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Wang R, Li G, Gao F, Xu F, Li X, Zhang J, Li J, Guan X. Ultrasound-responsive spherical nucleic acid against c-Myc/PD-L1 to enhance anti-tumoral macrophages in triple-negative breast cancer progression. SCIENCE CHINA. LIFE SCIENCES 2024; 67:698-710. [PMID: 38151609 DOI: 10.1007/s11427-023-2433-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 08/31/2023] [Indexed: 12/29/2023]
Abstract
Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype because of its aggressive behavior and limited therapeutic targets. c-Myc is hyperactivated in the majority of TNBC tissues, however, it has been considered an "undruggable" target due to its disordered structure. Herein, we developed an ultrasound-responsive spherical nucleic acid (SNA) against c-Myc and PD-L1 in TNBC. It is a self-assembled and carrier-free system composed of a hydrophilic small-interfering RNA (siRNA) shell and a hydrophobic core made of a peptide nucleic acid (PNA)-based antisense oligonucleotide (ASO) and a sonosensitizer. We accomplished significant enrichment in the tumor by enhanced permeability and retention (EPR) effect, the controllable release of effective elements by ultrasound activation, and the combination of targeted therapy, immunotherapy and physiotherapy. Our study demonstrated significant anti-tumoral effects in vitro and in vivo. Mass cytometry showed an invigorated tumor microenvironment (TME) characterized by a significant alteration in the composition of tumor-associated macrophages (TAM) and decreased proportion of PD-1-positive (PD-1+) T effector cells after appropriate treatment of the ultrasound-responsive SNA (USNA). Further experiments verified that tumor-conditioned macrophages residing in the TME were transformed into the anti-tumoral population. Our finding offers a novel therapeutic strategy against the "undruggable" c-Myc, develops a new targeted therapy for c-Myc/PD-L1 and provides a treatment option for the TNBC.
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Affiliation(s)
- Runtian Wang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Gaigai Li
- State Key Laboratory of Analytical Chemistry for Life Sciences, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, 210023, China
| | - Fangyan Gao
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Feng Xu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Xintong Li
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Jian Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
| | - Jinbo Li
- State Key Laboratory of Analytical Chemistry for Life Sciences, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, 210023, China.
| | - Xiaoxiang Guan
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China.
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Li JY, Tian T, Han B, Yang T, Guo YX, Wu JY, Chen YS, Yang Q, Xie RJ. Suberoylanilide hydroxamic acid upregulates reticulophagy receptor expression and promotes cell death in hepatocellular carcinoma cells. World J Gastroenterol 2023; 29:5038-5053. [PMID: 37753370 PMCID: PMC10518741 DOI: 10.3748/wjg.v29.i34.5038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 07/15/2023] [Accepted: 08/15/2023] [Indexed: 09/08/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a common clinical condition with a poor prognosis and few effective treatment options. Potent anticancer agents for treating HCC must be identified. Epigenetics plays an essential role in HCC tumorigenesis. Suberoylanilide hydroxamic acid (SAHA), the most common histone deacetylase inhibitor agent, triggers many forms of cell death in HCC. However, the underlying mechanism of action remains unclear. Family with sequence similarity 134 member B (FAM134B)-induced reticulophagy, a selective autophagic pathway, participates in the decision of cell fate and exhibits anticancer activity. This study focused on the relationship between FAM134B-induced reticulophagy and SAHA-mediated cell death. AIM To elucidate potential roles and underlying molecular mechanisms of reticulophagy in SAHA-induced HCC cell death. METHODS The viability, apoptosis, cell cycle, migration, and invasion of SAHA-treated Huh7 and MHCC97L cells were measured. Proteins related to the reticulophagy pathway, mitochondria-endoplasmic reticulum (ER) contact sites, intrinsic mitochondrial apoptosis, and histone acetylation were quantified using western blotting. ER and lysosome colocalization, and mitochondrial Ca2+ levels were characterized via confocal microscopy. The level of cell death was evaluated through Hoechst 33342 staining and propidium iodide colocalization. Chromatin immunoprecipitation was used to verify histone H4 lysine-16 acetylation in the FAM134B promoter region. RESULTS After SAHA treatment, the proliferation of Huh7 and MHCC97L cells was significantly inhibited, and the migration and invasion abilities were greatly blocked in vitro. This promoted apoptosis and caused G1 phase cells to increase in a concentration-dependent manner. Following treatment with SAHA, ER-phagy was activated, thereby triggering autophagy-mediated cell death of HCC cells in vitro. Western blotting and chromatin immunoprecipitation assays confirmed that SAHA regulated FAM134B expression by enhancing the histone H4 lysine-16 acetylation in the FAM134B promoter region. Further, SAHA disturbed the Ca2+ homeostasis and upregulated the level of autocrine motility factor receptor and proteins related to mitochondria-endoplasmic reticulum contact sites in HCC cells. Additionally, SAHA decreased the mitochondrial membrane potential levels, thereby accelerating the activation of the reticulophagy-mediated mitochondrial apoptosis pathway and promoting HCC cell death in vitro. CONCLUSION SAHA stimulates FAM134B-mediated ER-phagy to synergistically enhance the mitochondrial apoptotic pathway, thereby enhancing HCC cell death.
