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1
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Silnitsky S, Rubin SJS, Zerihun M, Qvit N. An Update on Protein Kinases as Therapeutic Targets-Part I: Protein Kinase C Activation and Its Role in Cancer and Cardiovascular Diseases. Int J Mol Sci 2023; 24:17600. [PMID: 38139428 PMCID: PMC10743896 DOI: 10.3390/ijms242417600] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 12/10/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023] Open
Abstract
Protein kinases are one of the most significant drug targets in the human proteome, historically harnessed for the treatment of cancer, cardiovascular disease, and a growing number of other conditions, including autoimmune and inflammatory processes. Since the approval of the first kinase inhibitors in the late 1990s and early 2000s, the field has grown exponentially, comprising 98 approved therapeutics to date, 37 of which were approved between 2016 and 2021. While many of these small-molecule protein kinase inhibitors that interact orthosterically with the protein kinase ATP binding pocket have been massively successful for oncological indications, their poor selectively for protein kinase isozymes have limited them due to toxicities in their application to other disease spaces. Thus, recent attention has turned to the use of alternative allosteric binding mechanisms and improved drug platforms such as modified peptides to design protein kinase modulators with enhanced selectivity and other pharmacological properties. Herein we review the role of different protein kinase C (PKC) isoforms in cancer and cardiovascular disease, with particular attention to PKC-family inhibitors. We discuss translational examples and carefully consider the advantages and limitations of each compound (Part I). We also discuss the recent advances in the field of protein kinase modulators, leverage molecular docking to model inhibitor-kinase interactions, and propose mechanisms of action that will aid in the design of next-generation protein kinase modulators (Part II).
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Affiliation(s)
- Shmuel Silnitsky
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, Safed 1311502, Israel; (S.S.); (M.Z.)
| | - Samuel J. S. Rubin
- Department of Medicine, School of Medicine, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA;
| | - Mulate Zerihun
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, Safed 1311502, Israel; (S.S.); (M.Z.)
| | - Nir Qvit
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, Safed 1311502, Israel; (S.S.); (M.Z.)
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2
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Aquino A, Bianchi N, Terrazzan A, Franzese O. Protein Kinase C at the Crossroad of Mutations, Cancer, Targeted Therapy and Immune Response. BIOLOGY 2023; 12:1047. [PMID: 37626933 PMCID: PMC10451643 DOI: 10.3390/biology12081047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/18/2023] [Accepted: 07/21/2023] [Indexed: 08/27/2023]
Abstract
The frequent PKC dysregulations observed in many tumors have made these enzymes natural targets for anticancer applications. Nevertheless, this considerable interest in the development of PKC modulators has not led to the expected therapeutic benefits, likely due to the complex biological activities regulated by PKC isoenzymes, often playing ambiguous and protective functions, further driven by the occurrence of mutations. The structure, regulation and functions of PKCs have been extensively covered in other publications. Herein, we focused on PKC alterations mostly associated with complete functional loss. We also addressed the modest yet encouraging results obtained targeting PKC in selected malignancies and the more frequent negative clinical outcomes. The reported observations advocate the need for more selective molecules and a better understanding of the involved pathways. Furthermore, we underlined the most relevant immune mechanisms controlled by PKC isoforms potentially impacting the immune checkpoint inhibitor blockade-mediated immune recovery. We believe that a comprehensive examination of the molecular features of the tumor microenvironment might improve clinical outcomes by tailoring PKC modulation. This approach can be further supported by the identification of potential response biomarkers, which may indicate patients who may benefit from the manipulation of distinctive PKC isoforms.
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Affiliation(s)
- Angelo Aquino
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy;
| | - Nicoletta Bianchi
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (N.B.); (A.T.)
| | - Anna Terrazzan
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (N.B.); (A.T.)
- Laboratory for Advanced Therapy Technologies (LTTA), University of Ferrara, 44121 Ferrara, Italy
| | - Ornella Franzese
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy;
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3
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Tian Z, Lu XT, Jiang X, Tian J. Bryostatin-1: a promising compound for neurological disorders. Front Pharmacol 2023; 14:1187411. [PMID: 37351510 PMCID: PMC10282138 DOI: 10.3389/fphar.2023.1187411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 05/23/2023] [Indexed: 06/24/2023] Open
Abstract
The central nervous system (CNS) is the most complex system in human body, and there is often a lack of effective treatment strategies for the disorders related with CNS. Natural compounds with multiple pharmacological activities may offer better options because they have broad cellular targets and potentially produce synergic and integrative effects. Bryostatin-1 is one of such promising compounds, a macrolide separated from marine invertebrates. Bryostatin-1 has been shown to produce various biological activities through binding with protein kinase C (PKC). In this review, we mainly summarize the pharmacological effects of bryostatin-1 in the treatment of multiple neurological diseases in preclinical studies and clinical trials. Bryostatin-1 is shown to have great therapeutic potential for Alzheimer's disease, multiple sclerosis, fragile X syndrome, stroke, traumatic brain injury, and depression. It exhibits significant rescuing effects on the deficits of spatial learning, cognitive function, memory and other neurological functions caused by diseases, producing good neuroprotective effects. The promising neuropharmacological activities of bryostatin-1 suggest that it is a potential candidate for the treatment of related neurological disorders although there are still some issues needed to be addressed before its application in clinic.
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Affiliation(s)
- Zhen Tian
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Xin-Tong Lu
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Xun Jiang
- Department of Pediatrics, Tangdu Hospital of Fourth Military Medical University, Xi’an, China
| | - Jiao Tian
- Department of Infection, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, The First Batch of Key Disciplines on Public Health in Chongqing, Chongqing, China
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4
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Bartusik-Aebisher D, Osuchowski M, Adamczyk M, Stopa J, Cieślar G, Kawczyk-Krupka A, Aebisher D. Advancements in photodynamic therapy of esophageal cancer. Front Oncol 2022; 12:1024576. [PMID: 36465381 PMCID: PMC9713848 DOI: 10.3389/fonc.2022.1024576] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 10/24/2022] [Indexed: 12/02/2023] Open
Abstract
The poor prognosis of patients with esophageal cancer leads to the constant search for new ways of treatment of this disease. One of the methods used in high-grade dysplasia, superficial invasive carcinoma, and sometimes palliative care is photodynamic therapy (PDT). This method has come a long way from the first experimental studies to registration in the treatment of esophageal cancer and is constantly being improved and refined. This review describes esophageal cancer, current treatment methods, the introduction to PDT, the photosensitizers (PSs) used in esophageal carcinoma PDT, PDT in squamous cell carcinoma (SCC) of the esophagus, and PDT in invasive adenocarcinoma of the esophagus. For this review, research and review articles from PubMed and Web of Science databases were used. The keywords used were "photodynamic therapy in esophageal cancer" in the years 2000-2020. The total number of papers returned was 1,000. After the review was divided into topic blocks and the searched publications were analyzed, 117 articles were selected.
