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1
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Mokrov GV. Linked biaromatic compounds as cardioprotective agents. Arch Pharm (Weinheim) 2021; 355:e2100428. [PMID: 34967027 DOI: 10.1002/ardp.202100428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 12/02/2021] [Accepted: 12/03/2021] [Indexed: 11/08/2022]
Abstract
Cardiovascular diseases (CVDs) are widespread in the modern world, and their number is constantly growing. For a long time, CVDs have been the leading cause of morbidity and mortality worldwide. Drugs for the treatment of CVD have been developed almost since the beginning of the 20th century, and a large number of effective cardioprotective agents of various classes have been created. Nevertheless, the need for the design and development of new safe drugs for the treatment of CVD remains. Literature data indicate that a huge number of cardioprotective agents of various generations and mechanisms correspond to a single generalized pharmacophore model containing two aromatic nuclei linked by a linear linker. In this regard, we put forward a concept for the design of a new generation of cardioprotective agents with a multitarget mechanism of action within the indicated pharmacophore model. This review is devoted to a generalization of the currently known compounds with cardioprotective properties and corresponding to the pharmacophore model of biaromatic compounds linked by a linear linker. Particular attention is paid to the history of the creation of these drugs, approaches to their design, and analysis of the structure-action relationship within each class.
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Affiliation(s)
- Grigory V Mokrov
- Department of Medicinal Chemistry, FSBI "Zakusov Institute of Pharmacology", Moscow, Russia
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2
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Song L, Zhang ZF, Hu LK, Zhang PH, Cao ZZ, Liu ZP, Zhang PP, Ma JH. Curcumin, a Multi-Ion Channel Blocker That Preferentially Blocks Late Na + Current and Prevents I/R-Induced Arrhythmias. Front Physiol 2020; 11:978. [PMID: 32973546 PMCID: PMC7472421 DOI: 10.3389/fphys.2020.00978] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 07/20/2020] [Indexed: 11/13/2022] Open
Abstract
Increasing evidence shows that Curcumin (Cur) has a protective effect against cardiovascular diseases. However, the role of Cur in the electrophysiology of cardiomyocytes is currently not entirely understood. Therefore, the present study was conducted to investigate the effects of Cur on the action potential and transmembrane ion currents in rabbit ventricular myocytes to explore its antiarrhythmic property. The whole-cell patch clamp was used to record the action potential and ion currents, while the multichannel acquisition and analysis system was used to synchronously record the electrocardiogram and monophasic action potential. The results showed that 30 μmol/L Cur shortened the 50 and 90% repolarization of action potential by 17 and 7%, respectively. In addition, Cur concentration dependently inhibited the Late-sodium current (I Na.L), Transient-sodium current (I Na.T), L-type calcium current (I Ca.L), and Rapidly delayed rectifying potassium current (I Kr), with IC50 values of 7.53, 398.88, 16.66, and 9.96 μmol/L, respectively. Importantly, the inhibitory effect of Cur on I Na.L was 52.97-fold higher than that of I Na.T. Moreover, Cur decreased ATX II-prolonged APD, suppressed the ATX II-induced early afterdepolarization (EAD) and Ca2+-induced delayed afterdepolarization (DAD) in ventricular myocytes, and reduced the occurrence and average duration of ventricular tachycardias and ventricular fibrillations induced by ischemia-reperfusion injury. In conclusion, Cur inhibited I Na.L, I Na.T, I Ca.L, and I Kr; shortened APD; significantly suppressed EAD and DAD-like arrhythmogenic activities at the cellular level; and exhibited antiarrhythmic effect at the organ level. It is first revealed that Cur is a multi-ion channel blocker that preferentially blocks I Na.L and may have potential antiarrhythmic property.
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Affiliation(s)
- Lv Song
- Cardio-Electrophysiological Research Laboratory, Medical College of Wuhan University of Science and Technology, Wuhan, China.,College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Medical College of Wuhan University of Science and Technology, Wuhan, China
| | - Ze-Fu Zhang
- Cardio-Electrophysiological Research Laboratory, Medical College of Wuhan University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Medical College of Wuhan University of Science and Technology, Wuhan, China
| | - Liang-Kun Hu
- Tianyou Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China
| | - Pei-Hua Zhang
- Cardio-Electrophysiological Research Laboratory, Medical College of Wuhan University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Medical College of Wuhan University of Science and Technology, Wuhan, China
| | - Zhen-Zhen Cao
- Cardio-Electrophysiological Research Laboratory, Medical College of Wuhan University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Medical College of Wuhan University of Science and Technology, Wuhan, China
| | - Zhi-Pei Liu
- Cardio-Electrophysiological Research Laboratory, Medical College of Wuhan University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Medical College of Wuhan University of Science and Technology, Wuhan, China
| | - Pei-Pei Zhang
- Cardio-Electrophysiological Research Laboratory, Medical College of Wuhan University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Medical College of Wuhan University of Science and Technology, Wuhan, China
| | - Ji-Hua Ma
- Cardio-Electrophysiological Research Laboratory, Medical College of Wuhan University of Science and Technology, Wuhan, China.,College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Medical College of Wuhan University of Science and Technology, Wuhan, China
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3
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Terranova-Barberio M, Thomas S, Munster PN. Epigenetic modifiers in immunotherapy: a focus on checkpoint inhibitors. Immunotherapy 2017; 8:705-19. [PMID: 27197539 DOI: 10.2217/imt-2016-0014] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Immune surveillance should be directed to suppress tumor development and progression, involving a balance of coinhibitory and costimulatory signals that amplify immune response without overwhelming the host. Immunotherapy confers durable clinical benefit in 'immunogenic tumors', whereas in other tumors the responses are modest. Thus, immune checkpoint inhibitors may need to be combined with strategies to boost immune response or increase the tumor immune profile. Epigenetic aberrations contribute significantly to carcinogenesis. Recent findings suggest that epigenetic drugs prime the immune response by increasing expression of tumor-associated antigens and immune-related genes, as well as modulating chemokines and cytokines involved in immune system activation. This review describes our current understanding regarding epigenetic and immunotherapy combination, focusing on immune response priming to checkpoint blockade.
