cancer cells in vitro, as well as their antiproliferative effects in animal models are presented. HDACIs constitute a promising treatment for pancreatic cancer with encouraging anti-tumor effects, at well-tolerated doses.
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15
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McCleary-Wheeler AL, Lomberk GA, Weiss FU, Schneider G, Fabbri M, Poshusta TL, Dusetti NJ, Baumgart S, Iovanna JL, Ellenrieder V, Urrutia R, Fernandez-Zapico ME. Insights into the epigenetic mechanisms controlling pancreatic carcinogenesis. Cancer Lett 2012; 328:212-21. [PMID: 23073473 DOI: 10.1016/j.canlet.2012.10.005] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2012] [Revised: 10/02/2012] [Accepted: 10/08/2012] [Indexed: 12/14/2022]
Abstract
During the last couple decades, we have significantly advanced our understanding of mechanisms underlying the development of pancreatic ductual adenocarcinoma (PDAC). In the late 1990s into the early 2000s, a model of PDAC development and progression was developed as a multi-step process associated with the accumulation of somatic mutations. The correlation and association of these particular genetic aberrations with the establishment and progression of PDAC has revolutionized our understanding of this process. However, this model leaves out other molecular events involved in PDAC pathogenesis that contribute to its development and maintenance, specifically those being epigenetic events. Thus, a new model considering the new scientific paradigms of epigenetics will provide a more comprehensive and useful framework for understanding the pathophysiological mechanisms underlying this disease. Epigenetics is defined as the type of inheritance not based on a particular DNA sequence but rather traits that are passed to the next generation via DNA and histone modifications as well as microRNA-dependent mechanisms. Key tumor suppressors that are well established to play a role in PDAC may be altered through hypermethylation, and oncogenes can be upregulated secondary to permissive histone modifications. Factors involved in tumor invasiveness can be aberrantly expressed through dysregulated microRNAs. A noteworthy characteristic of epigenetic-based inheritance is its reversibility, which is in contrast to the stable nature of DNA sequence-based alterations. Given this nature of epigenetic alterations, it becomes imperative that our understanding of epigenetic-based events promoting and maintaining PDAC continues to grow.
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Affiliation(s)
- Angela L McCleary-Wheeler
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Rochester, MN, USA
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16
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Ouaïssi M, Giger U, Louis G, Sielezneff I, Farges O, Sastre B. Ductal adenocarcinoma of the pancreatic head: A focus on current diagnostic and surgical concepts. World J Gastroenterol 2012; 18:3058-69. [PMID: 22791941 PMCID: PMC3386319 DOI: 10.3748/wjg.v18.i24.3058] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2011] [Revised: 12/13/2011] [Accepted: 04/28/2012] [Indexed: 02/06/2023] Open
Abstract
Complete surgical resection still remains the only possibility of curing pancreatic cancer, however, only 10% of patients undergo curative surgery. Pancreatic resection currently remains the only method of curing patients, and has a 5-year overall survival rate between 7%-34% compared to a median survival of 3-11 mo for unresected cancer. Pancreatic surgery is a technically demanding procedure requiring highly standardized surgical techniques. Nevertheless, even in experienced hands, perioperative morbidity rates (delayed gastric emptying, pancreatic fistula etc.) are as high as 50%. Different strategies to reduce postoperative morbidity, such as different techniques of gastroenteric reconstruction (pancreatico-jejunostomy vs pancreatico-gastrostomy), intraoperative placement of a pancreatic main duct stent or temporary sealing of the main pancreatic duct with fibrin glue have not led to a significant improvement in clinical outcome. The perioperative application of somatostatin or its analogues may decrease the incidence of pancreatic fistulas in cases with soft pancreatic tissue and a small main pancreatic duct (< 3 mm). The positive effects of external pancreatic main duct drainage and antecolic gastrointestinal reconstruction have been observed to decrease the rate of pancreatic fistulas and delayed gastric emptying, respectively. Currently, the concept of extended radical lymphadenectomy has been found to be associated with higher perioperative morbidity, but without any positive impact on overall survival. However, there is growing evidence that portal vein resections can be performed with acceptable low perioperative morbidity and mortality but does not achieve a cure.