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Affiliation(s)
- Dorota Bartusik-Aebisher
- Department of Biochemistry and General Chemistry, Medical College of The University of Rzeszów, Rzeszów, Poland
| | | | - Marta Adamczyk
- Medical Faculty, Medical University of Warsaw, Warsaw, Poland
| | - Joanna Stopa
- Medical College of The University of Rzeszów, Rzeszów, Poland
| | - Grzegorz Cieślar
- Department of Internal Medicine, Angiology, and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Bytom, Poland
| | - Aleksandra Kawczyk-Krupka
- Department of Internal Medicine, Angiology, and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Bytom, Poland
| | - David Aebisher
- Department of Photomedicine and Physical Chemistry, Medical College of The University of Rzeszów, Rzeszów, Poland
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5
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Teng M, Young DW, Tan Z. The Pursuit of Enzyme Activation: A Snapshot of the Gold Rush. J Med Chem 2022; 65:14289-14304. [PMID: 36265019 DOI: 10.1021/acs.jmedchem.2c01291] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
A range of enzymes drive human physiology, and their activities are tightly regulated through numerous signaling pathways. Depending on the context, these pathways may activate or inhibit an enzyme as a way to ensure proper execution of cellular functions. From a drug discovery and development perspective, pharmacological inhibition of enzymes has been a focus of interest, as many diseases are associated with the upregulation of enzyme function. On the other hand, however, pharmacological activation of enzymes such as kinases and phosphatases has been of increasing interest. In this review, we discuss seven case studies that highlight pharmacological activation strategy, describe the binding modes and pharmacology of the activators, and comment on how this on-demand activation strategy complements the commonly pursued inhibition strategy, thus jointly enabling bidirectional modulation of specific target of interest. Going forward, we expect activators to play important roles as chemical probes and drug leads.
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Affiliation(s)
- Mingxing Teng
- Department of Pathology & Immunology, and Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, Texas 77030, United States
| | - Damian W Young
- Department of Pathology & Immunology, and Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, Texas 77030, United States
| | - Zhi Tan
- Department of Pathology & Immunology, and Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, Texas 77030, United States
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6
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Wu XY, Liao BY, Xiao D, Wu WC, Xiao Y, Alexander T, Song SJ, Zhao ZH, Zhang Y, Wang ZH, Wang LB, Li X. Encapsulation of bryostatin-1 by targeted exosomes enhances remyelination and neuroprotection effects in the cuprizone-induced demyelinating animal model of multiple sclerosis. Biomater Sci 2021; 10:714-727. [PMID: 34928285 DOI: 10.1039/d1bm01142a] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Demyelination is a critical neurological disease, and there is still a lack of effective treatment methods. In the past two decades, stem cells have emerged as a novel therapeutic effector for neural regeneration. However, owing to the existence of the blood-brain barrier (BBB) and the complex microenvironment, targeted therapy still faces multiple challenges. Targeted exosome carriers for drug delivery may be considered a promising therapeutic method. Exosomes were isolated from mice neural stem cells. To develop targeting exosomes, we generated a lentivirus armed PDGFRα ligand that could anchor the membrane. Exosome targeting tests were carried out in vitro and in vivo. The modified exosomes showed an apparent ability to target OPCs in the lesion area. Next, the exosomes were loaded with Bryostatin-1 (Bryo), and the cuprizone-fed mice were administered with the targeting exosomes. The data show that Bryo exhibits a powerful therapeutic effect compared with Bryo alone after exosome encapsulation. Specifically, this novel exosome-based targeting delivery of Bryo significantly improves the protection ability of the myelin sheath and promotes remyelination. Moreover, it blocks astrogliosis and axon damage, and also has an inhibitory effect on pro-inflammatory microglia. The results of this investigation provide a straightforward strategy to produce targeting exosomes and indicate a potential therapeutic approach for demyelinating disease.
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Affiliation(s)
- Xiao-Yu Wu
- The General Hospital of Ningxia Medical University, Yinchuan, 750001, China.
| | - Bao-Ying Liao
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, 710119, China.
| | - Dan Xiao
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Wen-Cheng Wu
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, 710119, China.
| | - Yun Xiao
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, 710119, China.
| | - Tyler Alexander
- Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Sheng-Jiao Song
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, 710119, China.
| | - Zhuo-Hua Zhao
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, 710119, China.
| | - Yuan Zhang
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, 710119, China.
| | - Zhen-Hai Wang
- The General Hospital of Ningxia Medical University, Yinchuan, 750001, China.
| | - Li-Bin Wang
- The General Hospital of Ningxia Medical University, Yinchuan, 750001, China.
| | - Xing Li
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, 710119, China.
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7
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Activators and Inhibitors of Protein Kinase C (PKC): Their Applications in Clinical Trials. Pharmaceutics 2021; 13:pharmaceutics13111748. [PMID: 34834162 PMCID: PMC8621927 DOI: 10.3390/pharmaceutics13111748] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/18/2021] [Accepted: 10/19/2021] [Indexed: 02/05/2023] Open
Abstract
Protein kinase C (PKC), a family of phospholipid-dependent serine/threonine kinase, is classed into three subfamilies based on their structural and activation characteristics: conventional or classic PKC isozymes (cPKCs; α, βI, βII, and γ), novel or non-classic PKC isozymes (nPKCs; δ, ε, η, and θ), and atypical PKC isozymes (aPKCs; ζ, ι, and λ). PKC inhibitors and activators are used to understand PKC-mediated intracellular signaling pathways and for the diagnosis and treatment of various PKC-associated diseases, such as cancers, neurological diseases, cardiovascular diseases, and infections. Many clinical trials of PKC inhibitors in cancers showed no significant clinical benefits, meaning that there is a limitation to design a cancer therapeutic strategy targeting PKC alone. This review will focus on the activators and inhibitors of PKC and their applications in clinical trials.