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Affiliation(s)
- Jia-Yao Li
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Tian Tian
- Department of Eugenic Genetics, Guiyang Maternal and Child Health Care Hospital, Guiyang 550003, Guizhou Province, China
| | - Bing Han
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Ting Yang
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Yi-Xin Guo
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Jia-Yu Wu
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Yu-Si Chen
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Qin Yang
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Ru-Jia Xie
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
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Drees EEE, Pegtel DM. Circulating miRNAs as Biomarkers in Aggressive B Cell Lymphomas. Trends Cancer 2020; 6:910-923. [PMID: 32660885 DOI: 10.1016/j.trecan.2020.06.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 04/23/2020] [Accepted: 06/11/2020] [Indexed: 02/07/2023]
Abstract
B cell lymphomas are heterogeneous malignancies of hematological origin with vastly different biology and clinical outcomes. Histopathology of tissue biopsies and image-based assessment guide clinical decisions. Given that tissue biopsies cannot be frequently repeated and will not inform on systemic responses to the treatment, more accessible biomarkers, such as circulating miRNAs, are considered. Aberrant miRNA expression in lymphoma tissues and ongoing immune reactions may lead to miRNA alterations in circulation. miRNAs bound to extracellular vesicles (EVs) are of interest because of their role in intercellular communication and organ crosstalk. Herein, we highlight the role of miRNAs and EVs in B cell lymphomagenesis and explain how circulating miRNAs may be turned into robust liquid biopsy tests for aggressive B cell lymphoma.
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Affiliation(s)
- Esther E E Drees
- Amsterdam UMC, Vrije Universiteit Amsterdam, Exosomes Research Group, Department of Pathology, Cancer Center Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands
| | - D Michiel Pegtel
- Amsterdam UMC, Vrije Universiteit Amsterdam, Exosomes Research Group, Department of Pathology, Cancer Center Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands.
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Li QC, Xu H, Wang X, Wang T, Wu J. miR-34a increases cisplatin sensitivity of osteosarcoma cells in vitro through up-regulation of c-Myc and Bim signal. Cancer Biomark 2018; 21:135-144. [PMID: 29060932 DOI: 10.3233/cbm-170452] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND AND OBJECTIVE Osteosarcoma is the most common primary malignancy in bone. Patients who respond poorly to induction chemotherapy are at higher risk of adverse prognosis. The molecular basis for such poor prognosis remains unclear. Recently, increasing evidence has suggested decreased expression of miR-34a is observed in a number of cancer types, including human osteosarcoma, and decreased miR-34a is involved in drug resistance. However, the underlying molecular mechanisms of decreased miR-34a on cisplatin chemoresistance in osteosarcoma has not been reported. METHODS Osteosarcoma U2OS cells were transfected with miR-34a mimics for 48 h, then the cells were treated with 3.0 μm cisplatin for 24 h. Using siRNA targeting c-Myc and Bim to examine the relation between miR-34a, c-Myc and Bim expression exposure to cisplatin on cisplatin-induced apoptosis. RESULTS Treatment of U2OS cells with cisplatin induced cell apoptosis by upregulation of c-Myc -dependent Bim expression; Osteosarcoma U2OS cells transfected with miR-34a mimics (miR-34a/U2OS) induced cell apoptosis and inhibited cell survival, and increased the sensitivity of U2OS cells to cisplatin. U2OS cells transfected with miR-34a mimics upregulated the protein expression of c-Myc and Bim. Targeting c-Myc downregulated the expression of Bim in the miR-34a/U2OS cells. In addition, Targeting Bim reversed the chemeresistance of miR-34a/U2OS cells to cisplatin. CONCLUSIONS Our data indicated that miR-34a enhanced the sensitivity to cisplatin by upregulation of c-Myc and Bim pathway.