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Affiliation(s)
- Manuela Terranova-Barberio
- Department of Medicine, Division of Hematology & Oncology, University of California, Room A722, 1600 Divisadero St, Box 1770, San Francisco, CA 94115, USA
| | - Scott Thomas
- Department of Medicine, Division of Hematology & Oncology, University of California, Room A722, 1600 Divisadero St, Box 1770, San Francisco, CA 94115, USA
| | - Pamela N Munster
- Department of Medicine, Division of Hematology & Oncology, University of California, Room A722, 1600 Divisadero St, Box 1770, San Francisco, CA 94115, USA
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Carbone C, Di Gennaro E, Piro G, Milone MR, Pucci B, Caraglia M, Budillon A. Tissue transglutaminase (TG2) is involved in the resistance of cancer cells to the histone deacetylase (HDAC) inhibitor vorinostat. Amino Acids 2016; 49:517-528. [PMID: 27761756 DOI: 10.1007/s00726-016-2338-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 09/20/2016] [Indexed: 12/22/2022]
Abstract
Vorinostat demonstrated preclinical and clinical efficacy in human cancers and is the first histone deacetylase inhibitor (HDACi) approved for cancer treatment. Tissue transglutaminase (TG2) is a multifunctional enzyme that catalyzes a Ca2+ dependent transamidating reaction resulting in covalent cross-links between proteins. TG2 acts also as G-protein in trans-membrane signaling and as a cell surface adhesion mediator. TG2 up-regulation has been demonstrated in several cancers and its expression levels correlate with resistance to chemotherapy and metastatic potential. We demonstrated that the anti-proliferative effect of the HDACi vorinostat is paralleled by the induction of TG2 mRNA and protein expression in cancer cells but not in ex vivo treated peripheral blood lymphocytes. This effect was also shared by other pan-HDACi and resulted in increased TG2 transamidating activity. Notably, high TG2 basal levels in a panel of cancer cell lines correlated with lower vorinostat antiproliferative activity. Notably, in TG2-knockdown cancer cells vorinostat anti-proliferative and pro-apoptotic effects were enhanced, whereas in TG2-full-length transfected cells were impaired, suggesting that TG2 could represent a mechanism of intrinsic or acquired resistance to vorinostat. In fact, co-treatment of tumor cells with inhibitors of TG2 transamidating activity potentiated the antitumor effect of vorinostat. Moreover, vorinostat-resistant MCF7 cells selected by stepwise increasing concentrations of the drug, significantly overexpressed TG2 protein compared to parental cells, and co-treatment of these cells with TG2 inhibitors reversed vorinostat-resistance. Taken together, our data demonstrated that TG2 is involved in the resistance of cancer cells to vorinostat, as well as to other HDACi.
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Affiliation(s)
- Carmine Carbone
- Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, 80131, Naples, Italy.,Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, Verona, Italy
| | - Elena Di Gennaro
- Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, 80131, Naples, Italy
| | - Geny Piro
- Centro Ricerche Oncologiche Mercogliano, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, Naples, Italy.,Laboratory of Oncology and Molecular Therapy, Department of Medicine, University of Verona, Verona, Italy
| | - Maria Rita Milone
- Centro Ricerche Oncologiche Mercogliano, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, Naples, Italy
| | - Biagio Pucci
- Centro Ricerche Oncologiche Mercogliano, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, Naples, Italy
| | - Michele Caraglia
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy
| | - Alfredo Budillon
- Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, 80131, Naples, Italy. .,Centro Ricerche Oncologiche Mercogliano, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, Naples, Italy.
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5
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Spiegelberg D, Dascalu A, Mortensen AC, Abramenkovs A, Kuku G, Nestor M, Stenerlöw B. The novel HSP90 inhibitor AT13387 potentiates radiation effects in squamous cell carcinoma and adenocarcinoma cells. Oncotarget 2016; 6:35652-66. [PMID: 26452257 PMCID: PMC4742132 DOI: 10.18632/oncotarget.5363] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2015] [Accepted: 09/24/2015] [Indexed: 12/12/2022] Open
Abstract
Overexpression of heat shock protein 90 (HSP90) is associated with increased tumor cell survival and radioresistance. In this study we explored the efficacy of the novel HSP90 inhibitor AT13387 and examined its radiosensitizing effects in combination with gamma-radiation in 2D and 3D structures as well as mice-xenografts. AT13387 induced effective cytotoxic activity and radiosensitized cancer cells in monolayer and tumor spheroid models, where low drug doses triggered significant synergistic effects on cell survival together with radiation. Furthermore, AT13387 treatment resulted in G2/M-phase arrest and significantly reduced the migration capacity. The expression of selected client proteins involved in DNA repair, cell-signaling and cell growth was downregulated in vitro, though the expression of most investigated proteins recurred after 8–24 h. These results were confirmed in vivo where AT13387 treated tumors displayed effective downregulation of HSP90 and its oncogenic client proteins. In conclusion, our results demonstrate that AT13387 is a potent new cancer drug and effective radiosensitizer in vitro with an excellent in vivo efficacy. AT13387 treatment has the potential to improve external beam therapy and radionuclide therapy outcomes and restore treatment efficacy in cancers that are resistant to initial therapeutic regimes.