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8
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Zhang S, Xu Y, Zeng L, An X, Su D, Qu Y, Ma J, Tang X, Wang X, Yang J, Mishra C, Chandra SR, Ai J. Epigallocatechin-3-Gallate Allosterically Activates Protein Kinase C-α and Improves the Cognition of Estrogen Deficiency Mice. ACS Chem Neurosci 2021; 12:3672-3682. [PMID: 34505505 DOI: 10.1021/acschemneuro.1c00401] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Protein kinase C (PKC) isozymes play essential roles in biological processes, and activation of PKC is proposed to alleviate the symptoms of a variety of diseases. It would be of great significance to find effective pharmacological modulators of PKC isozymes that can be translated for clinical use. Here, using in vitro activity assay, we demonstrated that green tea extract (-)-epigallocatechin-3-gallate (EGCG) dose-dependently activated PKCα with a half effective concentration (EC50) of 0.49 μM. We also performed surface plasmon resonance analysis and found that EGCG binds PKCα with an equilibrium dissociation constant (KD) value of 4.11 × 10-6 mol/L. Further computational flexible docking analysis revealed that EGCG interacted with the catalytic C3-C4 domain of PKCα (PDB: 4RA4) through establishing polar hydrogen bonds with V420, T401, E387, and K368 of PKCα, and the benzene ring group of EGCG hydrophobically interacted with the hydrophobic pocket formed by L345, M470, I479, and V353 of PKCα. Interestingly, the PKCα-selective blocker Ro-32-0432 could compete with EGCG for the same substrate-binding pocket of PKCα. Moreover, we found that EGCG dose-dependently improved the spatial memory, object recognition ability, and hippocampal long-term potentiation of ovariectomized mice, which was offset by Ro-32-0432. Collectively, our findings reveal a novel PKCα agonist and open the way to a new perspective on PKCα pharmacology and the treatment of PKCα-related diseases, including cognitive impairment.
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Affiliation(s)
- Shuai Zhang
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - Yi Xu
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - Lu Zeng
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - Xiaobin An
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - Dan Su
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - Yang Qu
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - Jing Ma
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - Xin Tang
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - Xuqiao Wang
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - Junkai Yang
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - Chandan Mishra
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - Shah Ram Chandra
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - Jing Ai
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
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9
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Raghuvanshi R, Bharate SB. Preclinical and Clinical Studies on Bryostatins, A Class of Marine-Derived Protein Kinase C Modulators: A Mini-Review. Curr Top Med Chem 2021; 20:1124-1135. [PMID: 32209043 DOI: 10.2174/1568026620666200325110444] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 02/11/2020] [Accepted: 02/24/2020] [Indexed: 12/20/2022]
Abstract
Bryostatins are complex macrolactones isolated from marine organisms Bryozoan Bugula neritina. They are potent modulators of protein kinase C isozymes (PKCα: ki = 1.3-188 nM), and are one of the most extensively investigated marine natural products in clinical trials. Although ~21 natural bryostatins have been isolated, however only bryostatin-1 (1) has received much interest among medicinal chemists and clinicians. The structure-activity relationship of bryostatins has been well established, with the identification of key pharmacophoric features important for PKC modulation. The low natural abundance and the long synthetic route have prompted medicinal chemists to come-up with simplified analogs. Bryostatin skeleton comprises three pyran rings connected to each other to form a macrocyclic lactone. The simplest analog 27 contains only one pyran, which is also able to modulate the PKCα activity; however, the cyclic framework appears to be essential for the desired level of potency. Another simplified analog 17 ("picolog") exhibited potent and in-vivo efficacy against lymphoma. Bryostatin-1 (1) has shown an acceptable intravenous pharmacokinetic profile in mice and displayed promising in-vivo efficacy in mice models of various cancers and Alzheimer's disease. Bryostatin-1 was investigated in numerous Phase I/II oncology clinical trials; it has shown minimal effect as a single agent, however, provided encouraging results in combination with other chemotherapy agents. FDA has granted orphan drug status to bryostatin-1 in combination with paclitaxel for esophageal cancer. Bryostatin-1 has also received orphan drug status for fragile X syndrome. Bryostatin-1 was also investigated in clinical studies for Alzheimer's disease and HIV infection. In a nutshell, the natural as well as synthetic bryostatins have generated a strong hope to emerge as treatment for cancer along with many other diseases.
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Affiliation(s)
- Rinky Raghuvanshi
- Medicinal Chemistry Division, CSIR- Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.,Academy of Scientific & Innovative Research (AcSIR), Ghaziabad-201002, India
| | - Sandip B Bharate
- Medicinal Chemistry Division, CSIR- Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.,Academy of Scientific & Innovative Research (AcSIR), Ghaziabad-201002, India
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10
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Parker PJ, Brown SJ, Calleja V, Chakravarty P, Cobbaut M, Linch M, Marshall JJT, Martini S, McDonald NQ, Soliman T, Watson L. Equivocal, explicit and emergent actions of PKC isoforms in cancer. Nat Rev Cancer 2021; 21:51-63. [PMID: 33177705 DOI: 10.1038/s41568-020-00310-4] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/02/2020] [Indexed: 01/02/2023]
Abstract
The maturing mutational landscape of cancer genomes, the development and application of clinical interventions and evolving insights into tumour-associated functions reveal unexpected features of the protein kinase C (PKC) family of serine/threonine protein kinases. These advances include recent work showing gain or loss-of-function mutations relating to driver or bystander roles, how conformational constraints and plasticity impact this class of proteins and how emergent cancer-associated properties may offer opportunities for intervention. The profound impact of the tumour microenvironment, reflected in the efficacy of immune checkpoint interventions, further prompts to incorporate PKC family actions and interventions in this ecosystem, informed by insights into the control of stromal and immune cell functions. Drugging PKC isoforms has offered much promise, but when and how is not obvious.
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Affiliation(s)
- Peter J Parker
- Protein Phosphorylation Laboratory, Francis Crick Institute, London, UK.
- School of Cancer and Pharmaceutical Sciences, King's College London, Guy's Campus, London, UK.
| | - Sophie J Brown
- Protein Phosphorylation Laboratory, Francis Crick Institute, London, UK
| | - Veronique Calleja
- Protein Phosphorylation Laboratory, Francis Crick Institute, London, UK
| | | | - Mathias Cobbaut
- Protein Phosphorylation Laboratory, Francis Crick Institute, London, UK
| | - Mark Linch
- UCL Cancer Institute, University College London, London, UK
| | | | - Silvia Martini
- Protein Phosphorylation Laboratory, Francis Crick Institute, London, UK
| | - Neil Q McDonald
- Signalling and Structural Biology Laboratory, Francis Crick Institute, London, UK
- Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, London, UK
| | - Tanya Soliman
- Centre for Cancer Genomics and Computational Biology, Bart's Cancer Institute, London, UK
| | - Lisa Watson
- Protein Phosphorylation Laboratory, Francis Crick Institute, London, UK
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11
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Speidel JT, Affandi T, Jones DNM, Ferrara SE, Reyland ME. Functional proteomic analysis reveals roles for PKCδ in regulation of cell survival and cell death: Implications for cancer pathogenesis and therapy. Adv Biol Regul 2020; 78:100757. [PMID: 33045516 PMCID: PMC8294469 DOI: 10.1016/j.jbior.2020.100757] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 09/18/2020] [Accepted: 09/21/2020] [Indexed: 12/18/2022]
Abstract
Protein Kinase C-δ (PKCδ), regulates a broad group of biological functions and disease processes, including well-defined roles in immune function, cell survival and apoptosis. PKCδ primarily regulates apoptosis in normal tissues and non-transformed cells, and genetic disruption of the PRKCD gene in mice is protective in many diseases and tissue damage models. However pro-survival/pro-proliferative functions have also been described in some transformed cells and in mouse models of cancer. Recent evidence suggests that the contribution of PKCδ to specific cancers may depend in part on the oncogenic context of the tumor, consistent with its paradoxical role in cell survival and cell death. Here we will discuss what is currently known about biological functions of PKCδ and potential paradigms for PKCδ function in cancer. To further understand mechanisms of regulation by PKCδ, and to gain insight into the plasticity of PKCδ signaling, we have used functional proteomics to identify pathways that are dependent on PKCδ. Understanding how these distinct functions of PKCδ are regulated will be critical for the logical design of therapeutics to target this pathway.