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HDAC gene expression in pancreatic tumor cell lines following treatment with the HDAC inhibitors panobinostat (LBH589) and trichostatine (TSA). Pancreatology 2012; 12:146-55. [PMID: 22487525 DOI: 10.1016/j.pan.2012.02.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2011] [Revised: 02/18/2012] [Accepted: 02/19/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND In this study, the effect of LBH589 and trichostatin (TSA), a standard histone deacetylase inhibitor (HDACi) toward the growth of pancreatic cancer cell lines was studied. Thus, we examined for the first time, the HDAC family gene expression levels before and after drug treatment. METHODS Several human pancreatic cancer cell lines (Panc-1, BxPC-3, SOJ-6) and a normal human pancreatic duct immortalized epithelial cell line (HPDE/E6E7) were used as target cells. The cell growth was measured by MTT assay, cell cycle alteration, membrane phosphatidylserine exposure, DNA fragmentation, mitochondrial membrane potential loss, RT-PCR and Western blots were done using standard methods. The effect of drugs on tumor growth in vivo was studied using subcutaneous xenograft model. RESULTS Except in the case of certain HDAC gene/tumor cell line couples: (SIRT1/HPDE-SOJ6/TSA- or LBH589-treated cells; LBH589-treated Panc-1 Cells; HDAC2/BxPC-3/LBH589-treated cells or TSA-treated SOJ-6-1 cells), there were no major significant changes of HDACs genes transcription in cells upon drug treatment. However, significant variation in HDACs and SIRTs protein expression levels could be seen among individual cell samples. The in vivo results showed that LBH589 formulation exhibited similar tumor reduction efficacy as the commercial drug gemcitabine. CONCLUSION Our data demonstrate that LBH589 induced the death of pancreatic tumor cell by apoptosis. In line with its in vitro activity, LBH589 achieved a significant reduction in tumor growth in BxPC-3 pancreatic tumor cell line subcutaneous xenograft mouse model. Furthermore, exploring the impact of LBH589 on HDACs encoding genes expression revealed for the first time that some of them, depending on the cell line considered, seem to be regulated during translation.
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Abstract
INTRODUCTION Without any alteration of DNA sequence, heritable changes in gene expression, caused by epigenetic pathways, are gaining a spotlight in research of diseases, and in particular, cancer. Although the dominant paradigm in cancer research, proposed by Vogelstein, suggested that cancer progression was caused by a sequential accumulation of genetic aberrations, basic science studies in epigenetics have now advanced our knowledge enough to apply its concepts and methodology to the study of cancer. In fact, chromatin dynamics and small RNAs are altered far more prevalently in cancer than genetic alterations and most important, can be reversible, lending themselves as attractive therapeutic targets. CONCLUDING REMARKS In the current review, the inactivation of p16 will be utilized as the most prominent example of epigenetic silencing of a tumor suppressor gene in pancreatic cancer. In addition, fundamental insight will be given into why and how epigenetics can be targeted for therapeutic purposes. This knowledge will help the reader in determining the breadth and depth of this field of study with potentially high impact to oncology.
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Affiliation(s)
- Gwen A Lomberk
- Laboratory of Epigenetics and Chromatin Dynamics, Gastroenterology Research Unit, 10-24C Guggenheim Building, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
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19
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Zhou W, Liang IC, Yee NS. Histone deacetylase 1 is required for exocrine pancreatic epithelial proliferation in development and cancer. Cancer Biol Ther 2011; 11:659-670. [PMID: 21301206 PMCID: PMC3084970 DOI: 10.4161/cbt.11.7.14720] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2010] [Revised: 01/04/2011] [Accepted: 01/04/2011] [Indexed: 02/08/2023] Open
Abstract
Histone deacetylases (HDACs) play important roles in the epigenetic control of development, and aberrant expression of HDACs has been implicated in human diseases including cancer. Among the mammalian HDACs, HDAC1 has been extensively studied, but its role in exocrine pancreatic morphogenesis and cancer is still poorly understood. The goal of this study is to determine the functional role of HDAC1 in normal development of exocrine pancreas using zebrafish as the model organism as well as in human pancreatic adenocarcinoma. The zebrafish germline loss-of-function mutation hdac1(hi1618) caused impaired cell cycle progression in pancreatic epithelia, resulting in growth arrest and dysmorphogenesis of exocrine pancreas. In human pancreatic adenocarcinoma tissues and cell lines, HDAC1 was expressed at variably elevated levels. RNA interference-induced silencing of HDAC1 diminished proliferation of the cancer cells and cell cycle progression. The proliferative arrest in the developing exocrine pancreas and pancreatic cancer cells was associated with up-regulated expression of the cyclin-dependent kinase inhibitors and the sonic hedgehog signaling components. This study indicates that HDAC1 is required for pancreatic epithelial proliferation in development and cancer. We hypothesize that aberrant expression of HDAC1 modulates the developmental and signaling pathways in exocrine pancreatic epithelia and consequently the genes required for cellular proliferation during development and progression of pancreatic neoplasia.