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Affiliation(s)
- Diana Spiegelberg
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Adrian Dascalu
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Anja C Mortensen
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Andris Abramenkovs
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Gamze Kuku
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Marika Nestor
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.,Unit of Otolaryngology and Head and Neck Surgery, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Bo Stenerlöw
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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Leone A, Roca MS, Ciardiello C, Terranova-Barberio M, Vitagliano C, Ciliberto G, Mancini R, Di Gennaro E, Bruzzese F, Budillon A. Vorinostat synergizes with EGFR inhibitors in NSCLC cells by increasing ROS via up-regulation of the major mitochondrial porin VDAC1 and modulation of the c-Myc-NRF2-KEAP1 pathway. Free Radic Biol Med 2015; 89:287-99. [PMID: 26409771 DOI: 10.1016/j.freeradbiomed.2015.07.155] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Revised: 07/17/2015] [Accepted: 07/19/2015] [Indexed: 01/06/2023]
Abstract
In non-small-cell lung cancer (NSCLC) patients, the activation of alternative pathways contributes to the limited efficacy of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. The present study examines a panel of EGFR wild-type, K-Ras mutated, NSCLC lines, which were all intrinsically resistant to EGFR-TKIs, and demonstrates that the histone deacetylase inhibitor vorinostat can improve the therapeutic efficacy of gefitinib or erlotinib, inducing strong synergistic antiproliferative and pro-apoptotic effects that are paralleled by reactive oxygen species accumulation and by increased DNA damage. By knockdown experiments, we suggested that the up-regulation of voltage-dependent anion-selective channel protein 1 (VDAC1), the major mitochondrial porin of the outer mitochondrial membrane, which was induced by vorinostat and further increased by the combination, could be functionally involved in oxidative stress-dependent apoptosis. Significantly, we also observed the attenuation of the expression of both the enzyme hexokinase1, a negative VDAC1 regulator, and the anti-apoptotic porin VDAC2, only in the combination setting, suggesting convergent mechanisms that enhanced mitochondria-dependent apoptosis by targeting VDAC protein functions. Furthermore, the prosurvival capacities of the cells were also inhibited by the combination treatments, as shown by complete pAKT deactivation, increased GSK3β expression, and c-Myc down-regulation. Finally, we observed that the combination treatment of vorinostat and either of the EGFR-TKIs induced the down-regulation of the c-Myc-regulated nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor and the up-regulation of the NRF2 repressor Kelch-like ECH-associated protein 1 regulator (KEAP1). These two genes are crucial for the redox stress response, often dysfunctional in NSCLC, and involved in EGFR-TKI resistance. Taken together, these results are the first to demonstrate that altering redox homeostasis is a new mechanism underlying the observed synergism between vorinostat and EGFR TKIs in NSCLC.
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Affiliation(s)
- Alessandra Leone
- Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, 80131 Naples, Italy
| | - Maria Serena Roca
- Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, 80131 Naples, Italy
| | - Chiara Ciardiello
- Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, 80131 Naples, Italy
| | - Manuela Terranova-Barberio
- Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, 80131 Naples, Italy
| | - Carlo Vitagliano
- Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, 80131 Naples, Italy
| | - Gennaro Ciliberto
- Scientific Direction, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, 80131 Naples, Italy
| | - Rita Mancini
- Department of Surgery "P.Valdoni" and Department of Clinical and Molecular Medicine, La Sapienza University, 00161 Rome, Italy
| | - Elena Di Gennaro
- Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, 80131 Naples, Italy
| | - Francesca Bruzzese
- Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, 80131 Naples, Italy
| | - Alfredo Budillon
- Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, 80131 Naples, Italy.
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7
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Bishton M, Kenealy M, Johnstone R, Rasheed W, Prince HM. Epigenetic targets in hematological malignancies: combination therapies with HDACis and demethylating agents. Expert Rev Anticancer Ther 2014; 7:1439-49. [DOI: 10.1586/14737140.7.10.1439] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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8
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Newbold A, Matthews GM, Bots M, Cluse LA, Clarke CJP, Banks KM, Cullinane C, Bolden JE, Christiansen AJ, Dickins RA, Miccolo C, Chiocca S, Kral AM, Ozerova ND, Miller TA, Methot JL, Richon VM, Secrist JP, Minucci S, Johnstone RW. Molecular and biologic analysis of histone deacetylase inhibitors with diverse specificities. Mol Cancer Ther 2013; 12:2709-21. [PMID: 24092806 DOI: 10.1158/1535-7163.mct-13-0626] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Histone deacetylase inhibitors (HDACi) are anticancer agents that induce hyperacetylation of histones, resulting in chromatin remodeling and transcriptional changes. In addition, nonhistone proteins, such as the chaperone protein Hsp90, are functionally regulated through hyperacetylation mediated by HDACis. Histone acetylation is thought to be primarily regulated by HDACs 1, 2, and 3, whereas the acetylation of Hsp90 has been proposed to be specifically regulated through HDAC6. We compared the molecular and biologic effects induced by an HDACi with broad HDAC specificity (vorinostat) with agents that predominantly inhibited selected class I HDACs (MRLB-223 and romidepsin). MRLB-223, a potent inhibitor of HDACs 1 and 2, killed tumor cells using the same apoptotic pathways as the HDAC 1, 2, 3, 6, and 8 inhibitor vorinostat. However, vorinostat induced histone hyperacetylation and killed tumor cells more rapidly than MRLB-223 and had greater therapeutic efficacy in vivo. FDCP-1 cells dependent on the Hsp90 client protein Bcr-Abl for survival, were killed by all HDACis tested, concomitant with caspase-dependent degradation of Bcr-Abl. These studies provide evidence that inhibition of HDAC6 and degradation of Bcr-Abl following hyperacetylation of Hsp90 is likely not a major mechanism of action of HDACis as had been previously posited.
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Affiliation(s)
- Andrea Newbold
- Corresponding Author: Ricky Johnstone, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia.