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Affiliation(s)
- Jordan T Speidel
- Department of Craniofacial Biology, School of Dental Medicine, USA
| | - Trisiani Affandi
- Department of Craniofacial Biology, School of Dental Medicine, USA
| | | | - Sarah E Ferrara
- University of Colorado Comprehensive Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Mary E Reyland
- Department of Craniofacial Biology, School of Dental Medicine, USA.
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12
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Manning TJ, Thomas-Richardson J, Cowan M, Beard T. Vaporization, bioactive formulations and a marine natural product: different perspectives on antivirals. Drug Discov Today 2020; 25:956-958. [PMID: 32325124 PMCID: PMC7169894 DOI: 10.1016/j.drudis.2020.04.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 04/15/2020] [Indexed: 12/23/2022]
Abstract
Concept draws on 20 years of research with cancer drugs, antibiotics and synthesis of an antiviral. Advantages of inhalation sought include lower dose and improved efficacy for species such as hydroxychloroquine, with a bioactive bulk solvent Bulk constituents in vaporization process have some antiviral activity Bioactive ingredients can be included in the formulation that can accelerate viral replication which disrupts other processes improving the efficacy of the pharmaceutical Marine natural product bryostatin-1 has antiviral properties; when extracted from host, the complex mixture of bryostatin structures should be considered for medicinal administration This article examines three aspects of antivirals, such as hydroxychloroquine, chloroquine, and remdesvir, as they might relate to the treatment of a viral infection such as COVID-19: (i) the use of vaporization for the delivery of antivirals, with the bulk constituents having mild antiviral efficacy; (ii) the application of a marine natural product extract as opposed to a single molecule as an antiviral agent; and (iii) a counter intuitive approach to formulation that is, in part, based on delivering multiple species that fall into three categories: building blocks for the virus to accelerate replication; an energy source for the infected cell to boost its immune response; and the species that antagonize or provide toxicity to the virus.
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Affiliation(s)
| | | | - Matthew Cowan
- Chemistry, Valdosta State University, Valdosta, GA 31698, USA
| | - Torien Beard
- Chemistry, Valdosta State University, Valdosta, GA 31698, USA
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13
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Wang Y, Tian K, Yau SST. Protein Sequence Classification Using Natural Vector and Convex Hull Method. J Comput Biol 2019; 26:315-321. [PMID: 30762422 DOI: 10.1089/cmb.2018.0216] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Protein kinase C (PKC) is a superfamily of enzymes, which regulate numerous cellular responses. The specific function of PKC protein family is mainly governed by its individual protein domains. However, existing protein sequence classification methods based on sequence alignment and sequence analysis models focused little on the domain analysis. In this study, we introduce a novel protein kinase classification method that considers both domain sequence similarity and whole sequence similarity to quantify the evolutionary distance from a specific protein to a protein family. Using the natural vector method, we establish a 60-dimensional space, where each protein is uniquely represented by a vector. We also define a convex hull, consisting of the natural vectors corresponding to all members of a protein family. The sequence similarity between a protein and a protein family, therefore, can be quantified as the distance between the protein vector and the protein family convex hull. We have applied this method in a PKC sample library and the results showed a higher accuracy of classification compared with other alignment-free methods.
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Affiliation(s)
- Yi Wang
- Department of Mathematical Sciences, Tsinghua University, Beijing, P.R. China
| | - Kun Tian
- Department of Mathematical Sciences, Tsinghua University, Beijing, P.R. China
| | - Stephen S-T Yau
- Department of Mathematical Sciences, Tsinghua University, Beijing, P.R. China
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14
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El Bairi K, Amrani M, Afqir S. Starvation tactics using natural compounds for advanced cancers: pharmacodynamics, clinical efficacy, and predictive biomarkers. Cancer Med 2018; 7:2221-2246. [PMID: 29732738 PMCID: PMC6010871 DOI: 10.1002/cam4.1467] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 02/21/2018] [Accepted: 02/28/2018] [Indexed: 02/05/2023] Open
Abstract
The high mortality associated with oncological diseases is mostly due to tumors in advanced stages, and their management is a major challenge in modern oncology. Angiogenesis is a defined hallmark of cancer and predisposes to metastatic invasion and dissemination and is therefore an important druggable target for cancer drug discovery. Recently, because of drug resistance and poor prognosis, new anticancer drugs from natural sources targeting tumor vessels have attracted more attention and have been used in several randomized and controlled clinical trials as therapeutic options. Here, we outline and discuss potential natural compounds as salvage treatment for advanced cancers from recent and ongoing clinical trials and real-world studies. We also discuss predictive biomarkers for patients' selection to optimize the use of these potential anticancer drugs.