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Affiliation(s)
- Qi-Cai Li
- Department of Traumatology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.,Department of Traumatology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Haiyan Xu
- Department of Hemopurification Center, Yantaiyuhuangding Hospital, Yantai, Shandong, China.,Department of Traumatology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Xiaohui Wang
- Department of Traumatology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.,Department of Traumatology, The Central Hospital of Linyi, Linyi, Shandong, China
| | - Ting Wang
- Department of Traumatology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Jiang Wu
- Department of Hemopurification Center, Yantaiyuhuangding Hospital, Yantai, Shandong, China
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5
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Yuan Y, Kluiver J, Koerts J, de Jong D, Rutgers B, Abdul Razak FR, Terpstra M, Plaat BE, Nolte IM, Diepstra A, Visser L, Kok K, van den Berg A. miR-24-3p Is Overexpressed in Hodgkin Lymphoma and Protects Hodgkin and Reed-Sternberg Cells from Apoptosis. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:1343-1355. [PMID: 28432871 DOI: 10.1016/j.ajpath.2017.02.016] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Accepted: 02/16/2017] [Indexed: 12/11/2022]
Abstract
miRNAs play important roles in biological processes, such as proliferation, metabolism, differentiation, and apoptosis, whereas altered expression levels contribute to diseases, such as cancers. We identified miRNAs with aberrant expression in Hodgkin lymphoma (HL) and investigated their role in pathogenesis. Small RNA sequencing revealed 84 significantly differentially expressed miRNAs in HL cell lines as compared to germinal center B cells. Three up-regulated miRNAs-miR-23a-3p, miR-24-3p, and miR-27a-3p-were derived from one primary miRNA transcript. Loss-of-function analyses for these miRNAs and their seed family members resulted in decreased growth on miR-24-3p inhibition in three HL cell lines and of miR-27a/b-3p inhibition in one HL cell line. Apoptosis analysis indicated that the effect of miR-24-3p on cell growth is at least in part caused by an increase of apoptotic cells. Argonaute 2 immunoprecipitation revealed 1142 genes consistently targeted by miRNAs in at least three of four HL cell lines. Furthermore, 52 of the 1142 genes were predicted targets of miR-24-3p. Functional annotation analysis revealed a function related to cell growth, cell death, and/or apoptosis for 15 of the 52 genes. Western blotting of the top five genes showed increased protein levels on miR-24-3p inhibition for CDKN1B/P27kip1 and MYC. In summary, we showed that miR-24-3p is up-regulated in HL and its inhibition impairs cell growth possibly via targeting CDKN1B/P27kip1 and MYC.
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Affiliation(s)
- Ye Yuan
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Institute of Clinical Pharmacology of the Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Joost Kluiver
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Jasper Koerts
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Debora de Jong
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Bea Rutgers
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - F Reeny Abdul Razak
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Martijn Terpstra
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Boudewijn E Plaat
- Department of Otorhinolaryngology/Head and Neck Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Ilja M Nolte
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Arjan Diepstra
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Lydia Visser
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Klaas Kok
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Anke van den Berg
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
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Oncogenic KRAS triggers MAPK-dependent errors in mitosis and MYC-dependent sensitivity to anti-mitotic agents. Sci Rep 2016; 6:29741. [PMID: 27412232 PMCID: PMC4944194 DOI: 10.1038/srep29741] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2016] [Accepted: 06/23/2016] [Indexed: 12/21/2022] Open
Abstract
Oncogenic KRAS induces cell proliferation and transformation, but little is known about its effects on cell division. Functional genetic screens have recently revealed that cancer cell lines expressing oncogenic KRAS are sensitive to interference with mitosis, but neither the mechanism nor the uniformity of anti-mitotic drug sensitivity connected with mutant KRAS expression are yet clear. Here, we report that acute expression of oncogenic KRAS in HeLa cells induces mitotic delay and defects in chromosome segregation through mitogen-activated protein kinase (MAPK) pathway activation and de-regulated expression of several mitosis-related genes. These anomalies are accompanied by increased sensitivity to anti-mitotic agents, a phenotype dependent on the transcription factor MYC and its downstream target anti-apoptotic protein BCL-XL. Unexpectedly, we find no correlation between KRAS mutational status or MYC expression levels and anti-mitotic drug sensitivity when surveying a large database of anti-cancer drug responses. However, we report that the co-existence of KRAS mutations and high MYC expression predicts anti-mitotic drug sensitivity. Our findings reveal a novel function of oncogenic KRAS in regulating accurate mitotic progression and suggest new avenues to therapeutically target KRAS-mutant tumours and stratify patients in ongoing clinical trials of anti-mitotic drugs.