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DTNQ-Pro, a Mimetic Dipeptide, Sensitizes Human Colon Cancer Cells to 5-Fluorouracil Treatment. JOURNAL OF AMINO ACIDS 2013; 2013:509056. [PMID: 23710334 PMCID: PMC3654343 DOI: 10.1155/2013/509056] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2013] [Accepted: 03/27/2013] [Indexed: 11/25/2022]
Abstract
The resistance of growing human colon cancer cells to chemotherapy agents has been correlated to endogenous overexpression of stress proteins including the family of heat shock proteins (HSPs). Previously, we have demonstrated that a quinone-based mimetic dipeptide, named DTNQ-Pro, induced differentiation of growing Caco-2 cells through inhibition of HSP70 and HSP90. In addition, our product induced a HSP27 and vimentin intracellular redistribution. In the present study, we have evaluated whether a decrease of stress proteins induced by DTNQ-Pro in Caco-2 cells could sensitize these cells to treatment with 5-fluorouracil (5-FU) cytotoxicity. The pretreatment of Caco-2 with 500 nM of DTNQ-Pro increases lipid peroxidation and decreases expression of p38 mitogen-activated protein kinase (MAPK) and FOXO3a. At the same experimental conditions, an increase of the 5-FU-induced growth inhibition of Caco-2 cells was recorded. These effects could be due to enhanced DTNQ-Pro-induced membrane lipid peroxidation that, in turn, causes the sensitization of cancer cells to the cytotoxicity mediated by 5-FU.
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10
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Misso G, Giuberti G, Lombardi A, Grimaldi A, Ricciardiello F, Giordano A, Tagliaferri P, Abbruzzese A, Caraglia M. Pharmacological inhibition of HSP90 and ras activity as a new strategy in the treatment of HNSCC. J Cell Physiol 2012; 228:130-41. [DOI: 10.1002/jcp.24112] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Franco R, Nicoletti G, Lombardi A, Di Domenico M, Botti G, Zito Marino F, Caraglia M. Current treatment of cutaneous squamous cancer and molecular strategies for its sensitization to new target-based drugs. Expert Opin Biol Ther 2012; 13:51-66. [PMID: 22998482 DOI: 10.1517/14712598.2012.725720] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
INTRODUCTION Cutaneous squamous cell carcinoma (cSCC) is considered one of the most common skin malignancy with a relatively high risk of metastasis occurrence. AREAS COVERED We discuss the pathogenetic mechanisms of cSCC and the main therapeutic strategies available for the treatment of cSCC. EXPERT OPINION Chemotherapy and biological therapy with Interferon α (IFN-α) and cis retinoic acid are active but give limited results. Recently, strategies based on the use of molecularly target-based agents (MTA) have been used with promising results. Based on the available findings, we hypothesize that SCC cells can develop survival and resistance mechanisms to MTAs. The detection of these mechanisms could be useful in designing strategies able to overcome the latter and to potentiate the anticancer activity of MTAs. We describe the example of the EGF-dependent survival pathway elicited by IFN-α and the different strategies to abrogate this survival pathway. Other strategies to potentiate the antitumor activity of cytotoxic agents such as docetaxel or cisplatin are also discussed. Illuminating examples are the inhibition of multichaperone activity or the inactivation of the proteasome. In conclusion, a new dawn based upon the rationale use of MTAs is rising up in the treatment of advanced cSCC.
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Affiliation(s)
- Renato Franco
- Second University of Naples, Department of Biochemistry and Biophysics, Naples Italy
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12
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Bianchi L, Bruzzese F, Leone A, Gagliardi A, Puglia M, Di Gennaro E, Rocco M, Gimigliano A, Pucci B, Armini A, Bini L, Budillon A. Proteomic analysis identifies differentially expressed proteins after HDAC vorinostat and EGFR inhibitor gefitinib treatments in Hep-2 cancer cells. Proteomics 2012; 11:3725-42. [PMID: 21761561 DOI: 10.1002/pmic.201100092] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Several solid tumors are characterized by poor prognosis and few effective treatment options, other than palliative chemotherapy in the recurrent/metastatic setting. Epidermal growth factor receptor (EGFR) has been considered an important anticancer target because it is involved in the development and progression of several solid tumors; however, only a subset of patients show a clinically meaningful response to EGFR inhibition, particularly to EGFR tyrosine kinase inhibitors such as gefitinib. We have recently demonstrated synergistic antitumor effect of the histone deacetylase inhibitor vorinostat combined with gefitinib. To further characterize the interaction between these two agents, cellular extracts from Hep-2 cancer cells that were untreated or treated for 24 h with either vorinostat or gefitinib alone or with a vorinostat/gefitinib combination were analyzed using 2-D DIGE. Software analysis using DeCyder was performed, and numerous differentially expressed protein spots were visualized between the four examined settings. Using MALDI-TOF MS and ESI-Ion trap MS/MS, several differentially expressed proteins were identified; some of these were validated by Western blotting. Finally, a pathway analysis of experimental data performed using MetaCore highlighted a relevant relationship between the identified proteins and additional potential effectors. In conclusion, we performed a comprehensive analysis of proteins regulated by vorinostat and gefitinib, alone and in combination, providing a useful insight into their mechanisms of action as well as their synergistic interaction.