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Affiliation(s)
- Khalid El Bairi
- Faculty of Medicine and PharmacyMohamed Ist UniversityOujdaMorocco
| | - Mariam Amrani
- Equipe de Recherche en Virologie et Onco‐biologieFaculty of MedicinePathology DepartmentNational Institute of OncologyUniversité Mohamed VRabatMorocco
| | - Said Afqir
- Department of Medical OncologyMohamed VI University HospitalOujdaMorocco
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15
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Nelson TJ, Sun MK, Lim C, Sen A, Khan T, Chirila FV, Alkon DL. Bryostatin Effects on Cognitive Function and PKCɛ in Alzheimer's Disease Phase IIa and Expanded Access Trials. J Alzheimers Dis 2018; 58:521-535. [PMID: 28482641 PMCID: PMC5438479 DOI: 10.3233/jad-170161] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Bryostatin 1, a potent activator of protein kinase C epsilon (PKCɛ), has been shown to reverse synaptic loss and facilitate synaptic maturation in animal models of Alzheimer’s disease (AD), Fragile X, stroke, and other neurological disorders. In a single-dose (25 μg/m2) randomized double-blind Phase IIa clinical trial, bryostatin levels reached a maximum at 1-2 h after the start of infusion. In close parallel with peak blood levels of bryostatin, an increase of PBMC PKCɛ was measured (p = 0.0185) within 1 h from the onset of infusion. Of 9 patients with a clinical diagnosis of AD, of which 6 received drug and 3 received vehicle within a double-blind protocol, bryostatin increased the Mini-Mental State Examination (MMSE) score by +1.83±0.70 unit at 3 h versus –1.00±1.53 unit for placebo. Bryostatin was well tolerated in these AD patients and no drug-related adverse events were reported. The 25 μg/m2 administered dose was based on prior clinical experience with three Expanded Access advanced AD patients treated with bryostatin, in which return of major functions such as swallowing, vocalization, and word recognition were noted. In one Expanded Access patient trial, elevated PKCɛ levels closely tracked cognitive benefits in the first 24 weeks as measured by MMSE and ADCS-ADL psychometrics. Pre-clinical mouse studies showed effective activation of PKCɛ and increased levels of BDNF and PSD-95. Together, these Phase IIa, Expanded Access, and pre-clinical results provide initial encouragement for bryostatin 1 as a potential treatment for AD.
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Affiliation(s)
- Thomas J Nelson
- Blanchette Rockefeller Neurosciences Institute, Morgantown, WV, USA.,West Virginia University, Morgantown, WV, USA
| | - Miao-Kun Sun
- Blanchette Rockefeller Neurosciences Institute, Morgantown, WV, USA.,West Virginia University, Morgantown, WV, USA
| | - Chol Lim
- Blanchette Rockefeller Neurosciences Institute, Morgantown, WV, USA.,West Virginia University, Morgantown, WV, USA
| | - Abhik Sen
- Blanchette Rockefeller Neurosciences Institute, Morgantown, WV, USA.,West Virginia University, Morgantown, WV, USA
| | - Tapan Khan
- Blanchette Rockefeller Neurosciences Institute, Morgantown, WV, USA.,West Virginia University, Morgantown, WV, USA
| | - Florin V Chirila
- Blanchette Rockefeller Neurosciences Institute, Morgantown, WV, USA.,Neurodiagnostics, LLC, Rockville, MD, USA
| | - Daniel L Alkon
- Blanchette Rockefeller Neurosciences Institute, Morgantown, WV, USA.,Neurotrope Biosciences, LLC, New York, NY, USA
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16
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Comparative analysis of the anti-chikungunya virus activity of novel bryostatin analogs confirms the existence of a PKC-independent mechanism. Biochem Pharmacol 2016; 120:15-21. [PMID: 27664855 DOI: 10.1016/j.bcp.2016.09.020] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 09/20/2016] [Indexed: 11/22/2022]
Abstract
Previously, we reported that salicylate-based analogs of bryostatin protect cells from chikungunya virus (CHIKV)-induced cell death. Interestingly, 'capping' the hydroxyl group at C26 of a lead bryostatin analog, a position known to be crucial for binding to and modulation of protein kinase C (PKC), did not abrogate the anti-CHIKV activity of the scaffold, putatively indicating the involvement of a pathway independent of PKC. The work detailed in this study demonstrates that salicylate-derived analog 1 and two capped analogs (2 and 3) are not merely cytoprotective compounds, but act as selective and specific inhibitors of CHIKV replication. Further, a detailed comparative analysis of the effect of the non-capped versus the two capped analogs revealed that compound 1 acts both at early and late stages in the chikungunya virus replication cycle, while the capped analogs only interfere with a later stage process. Co-dosing with the PKC inhibitors sotrastaurin and Gö6976 counteracts the antiviral activity of compound 1 without affecting that of capped analogs 2 and 3, providing further evidence that the latter elicit their anti-CHIKV activity independently of PKC. Remarkably, treatment of CHIKV-infected cells with a combination of compound 1 and a capped analog resulted in a pronounced synergistic antiviral effect. Thus, these salicylate-based bryostatin analogs can inhibit CHIKV replication through a novel, yet still elusive, non-PKC dependent pathway.
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17
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Reyland ME, Jones DNM. Multifunctional roles of PKCδ: Opportunities for targeted therapy in human disease. Pharmacol Ther 2016; 165:1-13. [PMID: 27179744 DOI: 10.1016/j.pharmthera.2016.05.001] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The serine-threonine protein kinase, protein kinase C-δ (PKCδ), is emerging as a bi-functional regulator of cell death and proliferation. Studies in PKCδ-/- mice have confirmed a pro-apoptotic role for this kinase in response to DNA damage and a tumor promoter role in some oncogenic contexts. In non-transformed cells, inhibition of PKCδ suppresses the release of cytochrome c and caspase activation, indicating a function upstream of apoptotic pathways. Data from PKCδ-/- mice demonstrate a role for PKCδ in the execution of DNA damage-induced and physiologic apoptosis. This has led to the important finding that inhibitors of PKCδ can be used therapeutically to reduce irradiation and chemotherapy-induced toxicity. By contrast, PKCδ is a tumor promoter in mouse models of mammary gland and lung cancer, and increased PKCδ expression is a negative prognostic indicator in Her2+ and other subtypes of human breast cancer. Understanding how these distinct functions of PKCδ are regulated is critical for the design of therapeutics to target this pathway. This review will discuss what is currently known about biological roles of PKCδ and prospects for targeting PKCδ in human disease.
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Affiliation(s)
- Mary E Reyland
- Department of Craniofacial Biology, School of Dental Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
| | - David N M Jones
- Department of Pharmacology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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18
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Dagur RS, Hambarde S, Chandna S. Bryostatin-1 causes radiosensitization of BMG-1 malignant glioma cells through differential activation of protein kinase-Cδ not evident in the non-malignant AA8 fibroblasts. Mol Cell Biochem 2014; 401:49-59. [PMID: 25472878 DOI: 10.1007/s11010-014-2291-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Accepted: 11/26/2014] [Indexed: 10/24/2022]
Abstract
Bryostatin-1 (bryo-1), a non-phorbol ester, is known to sensitize mammalian cells against certain chemotherapeutic drugs. We assessed its ability to modify radiation response of mammalian cells using Chinese hamster fibroblasts AA8 cells and human malignant glioma BMG-1 cells. In the malignant glioma BMG-1 cell line, bryo-1 pre-treatment significantly enhanced radiation-induced growth inhibition and cytogenetic damage, and further reduced the clonogenic cell survival as compared to cells irradiated at the clinically relevant dose of 2 Gy. PKCδ expression increased significantly when bryo-1 pre-treated BMG-1 glioma cells were irradiated at 2 Gy and induced prolonged ERK-1/2 activation associated with p21 overexpression. Silencing PKCδ resulted in inhibition of bryo-1-induced radiosensitization. In contrast, bryo-1 failed to alter radiosensitivity (cell survival; growth inhibition; cytogenetic damage) or activate ERK1/2 pathway in the AA8 fibroblasts despite PKCδ phosphorylation at its regulatory (Y155) domain, indicating alternate mechanisms in these non-malignant cells as compared to the glioma cells. This study suggests that bryo-1 may effectively enhance the radiosensitivity of malignant cells and warrants further in-depth investigations to evaluate its radiosensitizing potential in various cell types.