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Zhang J, Cui Z, Feng G, Bao G, Xu G, Sun Y, Wang L, Chen J, Jin H, Liu J, Yang L, Li W. RBM5 and p53 expression after rat spinal cord injury: implications for neuronal apoptosis. Int J Biochem Cell Biol 2015; 60:43-52. [PMID: 25578565 DOI: 10.1016/j.biocel.2014.12.020] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2014] [Revised: 12/02/2014] [Accepted: 12/28/2014] [Indexed: 12/14/2022]
Abstract
RBM5 (RNA-binding motif protein 5), a nuclear RNA binding protein, is known to trigger apoptosis and induce cell cycle arrest by regulating the activity of the tumor suppressor protein p53. However, its expression and function in spinal cord injury (SCI) are still unknown. To investigate whether RBM5 is involved in central nervous system injury and repair, we performed an acute SCI model in adult rats in this study. Our results showed RBM5 was unregulated significantly after SCI, which was accompanied with an increase in the levels of apoptotic proteins such as p53, Bax, and active caspase-3. Immunofluorescent labeling also showed that traumatic SCI induced RBM5 location changes and co-localization with active caspase-3 in neurons. To further probe the role of RBM5, a neuronal cell line PC12 was employed to establish an apoptotic model. Knockdown of RBM5 apparently decreased the level of p53 as well as active caspase-3, demonstrating its pro-apoptotic role in neurons by regulating expressions of p53 and caspase-3. Taken together, our findings indicate that RBM5 promotes neuronal apoptosis through modulating p53 signaling pathway following SCI.
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Affiliation(s)
- Jinlong Zhang
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong University, 226001 Nantong, Jiangsu, People's Republic of China
| | - Zhiming Cui
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong University, 226001 Nantong, Jiangsu, People's Republic of China.
| | - Guijuan Feng
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, Nantong University, 226001 Nantong, Jiangsu, People's Republic of China
| | - Guofeng Bao
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong University, 226001 Nantong, Jiangsu, People's Republic of China
| | - Guanhua Xu
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong University, 226001 Nantong, Jiangsu, People's Republic of China
| | - Yuyu Sun
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong University, 226001 Nantong, Jiangsu, People's Republic of China
| | - Lingling Wang
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong University, 226001 Nantong, Jiangsu, People's Republic of China
| | - Jiajia Chen
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong University, 226001 Nantong, Jiangsu, People's Republic of China
| | - Huricha Jin
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong University, 226001 Nantong, Jiangsu, People's Republic of China
| | - Jian Liu
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong University, 226001 Nantong, Jiangsu, People's Republic of China
| | - Longfei Yang
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong University, 226001 Nantong, Jiangsu, People's Republic of China
| | - Weidong Li
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong University, 226001 Nantong, Jiangsu, People's Republic of China
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Histone deacetylase inhibitor-mediated cell death is distinct from its global effect on chromatin. Mol Oncol 2014; 8:1379-92. [PMID: 24954856 DOI: 10.1016/j.molonc.2014.05.001] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 03/23/2014] [Accepted: 05/01/2014] [Indexed: 01/01/2023] Open
Abstract
Romidepsin and vorinostat are histone deacetylase inhibitors (HDACis) that have activity in T-cell lymphomas, but have not gained traction in solid tumors. To gain deeper insight into mechanisms of HDACi efficacy, we systematically surveyed 19 cell lines with different molecular phenotypes, comparing romidepsin and vorinostat at equipotent doses. Acetylation at H3K9 and H4K8 along with 22 other histone lysine acetylation and methylation modifications were measured by reverse phase proteomics array (RPPA), and compared with growth inhibition (IC50), and cell cycle arrest. These assays typically used to assess HDACi effect showed that acetylation and methylation of specific lysine residues in response to HDACis were consistent across cell lines, and not related to drug sensitivity. Using a treatment duration more reflective of the clinical exposure, cell death detected by annexin staining following a 6 h drug exposure identified a subset of cell lines, including the T-cell lymphoma line, that was markedly more sensitive to HDAC inhibition. Kinetic parameters (Km values) were determined for lysine acetylation and for cell cycle data and were themselves correlated following HDACi exposure, but neither parameter correlated with cell death. The impact on cell survival signaling varied with the molecular phenotype. This study suggests that cellular response to HDACis can be viewed as two distinct effects: a chromatin effect and a cell death effect. All cells undergo acetylation, which is necessary but not sufficient for cell death. Cells not primed for apoptosis will not respond with cell death to the impact of altered histone acetylation. The divergent apoptotic responses observed reflect the variable clinical outcome of HDACi treatment. These observations should change our approach to the development of therapeutic strategies that exploit the dual activities of HDACis.