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Affiliation(s)
- Laura Bianchi
- Functional Proteomics Laboratory, Department of Molecular Biology, University of Siena, Siena, Italy
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Bruzzese F, Leone A, Rocco M, Carbone C, Piro G, Caraglia M, Di Gennaro E, Budillon A. HDAC inhibitor vorinostat enhances the antitumor effect of gefitinib in squamous cell carcinoma of head and neck by modulating ErbB receptor expression and reverting EMT. J Cell Physiol 2011; 226:2378-90. [PMID: 21660961 DOI: 10.1002/jcp.22574] [Citation(s) in RCA: 118] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Potentiation of epidermal growth factor receptor (EGFR) inhibitors is required in squamous cell carcinoma of head and neck (SCCHN) to improve their therapeutic index. We demonstrated that the histone deacetylase inhibitor vorinostat in combination with the EGFR tyrosine kinase inhibitor gefitinib induced synergistic inhibition of proliferation, migration, and invasion as well as induction of apoptosis in SCCHN cells, including cells resistant to gefitinib. We provided evidence suggesting that differential modulation of ErbB receptors together with reversion of epithelial-to-mesenchymal transition (EMT) by vorinostat represent mechanistic bases for the observed synergism. We demonstrated in epithelial CAL27 cells expressing EGFR, ErbB2, and ErbB3 that vorinostat downregulated the expression and signaling of all three receptors. In gefitinib-resistant KB and Hep-2 cells, both of which had undergone EMT and expressed very low levels of ErbB3, vorinostat reverted the mesenchymal phenotype by inducing both E-cadherin and ErbB3 and downregulating vimentin as well as EGFR and ErbB2. Both transcriptional and post-translational mechanisms were involved in the modulation of ErbB receptors by vorinostat. Attenuation of all ErbB transcripts in CAL27 cells as well as induction of ErbB3 transcript in Hep-2 and KB cells was seen upon vorinostat treatment. We showed that vorinostat induced ubiquitination of EGFR and ErbB2 and targeted them predominantly to lysosome-degradation in all cell lines, while the induction of ErbB3-ubiquitination in CAL27 cells led to proteasomes-degradation. Overall, this study suggests that the vorinostat/gefitinib combination represents a promising therapeutic strategy that warrants further clinical evaluation in SCCHN, including tumors intrinsically resistant to EGFR-inhibitors.
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Affiliation(s)
- Francesca Bruzzese
- Experimental Pharmacology Unit, Department of Research, National Cancer Institute Fondazione G Pascale, Naples, Italy
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14
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Histone deacetylase inhibitor treatment dramatically reduces cholesterol accumulation in Niemann-Pick type C1 mutant human fibroblasts. Proc Natl Acad Sci U S A 2011; 108:5620-5. [PMID: 21436030 DOI: 10.1073/pnas.1014890108] [Citation(s) in RCA: 156] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Niemann-Pick type C (NPC) disease is predominantly caused by mutations in the NPC1 protein that affect intracellular cholesterol trafficking and cause accumulation of unesterified cholesterol and other lipids in lysosomal storage organelles. We report the use of a series of small molecule histone deacetylase (HDAC) inhibitors in tissue culture models of NPC human fibroblasts. Some HDAC inhibitors lead to a dramatic correction in the NPC phenotype in cells with either one or two copies of the NPC1(I1061T) mutation, and for several of the inhibitors, correction is associated with increased expression of NPC1 protein. Increased NPC1(I1061T) protein levels may partially account for the correction of the phenotype, because this mutant can promote cholesterol efflux if it is delivered to late endosomes and lysosomes. The HDAC inhibitor treatment is ineffective in an NPC2 mutant human fibroblast line. Analysis of the isoform selectivity of the compounds used implicates HDAC1 and/or HDAC2 as likely targets for the observed correction, although other HDACs may also play a role. LBH589 (panobinostat) is an orally available HDAC inhibitor that crosses the blood-brain barrier and is currently in phase III clinical trials for several types of cancer. It restores cholesterol homeostasis in cultured NPC1 mutant fibroblasts to almost normal levels within 72 h when used at 40 nM. The findings that HDAC inhibitors can correct cholesterol storage defects in human NPC1 mutant cells provide the potential basis for treatment options for NPC disease.
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Di Gennaro E, Piro G, Chianese MI, Franco R, Di Cintio A, Moccia T, Luciano A, de Ruggiero I, Bruzzese F, Avallone A, Arra C, Budillon A. Vorinostat synergises with capecitabine through upregulation of thymidine phosphorylase. Br J Cancer 2010; 103:1680-91. [PMID: 21045833 PMCID: PMC2994231 DOI: 10.1038/sj.bjc.6605969] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Background: Potentiation of anticancer activity of capecitabine is required to improve its therapeutic index. In colorectal cancer (CRC) cells, we evaluated whether the histone deacetylase-inhibitor vorinostat may induce synergistic antitumour effects in combination with capecitabine by modulating the expression of thymidine phosphorylase (TP), a key enzyme in the conversion of capecitabine to 5-florouracil (5-FU), and thymidylate synthase (TS), the target of 5-FU. Methods: Expression of TP and TS was measured by real-time PCR, western blotting and immunohistochemistry. Knockdown of TP was performed by specific small interfering RNA. Antitumour activity of vorinostat was assessed in vitro in combination with the capecitabine active metabolite deoxy-5-fluorouridine (5′-DFUR) according to the Chou and Talay method and by evaluating apoptosis as well as in xenografts-bearing nude mice in combination with capecitabine. Results: Vorinostat induced both in vitro and in vivo upregulation of TP as well as downregulation of TS in cancer cells, but not in ex vivo treated peripheral blood lymphocytes. Combined treatment with vorinostat and 5′-DFUR resulted in a synergistic antiproliferative effect and increased apoptotic cell death in vitro. This latter effect was impaired in cells where TP was knocked. In vivo, vorinostat plus capecitabine potently inhibited tumour growth, increased apoptosis and prolonged survival compared with control or single-agent treatments. Conclusions: Overall, this study suggests that the combination of vorinostat and capecitabine is an innovative antitumour strategy and warrants further clinical evaluation for the treatment of CRC.
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Affiliation(s)
- E Di Gennaro
- Experimental Pharmacology Unit, Department of Research, Istituto Nazionale Tumori, National Cancer Institute Fondazione G, Via M Semmola, Pascale, Napoli 80131, Italy
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16
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Zhang X, Zhang Z, Chen G, Zhao M, Wang D, Zhang X, Du Z, Xu Y, Yu X. FK228 induces mitotic catastrophe in A549 cells by mistargeting chromosomal passenger complex localization through changing centromeric H3K9 hypoacetylation. Acta Biochim Biophys Sin (Shanghai) 2010; 42:677-87. [PMID: 20817931 DOI: 10.1093/abbs/gmq077] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Previous studies have shown that histone deacetylase inhibitors (HDACis) can kill cancer cells. In addition, HDACis can induce mitotic catastrophe in cancer cells due to insufficient localization of chromosomal passenger complex (CPC) to the centromere. However, the mechanisms behind these phenomena remain unclear. In this study, we found that a HDACi, FK228, affected multiple epigenetic modification characteristics of the centromere, including enhanced acetylation of histone H3 lysine 9 (H3K9), decreased trimethylation of H3K9, and decreased phosphorylation of histone H3 serine 10 (H3S10) and centromere protein A (CENP-A). These epigenetic changes implied that H3K9 hyperacetylation inhibits the CPC recruitment, induces impaired centromere assembly and function, and eventually leads to aberrant mitosis. These data suggested that hypoacetylation of histone in the pericentromere is the most important landmark for recruiting CPC and leading to the mitotic catastrophe in HDACi-induced killing of cancer cells.