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Affiliation(s)
- Raghubendra Singh Dagur
- Natural Radiation Response Mechanisms Group, Division of Radiation Biosciences, Institute of Nuclear Medicine & Allied Sciences, Brig. S K Mazumdar Road, Timarpur, Delhi, 110054, India
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19
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Shi J, Qu YP, Hou P. Pathogenetic mechanisms in gastric cancer. World J Gastroenterol 2014; 20:13804-13819. [PMID: 25320518 PMCID: PMC4194564 DOI: 10.3748/wjg.v20.i38.13804] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Revised: 01/15/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is a major public health issue as the fourth most common cancer and the second leading cause of cancer-related death. Recent advances have improved our understanding of its molecular pathogenesis, as best exemplified by elucidating the fundamental role of several major signaling pathways and related molecular derangements. Central to these mechanisms are the genetic and epigenetic alterations in these signaling pathways, such as gene mutations, copy number variants, aberrant gene methylation and histone modification, nucleosome positioning, and microRNAs. Some of these genetic/epigenetic alterations represent effective diagnostic and prognostic biomarkers and therapeutic targets for GC. This information has now opened unprecedented opportunities for better understanding of the molecular mechanisms of gastric carcinogenesis and the development of novel therapeutic strategies for this cancer. The pathogenetic mechanisms of GC are the focus of this review.
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20
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Abstract
Esophageal cancer comprises two different histological forms - squamous cell carcinoma (SCC) and adenocarcinoma (AC). While the incidence of AC has increased steeply in Western countries during the last few years, the incidence of SCC is fairly stable. Both forms differ in pathogenesis and response to chemotherapy and radiation therapy. Plenty of studies have evaluated new chemotherapy combination regimens in the neoadjuvant, adjuvant, and palliative setting. In addition, new radiation and chemoradiation protocols have been investigated. Finally, molecular-targeted therapy has been included in several new randomized prospective trials. Therefore, this review presents new data on this topic and critically discusses promising approaches towards a more effective treatment in a disease with a grim prognosis.
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Affiliation(s)
- Marcus W Wiedmann
- Department of Internal Medicine I, St Mary’s Hospital, Berlin, Germany
- Division of Gastroenterology and Rheumatology, Department of Medicine, Neurology and Dermatology, University Hospital of Leipzig, Leipzig, Germany
| | - Joachim Mössner
- Division of Gastroenterology and Rheumatology, Department of Medicine, Neurology and Dermatology, University Hospital of Leipzig, Leipzig, Germany
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21
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Digklia A, Voutsadakis IA. Targeted treatments for metastatic esophageal squamous cell cancer. World J Gastrointest Oncol 2013; 5:88-96. [PMID: 23799158 PMCID: PMC3682173 DOI: 10.4251/wjgo.v5.i5.88] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2012] [Revised: 01/27/2013] [Accepted: 05/18/2013] [Indexed: 02/05/2023] Open
Abstract
Squamous cell carcinoma, one of the two major sub-types of esophageal carcinomas, constitutes the great majority of tumors in the upper and middle third of the organ. Declining in incidence in western countries, it continues to be a significant public health problem in the far east. Targeted treatments are novel therapies introduced in the clinical therapeutic armamentarium of oncology in the last 10-15 years. They represent a rational way of treating various cancers based on their molecular lesions. Although no such agent has been approved so far for the treatment of esophageal squamous cell carcinomas (ESCC), several are in clinical trials and several others have displayed pre-clinical activity that would justify the efforts and risks of pursuing their clinical development in this disease. This paper discusses some of these targeted agents in more advanced development in metastatic ESCC, as well as some promising drugs with pre-clinical or initial clinical data in the disease.
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22
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Abstract
Protein kinase C (PKC) has been a tantalizing target for drug discovery ever since it was first identified as the receptor for the tumour promoter phorbol ester in 1982. Although initial therapeutic efforts focused on cancer, additional indications--including diabetic complications, heart failure, myocardial infarction, pain and bipolar disorder--were targeted as researchers developed a better understanding of the roles of eight conventional and novel PKC isozymes in health and disease. Unfortunately, both academic and pharmaceutical efforts have yet to result in the approval of a single new drug that specifically targets PKC. Why does PKC remain an elusive drug target? This Review provides a short account of some of the efforts, challenges and opportunities in developing PKC modulators to address unmet clinical needs.
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23
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Wang YQ, Miao ZH. Marine-derived angiogenesis inhibitors for cancer therapy. Mar Drugs 2013; 11:903-33. [PMID: 23502698 PMCID: PMC3705379 DOI: 10.3390/md11030903] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Revised: 02/25/2013] [Accepted: 03/01/2013] [Indexed: 12/18/2022] Open
Abstract
Angiogenesis inhibitors have been successfully used for cancer therapy in the clinic. Many marine-derived natural products and their analogues have been reported to show antiangiogenic activities. Compared with the drugs in the clinic, these agents display interesting characteristics, including diverse sources, unique chemical structures, special modes of action, and distinct activity and toxicity profiles. This review will first provide an overview of the current marine-derived angiogenesis inhibitors based on their primary targets and/or mechanisms of action. Then, the marine-derived antiangiogenic protein kinase inhibitors will be focused on. And finally, the clinical trials of the marine-derived antiangiogenic agents will be discussed, with special emphasis on their application potentials, problems and possible coping strategies in their future development as anticancer drugs.