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Amiri-Kordestani L, Luchenko V, Peer CJ, Ghafourian K, Reynolds J, Draper D, Frye R, Woo S, Venzon D, Wright J, Skarulis M, Figg WD, Fojo T, Bates SE, Piekarz RL. Phase I trial of a new schedule of romidepsin in patients with advanced cancers. Clin Cancer Res 2013; 19:4499-507. [PMID: 23757352 DOI: 10.1158/1078-0432.ccr-13-0095] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE Romidepsin is a potent histone deacetylase inhibitor (HDI) with activity in T-cell lymphoma. Given preclinical data showing greater induction of gene expression with longer exposures to HDIs, a phase I study of a day 1, 3, and 5 romidepsin schedule was evaluated. A secondary objective was to assess the effect of romidepsin on radioactive iodine (RAI) uptake in thyroid cancers. EXPERIMENTAL DESIGN Open-label, single-arm, phase I, 3 + 3 dose escalation study. Romidepsin was administered as a 4-hour infusion on days 1, 3, and 5 of a 21-day cycle. Pharmacokinetics (PK) and pharmacodynamics (PD) were assessed, including histone acetylation in peripheral blood mononuclear cells (PBMC), RAI uptake in refractory thyroid cancer, and HDI-related ECG changes. RESULTS Twenty-eight patients with solid tumors, including 11 patients with thyroid cancer were enrolled. Six dose levels were explored, and 7 mg/m(2) on days 1, 3, and 5 was identified as tolerable. No Response Evaluation Criteria In Solid Tumors-defined objective responses were recorded although 9 patients had stable disease a median 30 weeks (range, 21-112) including 6 with thyroid cancer a median of 33 weeks. PD studies detected acetylated histones in PBMCs and ECG changes beginning at low dose levels. Follow-up RAI scans in patients with RAI refractory thyroid cancer did not detect meaningful increases. CONCLUSIONS A romidepsin dose of 7 mg/m(2) administered on days 1, 3, and 5 was found tolerable and resulted in histone acetylation in PBMCs. Although there were no objective responses with romidepsin alone, this schedule may be useful for developing combination studies in solid tumors.
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Affiliation(s)
- Laleh Amiri-Kordestani
- Medical Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland 20892, USA
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Talbert DR, Wappel RL, Moran DM, Shell SA, Bacus SS. The Role of Myc and the miR-17~92 Cluster in Histone Deacetylase Inhibitor Induced Apoptosis of Solid Tumors. ACTA ACUST UNITED AC 2013. [DOI: 10.4236/jct.2013.44102] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Lambrou GI, Papadimitriou L, Chrousos GP, Vlahopoulos SA. Glucocorticoid and proteasome inhibitor impact on the leukemic lymphoblast: multiple, diverse signals converging on a few key downstream regulators. Mol Cell Endocrinol 2012; 351:142-51. [PMID: 22273806 DOI: 10.1016/j.mce.2012.01.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2011] [Accepted: 01/01/2012] [Indexed: 11/28/2022]
Abstract
Twenty years ago a proteasome inhibitor was suggested as therapy for glucocorticoid-resistant multiple myeloma, a disease that involves terminally differentiated B cells. Since then, research has proven that it has utility on a number of tumors resistant to chemotherapy. Hematologic malignancy, however, often involves lesser differentiated cells, which have a high potential to modulate their intrinsic machinery and thereby activate alternative rescue pathways. A corresponding multiplicity of therapies is not always practical. One approach to conditions with heterogeneous physiology is to identify key biochemical mediators, thereby reducing the number of treatment targets. Results from several ongoing studies indicate convergence of genomically diverse signal pathways to a limited number of key downstream regulators of apoptosis. Convergence of pathways can be exploited to address the problem of genetic heterogeneity in acute leukemia: this would mean treating multiple molecular aberrations with fewer drugs and enhanced therapeutic benefit.