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Affiliation(s)
- Xuhui Zhang
- Department of Pathology, Beijing Institute of Basic Medical Sciences, China
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Missner E, Bahr I, Badock V, Lücking U, Siemeister G, Donner P. Off-target decoding of a multitarget kinase inhibitor by chemical proteomics. Chembiochem 2009; 10:1163-74. [PMID: 19350611 DOI: 10.1002/cbic.200800796] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Unbiased: Chemical proteomics was used to profile compound interactions in an unbiased fashion. We present here the application of different compound-immobilization routes for decoding nonprotein kinase off-targets of the multitarget kinase inhibitor C1, which interacts with distinct compound moieties. Since the approval of the first selective tyrosine kinase inhibitor, imatinib, various drugs have been developed to target protein kinases. However, due to a high degree of structural conservation of the ATP binding site, off-target effects have been reported for several drugs. Here, we report on off-target decoding for a multitarget protein kinase inhibitor by chemical proteomics, by focusing on interactions with nonprotein kinases. We tested two different routes for the immobilization of the inhibitor on a carrier matrix, and thus identified off-targets that interact with distinct compound moieties. Besides several of the kinases known to bind to the compound, the pyridoxal kinase (PDXK), which has been described to interact with the CDK inhibitor (R)-roscovitine, was captured. The PDXK-inhibitor interaction was shown to occur at the substrate binding site rather than at the ATP binding site. In addition, carbonic anhydrase 2 (CA2) binding was demonstrated, and the determination of the IC(50) revealed an enzyme inhibition in the submicromolar range. The data demonstrate that different compound immobilization routes for chemical proteomics approaches are a valuable method to improve the knowledge about the off-target profile of a compound.
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Affiliation(s)
- Enrico Missner
- Bayer Schering Pharma AG, Global Drug Discovery, 13342 Berlin, Germany.
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Espinoza-Fonseca LM. Knowledgebase for addiction-related genes: is it possible an extrapolation to rational multi-target drug design? Bioorg Med Chem 2008; 16:9346-8. [PMID: 18815048 DOI: 10.1016/j.bmc.2008.08.080] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2008] [Revised: 08/19/2008] [Accepted: 08/26/2008] [Indexed: 10/21/2022]
Abstract
In recent years the single-probe-single-target approach in drug design has started to be smoothly replaced by the single-probe-multiple-target (or multi-target) one, where a single drug is able to tackle different, but disease-related targets in a selective manner. However, the design of multi-target drugs has been hindered by a lack of a systematic network of disease-related common pathways. The recent development of the knowledgebase of addiction-related genes (KARG) has provided important hints on how to rationally design multi-target probes by connecting experimental techniques with available network models. In this perspective, the use of KARG as a template to build knowledgebases of disease-related genes for the rational multi-target drug design is suggested. Moreover, it is proposed that building knowledgebases of disease-related genes will become a necessary and ubiquitous tool in the rational design of multi-target drugs.
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Affiliation(s)
- L Michel Espinoza-Fonseca
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
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Kruse U, Bantscheff M, Drewes G, Hopf C. Chemical and pathway proteomics: powerful tools for oncology drug discovery and personalized health care. Mol Cell Proteomics 2008; 7:1887-901. [PMID: 18676365 DOI: 10.1074/mcp.r800006-mcp200] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
In recent years mass spectrometry-based proteomics has moved beyond a mere quantitative description of protein expression levels and their possible correlation with disease or drug action. Impressive progress in LC-MS instrumentation together with the availability of new enabling tools and methods for quantitative proteome analysis and for identification of posttranslational modifications has triggered a surge of chemical and functional proteomics studies dissecting mechanisms of action of cancer drugs and molecular mechanisms that modulate signal transduction pathways. Despite the tremendous progress that has been made in the field, major challenges, relating to sensitivity, dynamic range, and throughput of the described methods, remain. In this review we summarize recent advances in LC-MS-based approaches and their application to cancer drug discovery and to studies of cancer-related pathways in cell culture models with particular emphasis on mechanistic studies of drug action in these systems. Moreover we highlight the emerging utility of pathway and chemical proteomics techniques for translational research in patient tissue.
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Affiliation(s)
- Ulrich Kruse
- Deptartment of Discovery Technology, Cellzome AG, Meyerhofstrasse 1, D-69117 Heidelberg, Germany
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20
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Haefner M, Bluethner T, Niederhagen M, Moebius C, Wittekind C, Mossner J, Caca K, Wiedmann M. Experimental treatment of pancreatic cancer with two novel histone deacetylase inhibitors. World J Gastroenterol 2008; 14:3681-92. [PMID: 18595135 PMCID: PMC2719231 DOI: 10.3748/wjg.14.3681] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate in vitro and in vivo treatment with histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 in pancreatic cancer.
METHODS: Cell-growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 8 human pancreatic cancer cell lines using the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In addition, the anti-tumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral activity of the drugs was assessed by immunoblotting for p21WAF-1, acH4, cell cycle analysis, TUNEL assay, and immunohistochemistry for MIB-1.
RESULTS: In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines and was associated with hyperacetylation of nucleosomal histone H4, increased expression of p21WAF-1, cell cycle arrest at G2/M-checkpoint, and increased apoptosis. In vivo, NVP-LBH589 alone significantly reduced tumor mass and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed slightly increased apoptosis and no significant reduction of cell proliferation.