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Affiliation(s)
- Weiqiang Zhou
- Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Internal Medicine, Carver College of Medicine, Program of Cancer Signaling and Experimental Therapeutics, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, USA
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Lundh M, Christensen DP, Rasmussen DN, Mascagni P, Dinarello CA, Billestrup N, Grunnet LG, Mandrup-Poulsen T. Lysine deacetylases are produced in pancreatic beta cells and are differentially regulated by proinflammatory cytokines. Diabetologia 2010; 53:2569-78. [PMID: 20878317 DOI: 10.1007/s00125-010-1892-8] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2010] [Accepted: 07/13/2010] [Indexed: 12/25/2022]
Abstract
AIMS/HYPOTHESIS Cytokine-induced beta cell toxicity is abrogated by non-selective inhibitors of lysine deacetylases (KDACs). The KDAC family consists of 11 members, namely histone deacetylases HDAC1 to HDAC11, but it is not known which KDAC members play a role in cytokine-mediated beta cell death. The aim of the present study was to examine the KDAC gene expression profile of the beta cell and to investigate whether KDAC expression is regulated by cytokines. In addition, the protective effect of the non-selective KDAC inhibitor ITF2357 and interdependent regulation of four selected KDACs were investigated. METHODS The beta cell line INS-1 and intact rat and human islets were exposed to cytokines with or without ITF2357. Expression of mRNA was assessed by real-time PCR and selected targets validated at the protein level by immunoblotting. Effects on cytokine-induced toxicity were investigated by in vitro assays. RESULTS Hdac1 to Hdac11 were expressed and differentially regulated by cytokines in INS-1 cells and rat islets. HDAC1, -2, -6 and -11 were found to be expressed and regulated by cytokines in human islets. ITF2357 protected against cytokine-induced beta cell apoptosis and counteracted cytokine-induced attenuation of basal insulin secretion. In addition, cytokine-induced regulation of Hdac2 and Hdac6, but not Hdac1 and Hdac11, was reduced by KDAC inhibition. CONCLUSIONS/INTERPRETATION All classical KDAC genes are expressed by beta cells and differentially regulated by cytokines. Based on the relative expression levels and degree of regulation by cytokines, we propose that HDAC1, -2, -6 and -11 are of particular importance for beta cell function. These observations may help in the design of specific KDAC inhibitors to prevent beta cell destruction in situ and in islet grafts.
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Affiliation(s)
- M Lundh
- Center for Medical Research Methodology, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark
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21
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Rationale for possible targeting of histone deacetylase signaling in cancer diseases with a special reference to pancreatic cancer. J Biomed Biotechnol 2010; 2011:315939. [PMID: 20981265 PMCID: PMC2964042 DOI: 10.1155/2011/315939] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2010] [Revised: 09/09/2010] [Accepted: 09/23/2010] [Indexed: 01/26/2023] Open
Abstract
There is ongoing interest to identify signaling pathways and genes that play a key role in carcinogenesis and the development of resistance to antitumoral drugs. Given that histone deacetylases (HDACs) interact with various partners through complex molecular mechanims leading to the control of gene expression, they have captured the attention of a large number of researchers. As a family of transcriptional corepressors, they have emerged as important regulators of cell differentiation, cell cycle progression, and apoptosis. Several HDAC inhibitors (HDACis) have been shown to efficiently protect against the growth of tumor cells in vitro as well as in vivo. The pancreatic cancer which represents one of the most aggressive cancer still suffers from inefficient therapy. Recent data, although using in vitro tumor cell cultures and in vivo chimeric mouse model, have shown that some of the HDACi do express antipancreatic tumor activity. This provides hope that some of the HDACi could be potential efficient anti-pancreatic cancer drugs. The purpose of this review is to analyze some of the current data of HDACi as possible targets of drug development and to provide some insight into the current problems with pancreatic cancer and points of interest for further study of HDACi as potential molecules for pancreatic cancer adjuvant therapy.