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Affiliation(s)
- Ying-Qing Wang
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
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24
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Kikumori M, Yanagita RC, Tokuda H, Suzuki N, Nagai H, Suenaga K, Irie K. Structure–Activity Studies on the Spiroketal Moiety of a Simplified Analogue of Debromoaplysiatoxin with Antiproliferative Activity. J Med Chem 2012; 55:5614-26. [DOI: 10.1021/jm300566h] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Masayuki Kikumori
- Division of
Food Science and
Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan
| | - Ryo C. Yanagita
- Division of
Food Science and
Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan
- Department of Applied Biological
Science, Faculty of Agriculture, Kagawa University, Kagawa 761-0795, Japan
| | - Harukuni Tokuda
- Department of Complementary and Alternative Medicine, Clinical R&D, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8640, Japan
| | - Nobutaka Suzuki
- Department of Complementary and Alternative Medicine, Clinical R&D, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8640, Japan
| | - Hiroshi Nagai
- Department
of Ocean Sciences, Tokyo University of Marine Science and Technology,
Tokyo 108-8477, Japan
| | - Kiyotake Suenaga
- Faculty
of Science and Technology, Keio University, Yokohama 223-8522, Japan
| | - Kazuhiro Irie
- Division of
Food Science and
Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan
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25
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Khattak MA, Martin HL, Karapetis CS. Targeted therapy for esophagogastric cancers: a review. Onco Targets Ther 2012; 5:91-102. [PMID: 22719211 PMCID: PMC3377432 DOI: 10.2147/ott.s25117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The incidence of esophagogastric cancers is increasing rapidly in the Western population. Despite better understanding of the biology and intense research in the treatment of these cancers, the long-term survival remains poor both in the locally advanced and metastatic settings. The addition of combined modality strategies has resulted in modest improvement in 5-year survival rates. A number of biologic agents targeting epidermal-derived growth factor receptor, vascular endothelial derived growth factor and its receptor, and mammalian target of rapamycin (mTOR) are being currently evaluated in Phase II and III clinical trials. Some of these, like trastuzumab, cetuximab, and bevacizumab, have shown promising results. This review provides a brief overview of the recent developments in biologic agents for the treatment of esophagogastric cancers.
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Affiliation(s)
| | | | - Christos S Karapetis
- Flinders Medical Centre, Adelaide, South Australia
- Flinders University, Adelaide, SA, Australia
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26
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DeChristopher BA, Fan AC, Felsher DW, Wender PA. "Picolog," a synthetically-available bryostatin analog, inhibits growth of MYC-induced lymphoma in vivo. Oncotarget 2012; 3:58-66. [PMID: 22308267 PMCID: PMC3292892 DOI: 10.18632/oncotarget.438] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2012] [Accepted: 02/02/2012] [Indexed: 12/22/2022] Open
Abstract
Bryostatin 1 is a naturally occurring complex macrolide with potent anti-neoplastic activity. However, its extremely low natural occurrence has impeded clinical advancement. We developed a strategy directed at the design of simplified and synthetically more accessible bryostatin analogs. Our lead analog, "picolog", can be step-economically produced. Picolog, compared to bryostatin, exhibited superior growth inhibition of MYC-induced lymphoma in vitro. A key mechanism of picolog's (and bryostatin's) activity is activation of PKC. A novel nano-immunoassay (NIA) revealed that picolog treatment increased phospho-MEK2 in the PKC pathway. Moreover, the inhibition of PKC abrogated picolog's activity. Finally, picolog was highly potent at 100 micrograms/kg and well tolerated at doses ranging from 100 micrograms/kg to 1 milligram/kg in vivo for the treatment of our aggressive model of MYC-induced lymphoma. We provide the first in vivo validation that the bryostatin analog, picolog, is a potential therapeutic agent for the treatment of cancer and other diseases.
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Affiliation(s)
- Brian A. DeChristopher
- Departments of Chemistry and Chemical and Systems Biology, Stanford University, Stanford, CA 94305-5080
| | - Alice C. Fan
- Division of Oncology, Stanford University School of Medicine, Stanford, CA 94305
| | - Dean W. Felsher
- Division of Oncology, Stanford University School of Medicine, Stanford, CA 94305
| | - Paul A. Wender
- Departments of Chemistry and Chemical and Systems Biology, Stanford University, Stanford, CA 94305-5080
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27
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28
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Abstract
The prognosis and long-term survival for patients with metastatic esophagogastric cancer (EGC) is poor. Historically, the mainstay of treatment has been combination chemotherapy. More recently, a number of targeted therapies have been developed and are being studied with the goal of improving response rate and survival in patients with metastatic EGC. To date, the only targeted therapy which has been clinically approved is trastuzumab which targets the HER2/Neu oncogene. However, only a small group of patients with EGCs are HER2 amplified, and there are other important targets/pathways which play a role in the development of these cancers that are currently being studied. With the identification of these other clinically relevant pathways, it is anticipated that several other therapies will be approved in the future.
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Affiliation(s)
- Deepa Reddy
- UCLA Department of Hematology and Oncology, 10945 Le Conte Avenue, Suite 2338, Los Angeles, CA 90095 USA
| | - Zev A. Wainberg
- UCLA Department of Hematology and Oncology, 10945 Le Conte Avenue, Suite 2338, Los Angeles, CA 90095 USA
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29
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Qi Y, Ma S. The medicinal potential of promising marine macrolides with anticancer activity. ChemMedChem 2011; 6:399-409. [PMID: 21302362 DOI: 10.1002/cmdc.201000534] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2010] [Revised: 01/08/2011] [Indexed: 12/12/2022]
Abstract
Marine natural products have become a major source of new chemical entities in the discovery of potential anticancer agents that potently suppress various molecular targets. In particular, the marine macrolides, which include an array of novel biomolecules endowed with outstanding cytotoxic and/or antiproliferative activities, are a prominent class of marine natural products that offer continued promise for breakthroughs in anticancer research. Herein we highlight some recent studies of promising marine macrolides, paying particular attention to their discovery, anticancer activities, mechanisms of action, chemical synthesis, and representative analogues.
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Affiliation(s)
- Yunkun Qi
- Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, Jinan 250012, PR China
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30
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Protein kinase C: an attractive target for cancer therapy. Cancers (Basel) 2011; 3:531-67. [PMID: 24212628 PMCID: PMC3756376 DOI: 10.3390/cancers3010531] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2010] [Revised: 01/19/2011] [Accepted: 01/26/2011] [Indexed: 12/21/2022] Open
Abstract
Apoptosis plays an important role during all stages of carcinogenesis and the development of chemoresistance in tumor cells may be due to their selective defects in the intracellular signaling proteins, central to apoptotic pathways. Consequently, many studies have focused on rendering the chemotherapy more effective in order to prevent chemoresistance and pre-clinical and clinical data has suggested that protein kinase C (PKC) may represent an attractive target for cancer therapy. Therefore, a complete understanding of how PKC regulates apoptosis and chemoresistance may lead to obtaining a PKC-based therapy that is able to reduce drug dosages and to prevent the development of chemoresistance.