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Affiliation(s)
- George I Lambrou
- Horemio Research Institute, First Department of Pediatrics, University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece
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Robey RW, Chakraborty AR, Basseville A, Luchenko V, Bahr J, Zhan Z, Bates SE. Histone deacetylase inhibitors: emerging mechanisms of resistance. Mol Pharm 2011; 8:2021-31. [PMID: 21899343 DOI: 10.1021/mp200329f] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The histone deacetylase inhibitors (HDIs) have shown promise in the treatment of a number of hematologic malignancies, leading to the approval of vorinostat and romidepsin for the treatment of cutaneous T-cell lymphoma and romidepsin for the treatment of peripheral T-cell lymphoma by the U.S. Food and Drug Administration. Despite these promising results, clinical trials with the HDIs in solid tumors have not met with success. Examining mechanisms of resistance to HDIs may lead to strategies that increase their therapeutic potential in solid tumors. However, relatively few examples of drug-selected cell lines exist, and mechanisms of resistance have not been studied in depth. Very few clinical translational studies have evaluated resistance mechanisms. In the current review, we summarize many of the purported mechanisms of action of the HDIs in clinical trials and examine some of the emerging resistance mechanisms.
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Affiliation(s)
- Robert W Robey
- Medical Oncology Branch, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, United States.
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Brodská B, Otevřelová P, Holoubek A. Decitabine-induced apoptosis is derived by Puma and Noxa induction in chronic myeloid leukemia cell line as well as in PBL and is potentiated by SAHA. Mol Cell Biochem 2010; 350:71-80. [PMID: 21153863 DOI: 10.1007/s11010-010-0683-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2010] [Accepted: 12/02/2010] [Indexed: 10/18/2022]
Abstract
Restoration of cellular apoptotic pathways plays a crucial role in cancer therapy strategies. In a broad spectrum of anticancer drugs, epigenetic effectors are in the center of interest mostly because of potential reversibility of their action. Methylation status of the cells is influenced by methyltransferase inhibitor 2-deoxy-5'-azacytidine (decitabine, DAC), but higher concentrations of this agent cause a DNA-damage. In our study, tumor supressor p53-apoptotic pathway was activated in decitabine-induced cell death. Expression of p53-inducible BH3-only apoptotic proteins Puma and Noxa was elevated and large activation of executive caspases was observed. The extent of acetylation in the cell is affected by histonedeacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). Combination of SAHA with decitabine brought synergistic effect on apoptosis triggering in CML-T1 cell line, but apoptosis as well as necrosis occurred also in normal peripheral blood lymphocytes. Therefore, promising potential of such combined therapy calls for more detailed investigation of unwanted effects in normal cells.
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Affiliation(s)
- Barbora Brodská
- Institute of Hematology and Blood Transfusion, Prague 2, Czech Republic.