CONCLUSION: Our findings suggest that NVP-LBH589 and NVP-LAQ824 are active against human pancreatic cancer, although the precise mechanism of in vivo drug action is not yet completely understood. Therefore, further preclinical and clinical studies for the treatment of pancreatic cancer are recommended.
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Nacher JC, Schwartz JM. A global view of drug-therapy interactions. BMC Pharmacol 2008; 8:5. [PMID: 18318892 PMCID: PMC2294115 DOI: 10.1186/1471-2210-8-5] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2007] [Accepted: 03/04/2008] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Network science is already making an impact on the study of complex systems and offers a promising variety of tools to understand their formation and evolution in many disparate fields from technological networks to biological systems. Even though new high-throughput technologies have rapidly been generating large amounts of genomic data, drug design has not followed the same development, and it is still complicated and expensive to develop new single-target drugs. Nevertheless, recent approaches suggest that multi-target drug design combined with a network-dependent approach and large-scale systems-oriented strategies create a promising framework to combat complex multi-genetic disorders like cancer or diabetes. RESULTS We here investigate the human network corresponding to the interactions between all US approved drugs and human therapies, defined by known relationships between drugs and their therapeutic applications. Our results show that the average paths in this drug-therapy network are shorter than three steps, indicating that distant therapies are separated by a surprisingly low number of chemical compounds. We also identify a sub-network composed by drugs with high centrality measures in the drug-therapy network, which represent the structural backbone of this system and act as hubs routing information between distant parts of the network. CONCLUSION These findings provide for the first time a global map of the large-scale organization of all known drugs and associated therapies, bringing new insights on possible strategies for future drug development. Special attention should be given to drugs which combine the two properties of (a) having a high centrality value in the drug-therapy network and (b) acting on multiple molecular targets in the human system.
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Affiliation(s)
- Jose C Nacher
- Department of Complex Systems, Future University-Hakodate, Hokkaido 041-8655, Japan
| | - Jean-Marc Schwartz
- Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK
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Bluethner T, Niederhagen M, Caca K, Serr F, Witzigmann H, Moebius C, Mossner J, Wiedmann M. Inhibition of histone deacetylase for the treatment of biliary tract cancer: A new effective pharmacological approach. World J Gastroenterol 2007; 13:4761-70. [PMID: 17729398 PMCID: PMC4611198 DOI: 10.3748/wjg.v13.i35.4761] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate in vitro and in vivo therapeutic effects of histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 on biliary tract cancer.
METHODS: Cell growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 7 human biliary tract cancer cell lines by MTT assay. In addition, the anti-tumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral drug mechanism was assessed by immunoblotting for acH4 and p21WAF-1/CIP-1, PARP assay, cell cycle analysis, TUNEL assay, and immunhistochemistry for MIB-1.
RESULTS: In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines [mean IC50 (3 d) 0.11 and 0.05 μmol/L, respectively], and was associated with hyperacetylation of nucleosomal histone H4, increased expression of p21WAF-1/CIP-1, induction of apoptosis (PARP cleavage), and cell cycle arrest at G2/M checkpoint. After 28 d, NVP-LBH589 significantly reduced tumor mass by 66% (bile duct cancer) and 87% (gallbladder cancer) in vivo in comparison to placebo, and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed increased apoptosis by TUNEL assay and reduced cell proliferation (MIB-1).
CONCLUSION: Our findings suggest that NVP-LBH589 and NVP-LAQ824 are active against human biliary tract cancer in vitro. In addition, NVP-LBH589 demonstrated significant in vivo activity and potentiated the efficacy of gemcitabine. Therefore, further clinical evaluation of this new drug for the treatment of biliary tract cancer is recommended.
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Affiliation(s)
- Thilo Bluethner
- Department of Internal Medicine II, University of Leipzig, Philipp-Rosenthal-Str. 27, 04103 Leipzig, Germany
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Konstantinopoulos PA, Karamouzis MV, Papavassiliou AG. Focus on acetylation: the role of histone deacetylase inhibitors in cancer therapy and beyond. Expert Opin Investig Drugs 2007; 16:569-71. [PMID: 17461732 DOI: 10.1517/13543784.16.5.569] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Reversal of tumorigenic epigenetic alterations is an exciting strategy for anticancer drug development. Pharmacologic inhibition of histone deacetylases (HDACs) induces differentiation, proliferation arrest and apoptosis of cancer cells. In addition to their effects on histones, HDAC inhibitors increase the acetylation level of several non-histone proteins, such as transcription factors, cytoskeletal proteins and molecular chaperones, which are crucial in tumorigenesis. Most importantly, the therapeutic potential of HDAC inhibitors goes well beyond carcinogenesis and may include neurodegenerative and inflammatory disorders. This editorial discusses the implication of HDACs in carcinogenesis, the molecular basis of the selectivity of HDAC inhibitors and their possible therapeutic role in non-malignant pathologic conditions.