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31
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Irie K, Yanagita RC, Nakagawa Y. Challenges to the development of bryostatin-type anticancer drugs based on the activation mechanism of protein kinase Cδ. Med Res Rev 2010; 32:518-35. [DOI: 10.1002/med.20220] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Kazuhiro Irie
- Division of Food Science and Biotechnology; Graduate School of Agriculture; Kyoto University; Kitashirakawa Oiwake-cho, Sakyo-ku Kyoto Japan
| | - Ryo C. Yanagita
- Division of Food Science and Biotechnology; Graduate School of Agriculture; Kyoto University; Kitashirakawa Oiwake-cho, Sakyo-ku Kyoto Japan
| | - Yu Nakagawa
- Synthetic Cellular Chemistry Laboratory; Advanced Science Institute; RIKEN; Wako-shi Saitama Japan
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32
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Hale KJ, Manaviazar S. New approaches to the total synthesis of the bryostatin antitumor macrolides. Chem Asian J 2010; 5:704-54. [PMID: 20354984 DOI: 10.1002/asia.200900634] [Citation(s) in RCA: 92] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
In this Focus Review, we give an overview of various bryostatin total syntheses. We also discuss the synthesis of various bryostatin analogues and their biological activity. Work reviewed includes that of Masamune, Evans, Nishiyama and Yamamura, Hale and Manaviazar, Trost, Wender, Keck, Burke, Thomas, and Krische. Our coverage is primarily for the period 2001-2009, since detailed reviews already exist on bryostatin total synthesis work and biology up to this time.
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Affiliation(s)
- Karl J Hale
- School of Chemistry & Chemical Engineering, Queen's Universty Belfast, Stranmillis Road, Belfast BT9 5AG, Northern Ireland, UK.
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Abstract
This review discusses the biosynthesis of natural products that are generated by trans-AT polyketide synthases, a family of catalytically versatile enzymes that have recently been recognized as one of the major group of proteins involved in the production of bioactive polyketides. 436 references are cited.
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Affiliation(s)
- Jörn Piel
- Kekulé Institute of Organic Chemistry and Biochemistry, University of Bonn, Bonn, Germany.
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Phase II study of paclitaxel plus the protein kinase C inhibitor bryostatin-1 in advanced pancreatic carcinoma. Am J Clin Oncol 2010; 33:121-4. [PMID: 19738452 DOI: 10.1097/coc.0b013e3181a31920] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE To determine the efficacy and toxicity of the protein kinase C inhibitor bryostatin-1 plus paclitaxel in patients with advanced pancreatic carcinoma. METHODS Each treatment cycle consisted of paclitaxel 90 mg/m by intravenous infusion over 1 hour on days 1, 8, and 16, plus bryostatin 25 mcg/m as a 1-hour intravenous infusion on days 2, 9, and 15, given every 28 days. Patients were evaluated for response after every 2 treatment cycles, and continued therapy until disease progression or prohibitive toxicity. The primary objective was to determine whether the combination produced a response rate of at least 30%. RESULTS Nineteen patients with locally advanced or metastatic pancreatic adenocarcinoma received a total of 52 cycles of therapy (range: 1-10). Patients received the combination as first-line therapy for advanced disease (N = 5) or after prior chemotherapy used alone or in combination with local therapy. No patients had a confirmed objective response. The median time to treatment failure was 1.9 months (95% confidence intervals: 1.2, 2.6 months). Reasons for discontinuing therapy included progressive disease or death in 14 patients (74%) or because of adverse events or patient choice in 5 patients (26%). The most common grade 3 to 4 toxicities included leukopenia in 26%, anemia in 11%, myalgias in 11%, gastrointestinal bleeding in 11%, infection in 10%, and thrombosis in 10%. CONCLUSION The combination of weekly paclitaxel and bryostatin-1 is not an effective therapy for patients with advanced pancreatic carcinoma.
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Ku GY, Ilson DH. Esophagogastric cancer: targeted agents. Cancer Treat Rev 2010; 36:235-48. [PMID: 20122806 DOI: 10.1016/j.ctrv.2009.12.009] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2009] [Revised: 12/09/2009] [Accepted: 12/14/2009] [Indexed: 02/07/2023]
Abstract
Because of the poor prognosis for patients with locally advanced and metastatic esophageal, gastroesophageal junction and gastric cancers, increasing attention has focused on the integration of targeted agents into current therapies. The molecular targets of these agents include epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) or its receptor, cyclooxygenase-2 (COX-2), mammalian target of rapamycin (mTOR) and components and regulators of the cell cycle. In this review article, we briefly discuss pre-clinical data and the rationale for targeting these pathways and summarize the results of clinical trials to-date, including completed and ongoing phase III evaluations.
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Affiliation(s)
- Geoffrey Y Ku
- Ludwig Center for Cancer Immunotherapy, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
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36
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Heat shock protein 27 mediates repression of androgen receptor function by protein kinase D1 in prostate cancer cells. Oncogene 2009; 28:4386-96. [DOI: 10.1038/onc.2009.291] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Abstract
The cell cycle governs the transition from quiescence through cell growth to proliferation. The key parts of the cell cycle machinery are the cyclin-dependent kinases (CDKS) and the regulatory proteins called cyclins. The CDKS are rational targets for cancer therapy because their expression in cancer cells is often aberrant and their inhibition can induce cell death. Inhibitors of CDKS can also block transcription.Several drugs targeting the cell cycle have entered clinical trials. These agents include flavopiridol, indisulam, AZD5438, SNS-032, bryostatin-1, seliciclib, PD 0332991, and SCH 727965. Phase i studies have demonstrated that these drugs can generally be administered safely. Phase ii studies have shown little single-agent activity in solid tumors, but combination studies with cytotoxic chemotherapy have been more promising. In hematologic malignancies, reports have shown encouraging single-agent and combination activity. Pharmacodynamic studies show that the dose and schedule of these drugs are crucial to permit maximum therapeutic effect.
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Affiliation(s)
- M.A. Dickson
- Department of Medicine, Division of Solid Tumor Oncology, Melanoma and Sarcoma Service, and Laboratory of New Drug Development, Memorial Sloan–Kettering Cancer Center, New York, NY, U.S.A
| | - G.K. Schwartz
- Department of Medicine, Division of Solid Tumor Oncology, Melanoma and Sarcoma Service, and Laboratory of New Drug Development, Memorial Sloan–Kettering Cancer Center, New York, NY, U.S.A
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Leong SS, Wee J, Rajan S, Toh CK, Lim WT, Hee SW, Tay MH, Poon D, Tan EH. Triplet combination of gemcitabine, paclitaxel, and carboplatin followed by maintenance 5-fluorouracil and folinic acid in patients with metastatic nasopharyngeal carcinoma. Cancer 2008; 113:1332-7. [DOI: 10.1002/cncr.23687] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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