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Kovacic P, Edwards CL. Hydroxamic acids (therapeutics and mechanism): chemistry, acyl nitroso, nitroxyl, reactive oxygen species, and cell signaling. J Recept Signal Transduct Res 2010; 31:10-9. [PMID: 20590405 DOI: 10.3109/10799893.2010.497152] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Hrzenjak A, Moinfar F, Kremser ML, Strohmeier B, Petru E, Zatloukal K, Denk H. Histone deacetylase inhibitor vorinostat suppresses the growth of uterine sarcomas in vitro and in vivo. Mol Cancer 2010; 9:49. [PMID: 20202195 PMCID: PMC2843655 DOI: 10.1186/1476-4598-9-49] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2009] [Accepted: 03/04/2010] [Indexed: 11/29/2022] Open
Abstract
Background Uterine sarcomas are very rare malignancies with no approved chemotherapy protocols. Histone deacetylase (HDAC) inhibitors belong to the most promising groups of compounds for molecular targeting therapy. Here, we described the antitumor effects of suberoylanilide hydroxamic acid (SAHA; vorinostat) on MES-SA uterine sarcoma cells in vitro and in vivo. We investigated effects of vorinostat on growth and colony forming ability by using uterine sarcoma MES-SA cells. We analyzed the influence of vorinostat on expression of different HDACs, p21WAF1 and activation of apoptosis. Finally, we examined the antitumor effects of vorinostat on uterine sarcoma in vivo. Results Vorinostat efficiently suppressed MES-SA cell growth at a low dosage (3 μM) already after 24 hours treatment. Decrease of cell survival was even more pronounced after prolonged treatment and reached 9% and 2% after 48 and 72 hours of treatment, respectively. Colony forming capability of MES-SA cells treated with 3 μM vorinostat for 24 and 48 hours was significantly diminished and blocked after 72 hours. HDACs class I (HDAC2 and 3) as well as class II (HDAC7) were preferentially affected by this treatment. Vorinostat significantly increased p21WAF1 expression and apoptosis. Nude mice injected with 5 × 106 MES-SA cells were treated for 21 days with vorinostat (50 mg/kg/day) and, in comparison to placebo group, a tumor growth reduction of more than 50% was observed. Results obtained by light- and electron-microscopy suggested pronounced activation of apoptosis in tumors isolated from vorinostat-treated mice. Conclusions Our data strongly indicate the high therapeutic potential of vorinostat in uterine sarcomas.
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Affiliation(s)
- Andelko Hrzenjak
- Lore Saldow Research Unit for Molecular Pathology of Gynecologic Tumors, Department of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria.
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Brodska B, Otevrelova P, Kalousek I. Variations in c-Myc and p21WAF1 expression protect normal peripheral blood lymphocytes against BimEL-mediated cell death. Cell Biochem Funct 2009; 27:167-75. [PMID: 19330811 DOI: 10.1002/cbf.1552] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Pitts TM, Morrow M, Kaufman SA, Tentler JJ, Eckhardt SG. Vorinostat and bortezomib exert synergistic antiproliferative and proapoptotic effects in colon cancer cell models. Mol Cancer Ther 2009; 8:342-9. [PMID: 19174560 DOI: 10.1158/1535-7163.mct-08-0534] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Despite the availability of several Food and Drug Administration-approved drugs, advanced inoperable colorectal cancer remains incurable. In this study, we focused on the development of combined molecular targeted therapies against colon cancer by testing the efficacy of the combination of the histone deacetylase inhibitor vorinostat with the proteasome inhibitor bortezomib to determine if this resulted in synergistic antitumor effects against colorectal cancer. The effects of the histone deacetylase inhibitor vorinostat in combination with the proteasome inhibitor bortezomib on the growth of two colorectal cancer cell lines were assessed with regard to proliferation, cell cycle arrest, and apoptosis. Treatment with the combination of vorinostat and bortezomib resulted in a synergistic decrease in proliferation of both colorectal cancer cell lines compared with treatment with single agents alone. This inhibition was associated with a synergistic increase in apoptosis as measured by caspase-3/7 activity and cleaved poly(ADP-ribose) polymerase. In addition, we observed an increase in the proapoptotic protein BIM and in the number of cells arrested in the G(2)-M phase of the cell cycle. Although p21 levels were significantly increased, short hairpin RNA knockdown of p21 did not lead to changes in proliferation in response to the combination of drugs, indicating that although p21 is a target of these drugs, it is not required to mediate their antiproliferative effects. These data indicate that combination treatment with vorinostat and bortezomib result in synergistic antiproliferative and proapoptotic effects against colon cancer cell lines, providing a rational basis for the clinical use of this combination for the treatment of colorectal cancer.
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Affiliation(s)
- Todd M Pitts
- Division of Medical Oncology, University of Colorado Health Sciences Center, Aurora, CO 80045, USA.