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Affiliation(s)
- Panagiotis A Konstantinopoulos
- Department of Biological Chemistry, Medical School, University of Athens, 75, M. Asias Street, GR-11527 Goudi-Athens, Greece
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Lattouf JB, Srinivasan R, Pinto PA, Linehan WM, Neckers L. Mechanisms of disease: the role of heat-shock protein 90 in genitourinary malignancy. ACTA ACUST UNITED AC 2007; 3:590-601. [PMID: 17088927 DOI: 10.1038/ncpuro0604] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2006] [Accepted: 08/14/2006] [Indexed: 12/28/2022]
Abstract
Insight into the molecular biology of cancer has allowed the development of novel therapeutic strategies that target specific oncogenic pathways. Molecular therapeutic strategies are now part of the armamentarium available against urologic malignancy. Among the many targets of interest in urologic cancer, heat-shock protein 90 (HSP90) shows great promise. This molecule has a major role in prostate as well as in renal malignancy. In contrast to other targets, where cancer might escape inhibition via alternative pathways, HSP90 operates at multiple checkpoints in a cancer cell. Its inhibition could, therefore, prove more difficult for neoplastic cells to overcome. Inhibitors of HSP90, such as geldanamycin and its derivatives (17-allylamino-17-demethoxygeldanamycin and 17-dimethylaminoethylamino-17-demethoxygeldanamycin, known as 17AAG and 17DMAG, respectively) are available and have shown activity both in vivo and in vitro. 17AAG is currently being tested for efficacy in humans after having completed phase I trials, while 17DMAG is still in phase I evaluation. Phase II trials of HSP90 inhibitors in urologic malignancy are being conducted in kidney and advanced prostate cancer. Beyond monotherapy, HSP90 inhibitors might also prove to be beneficial in combination therapy with other chemotherapeutic agents in advanced disease. Studies being conducted in prostate cancer will hopefully help to define this potential application better.
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Affiliation(s)
- Jean-Baptiste Lattouf
- Urologic Oncology Branch, National Cancer Institute, Room 1-5942, Building 10 CRC, 9000 Rockville Pike, Bethesda, MD 20892, USA
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25
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Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 2006; 5:769-84. [PMID: 16955068 DOI: 10.1038/nrd2133] [Citation(s) in RCA: 2291] [Impact Index Per Article: 120.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Histone deacetylases (HDACs) are enzymes involved in the remodelling of chromatin, and have a key role in the epigenetic regulation of gene expression. In addition, the activity of non-histone proteins can be regulated through HDAC-mediated hypo-acetylation. In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and several classes of HDAC inhibitors have been found to have potent and specific anticancer activities in preclinical studies. However, such studies have also indicated that the effects of HDAC inhibitors could be considerably broader and more complicated than originally understood. Here we summarize recent advances in the understanding of the molecular events that underlie the anticancer effects of HDAC inhibitors, and discuss how such information could be used in optimizing the development and application of these agents in the clinic, either as monotherapies or in combination with other anticancer drugs.
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Affiliation(s)
- Jessica E Bolden
- Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne 3002, Victoria, Australia
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Abstract
Raf kinase signaling has been thoroughly investigated over the last 20 years. A-Raf, B-Raf and C-Raf, the 3 mammalian members of the Raf family, are involved in a variety of cellular processes such as growth, proliferation, survival, differentiation and transformation. The detection of B-RAF mutations in a wide variety of human cancers, the description of wildtype and mutant B-RAF as tumor antigens in melanoma and the promising outcome of clinical trials evaluating the Raf inhibitor Nexavar (Sorafenib, BAY 43-9006) have sparked a broad interest in the scientific community. After a short historical detour and an introduction into Raf kinase signaling, we are going to discuss here recent outcomes of Raf kinase research with respect to tumor formation and give an overview on current efforts to develop anticancer therapies interfering with aberrant Raf kinase signaling.
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Affiliation(s)
- Ralf Schreck
- Institut für Medizinische Strahlenkunde und Zellforschung, MSZ, Universität Würzburg, Würzburg, Germany
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Highlights From: 97th Annual Meeting of the American Association for Cancer Research; Washington, DC, April 2006. Clin Lung Cancer 2006. [DOI: 10.1016/s1525-7304(11)70710-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Appendino G, Cascio MG, Bacchiega S, Moriello AS, Minassi A, Thomas A, Ross R, Pertwee R, De Petrocellis L, Di Marzo V. First “hybrid” ligands of vanilloid TRPV1 and cannabinoid CB2receptors and non-polyunsaturated fatty acid-derived CB2-selective ligands. FEBS Lett 2005; 580:568-74. [PMID: 16406364 DOI: 10.1016/j.febslet.2005.12.069] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2005] [Revised: 12/07/2005] [Accepted: 12/20/2005] [Indexed: 01/21/2023]
Abstract
12-Phenylacetyl-ricinoleoyl-vanillamide (phenylacetylrinvanil, PhAR, IDN5890), is an ultra-potent agonist of human vanilloid TRPV1 receptors also endowed with moderate affinity for human cannabinoid CB(2) receptors. To improve its CB(2) affinity and temper its potency at TRPV1, the modification of the polar headgroup and the lipophilic 12-acylgroup of PhAR was pursued. Replacement of the vanillyl headgroup of PhAR with various aromatic or alkyl amino groups decreased activity at TRPV1 receptors, although the dopamine, cyclopropylamine, 1'-(R)- and 1'-(S)-methyl-ethanolamine, and ethanolamine derivatives retained significant potency (EC(50) 31-126 nM). Within these compounds, the 12-phenylacetylricinoleyl cyclopropylamide and ethanolamide were the strongest ligands at CB(2) receptors, with K(i) of 22 and 44 nM, and 14- and >20-fold selectivity over cannabinoid CB(1) receptors, respectively. The propyl- and allyl-derivatives also exhibited high affinity at CB(2) receptors (K(i)=40 and 22 nM, with 40 and >80-fold selectivity over CB(1) receptors, respectively), but no activity at TRPV1 receptors. The cyclopropyl- and allyl-derivatives behaved as CB(2) inverse agonists in the GTP-gamma-S binding assay. Addition of para-methoxy, -tert-butyl or -chlorine groups to the 12-phenylacetyl moiety of PhAR produced compounds that retained full potency at TRPV1 receptors, but with improved selectivity over CB(2) or CB(1) receptors. Thus, the manipulation of PhAR led to the development of the first CB(2)/TRPV1 dual ligands and of an entirely new class of inverse agonists at CB(2) receptors. Both types of compounds might find application in the treatment of inflammation, and represent new molecular probes to investigate the endocannabinoid-endovanilloid signalling system.
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Affiliation(s)
- Giovanni Appendino
- Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Via Bovio 6, 28100 Novara, Italy.
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