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Hoskins C, Ouaissi M, Lima SC, Cheng WP, Loureirio I, Mas E, Lombardo D, Cordeiro-da-Silva A, Ouaissi A, Kong Thoo Lin P. In vitro and in vivo anticancer activity of a novel nano-sized formulation based on self-assembling polymers against pancreatic cancer. Pharm Res 2010; 27:2694-703. [PMID: 20872054 DOI: 10.1007/s11095-010-0268-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2010] [Accepted: 08/30/2010] [Indexed: 12/15/2022]
Abstract
PURPOSE To evaluate the in vitro and in vivo pancreatic anticancer activity of a nano-sized formulation based on novel polyallylamine grafted with 5% mole cholesteryl pendant groups (CH(5)-PAA). METHODS Insoluble novel anticancer drug, Bisnaphthalimidopropyldiaaminooctane (BNIPDaoct), was loaded into CH(5)-PAA polymeric self-assemblies by probe sonication. Hydrodynamic diameters and polydispersity index measurements were determined by photon correlation spectroscopy. The in vitro cytotoxicity evaluation of the formulation was carried out by the sulforhodamine B dye assay with human pancreatic adenocarcinoma BxPC-3 cells, while for the in vivo study, Xenograff mice were used. In vitro apoptotic cell death from the drug formulation was confirmed by flow cytometric analysis. RESULTS The aqueous polymer-drug formulation had a mean hydrodynamic size of 183 nm. The drug aqueous solubility was increased from negligible concentration to 0.3 mg mL(-1). CH(5)-PAA polymer alone did not exhibit cytotoxicity, but the new polymer-drug formulation showed potent in vitro and in vivo anticancer activity. The mode of cell death in the in vitro study was confirmed to be apoptotic. The in vivo results revealed that the CH(5)-PAA alone did not have any anti-proliferative effect, but the CH(5)-PAA-drug formulation exhibited similar tumour reduction efficacy as the commercial drug, gemcitabine. CONCLUSIONS The proposed formulation shows potential as pancreatic cancer therapeutics.
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Affiliation(s)
- Clare Hoskins
- School of Pharmacy and Life Sciences, Robert Gordon University, St. Andrew Street, Aberdeen, Scotland, UK
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Schneider G, Krämer OH, Fritsche P, Schüler S, Schmid RM, Saur D. Targeting histone deacetylases in pancreatic ductal adenocarcinoma. J Cell Mol Med 2009; 14:1255-63. [PMID: 19929947 PMCID: PMC3828843 DOI: 10.1111/j.1582-4934.2009.00974.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a median survival below 6 months and a 5-year survival rate below 1%. Effective therapies for locally advanced or metastatic tumours are missing and curatively resected patients relapse in over 80% of the cases. Although histone deacetylases (HDACs) are involved in the control of proliferation, apoptosis, differentiation, migration and angiogenesis of cancer cells, knowledge about the expression patterns and functions of individual HDAC isoenzymes in pancreatic cancer is sparse. This review summarizes the roles of HDACs as novel therapeutic targets and the molecular mode of action of HDAC-inhibitors (HDACI) in PDACs. Success of HDACI in clinical settings will depend on an increased knowledge of HDAC functions as well as on a better understanding of the mode of action of HDACI. Pre-clinical experimental data that constitute the basis for rational therapeutic strategies to treat PDAC are described here. Translating these rational-based therapies into the clinic will finally increase our chance to establish an effective HDACI-containing combination therapy effective against PDAC.
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Affiliation(s)
- Günter Schneider
- Technische Universität München, Klinikum rechts der Isar, II. Medizinische Klinik, München, Germany.
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