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Hrzenjak A, Kremser ML, Strohmeier B, Moinfar F, Zatloukal K, Denk H. SAHA induces caspase-independent, autophagic cell death of endometrial stromal sarcoma cells by influencing the mTOR pathway. J Pathol 2008; 216:495-504. [PMID: 18850582 DOI: 10.1002/path.2434] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Endometrial stromal sarcomas are rare and molecular mechanisms involved in their pathogenesis are poorly understood. Covalent modifications of histone proteins, in particular de/acetylation of lysine residues, play an important role in the regulation of gene transcription in normal and neoplastic cells, but there are only limited data about these processes in solid mesenchymal tumours. We treated endometrial stromal sarcoma cells (ESS-1) and non-malignant human endometrial stromal cells (HESCs) with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor. SAHA was able to mediate the cell cycle and expression of genes related to the malignant phenotype of endometrial stromal tumours, eg p21(WAF1) and HDAC7. SAHA led to dose-dependent differentiation and death of ESS-1 cells but not of HESCs. Exposure of HESCs to SAHA resulted only in slightly decreased cell proliferation. SAHA also increased the p21(WAF1) expression and caused significant changes in the cell cycle by inhibiting the G1/S transition in ESS-1 cells. Recovery experiments indicated that these changes became irreversible when the tumour cells were treated with SAHA for longer than 24 h. In our experimental system, not apoptotic but autophagic processes were responsible for the cell death. Monodansyl cadaverine accumulation in treated ESS-1 cells and decreased expression of the mTOR and phospho-S6 ribosomal protein (S6rp) additionally supported this observation. Taken together, our study indicates that HDACs might be considered as potential drug targets in the therapy of stromal sarcomas and that SAHA might be a promising therapeutic agent for endometrial stromal sarcoma.
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Affiliation(s)
- A Hrzenjak
- Saldow Research Unit for Molecular Pathology of Gynecologic Tumors, Department of Pathology, Medical University of Graz, Graz, Austria.
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Nickel compounds induce apoptosis in human bronchial epithelial Beas-2B cells by activation of c-Myc through ERK pathway. Toxicol Appl Pharmacol 2008; 235:191-8. [PMID: 19135467 DOI: 10.1016/j.taap.2008.12.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2008] [Revised: 11/21/2008] [Accepted: 12/02/2008] [Indexed: 11/24/2022]
Abstract
Nickel compounds are carcinogenic to humans and have been shown to alter epigenetic homeostasis. The c-Myc protein controls 15% of human genes and it has been shown that fluctuations of c-Myc protein alter global epigenetic marks. Therefore, the regulation of c-Myc by nickel ions in immortalized but not tumorigenic human bronchial epithelial Beas-2B cells was examined in this study. It was found that c-Myc protein expression was increased by nickel ions in non-tumorigenic Beas-2B and human keratinocyte HaCaT cells. The results also indicated that nickel ions induced apoptosis in Beas-2B cells. Knockout of c-Myc and its restoration in a rat cell system confirmed the essential role of c-Myc in nickel ion-induced apoptosis. Further studies in Beas-2B cells showed that nickel ion increased the c-Myc mRNA level and c-Myc promoter activity, but did not increase c-Myc mRNA and protein stability. Moreover, nickel ion upregulated c-Myc in Beas-2B cells through the MEK/ERK pathway. Collectively, the results demonstrate that c-Myc induction by nickel ions occurs via an ERK-dependent pathway and plays a crucial role in nickel-induced apoptosis in Beas-2B cells.
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Abstract
c-MYC has a pivotal function in growth control, differentiation and apoptosis, and its abnormal expression is associated with many tumors. Overexpression of c-MYC sensitizes cells to apoptosis by a variety of stimuli. The decision of a cell to undergo apoptosis and how this apoptotic response is regulated by c-MYC depends on the specific cell type and the physiological status of the cell. Multiple cooperating molecular pathways of cell survival and apoptosis determine whether a cell lives or dies, and understanding how c-MYC interfaces with these pathways to influence the survival of cells is important to understand normal and abnormal development, tumor initiation and progression, and response of tumors to different treatment regimens. This article will provide an overview of the function of the tumor suppressor gene product p53 in the c-MYC-mediated apoptotic response and how c-MYC amplifies the intrinsic mitochondrial pathway and triggers and/or amplifies the death receptor pathways. Finally, a model for how deregulated c-MYC prematurely triggers the normal apoptotic response associated with terminal myeloid differentiation while also blocking the differentiation program is presented.
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Kalousek I, Brodska B, Otevrelova P, Röselova P. BimEL-dependent apoptosis induced in peripheral blood lymphocytes withn-butyric acid is moderated by variation in expression of c-myc and p21(WAF1). Cell Biochem Funct 2008; 26:509-21. [DOI: 10.1002/cbf.1474] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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