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Li X, Xu F, Wang R, Shen L, Luo B, Zhou S, Zhang J, Zhang Z, Cao Z, Zhan K, Zhao Y, Zhao G. Aspirin enhances radio/chemo-therapy sensitivity in C. elegans by inducing germ cell apoptosis and suppresses RAS overactivated tumorigenesis via mtROS-mediated DNA damage and MAPK pathway. Biochem Biophys Res Commun 2024; 735:150828. [PMID: 39418772 DOI: 10.1016/j.bbrc.2024.150828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 10/10/2024] [Accepted: 10/11/2024] [Indexed: 10/19/2024]
Abstract
Previous studies have demonstrated that combination therapy involving radiotherapy and aspirin decreases the survival rate of cancer cells. However, the mechanism by which aspirin exerts its radiation sensitization effect at the in vivo level remains largely unclear. In this study, we employed Caenorhabditis elegans (C. elegans) as a model organism to investigate the effect of aspirin combined with radio/chemo-therapy on tumors at the individual level. Here, we illustrate that high-dose aspirin increases the expression of genes involved in core apoptosis pathways (egl-1, ced-9, ced-4 and ced-3) and induces germ cell apoptosis in C. elegans through mitochondrial outer membrane permeabilization (MOMP) and elevation of reactive oxygen species (ROS) levels. Crucially, aspirin-induces ROS upregulates the expression of genes critical for DNA damage response (hus-1, clk-2 and cep-1) and genes involved in MAPK pathways (lin-45, mek-2, mpk-1, sek-1 and pmk-1), thereby mediating the enhanced sensitivity of radio/chemo-therapy by aspirin. Notably, aspirin fails to induce germ cell apoptosis and enhance radio/chemo-therapy in C. elegans lacking the expression of each of those genes. Furthermore, in a C. elegans tumor-like symptom model, aspirin enhances radio/chemo-therapy sensitivity through ROS induction. However, low-dose aspirin can diminish the apoptotic signal of reproductive cells in C. elegans and exert anti-inflammatory effects. Our research results suggest that the tumor-suppressive and radio/chemo-therapy sensitizing effects of aspirin provide robust experimental evidence for improving the clinical efficacy of tumor radio/chemo-therapy and deepening our understanding of aspirin's mechanism of action in cancer.
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Affiliation(s)
- Xiaona Li
- Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China; High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences, China; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, China
| | - Feng Xu
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences, China; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, China; University of Science and Technology of China, Hefei, Anhui, 230026, China
| | - Ruru Wang
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences, China; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, China; University of Science and Technology of China, Hefei, Anhui, 230026, China
| | - Lili Shen
- The Second People's Hospital of Chizhou, Chizhou, Anhui, 247099, China
| | - Bowen Luo
- Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Shenglan Zhou
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences, China; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, China; University of Science and Technology of China, Hefei, Anhui, 230026, China
| | - Jie Zhang
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences, China; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, China; University of Science and Technology of China, Hefei, Anhui, 230026, China
| | - Zhaoyang Zhang
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences, China; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, China; University of Science and Technology of China, Hefei, Anhui, 230026, China
| | - Zhizun Cao
- Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Kangren Zhan
- Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Ye Zhao
- Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.
| | - Guoping Zhao
- Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China; High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences, China; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, China.
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Jagtap YA, Kumar P, Dubey AR, Kinger S, Choudhary A, Karmakar S, Lal G, Kumar A, Kumar A, Prasad A, Mishra A. Acetaminophen induces mitochondrial apoptosis through proteasome dysfunctions. Life Sci 2024; 349:122732. [PMID: 38768775 DOI: 10.1016/j.lfs.2024.122732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 03/12/2024] [Accepted: 05/15/2024] [Indexed: 05/22/2024]
Abstract
Acetaminophen is a known antipyretic and non-opioid analgesic for mild pain and fever. Numerous studies uncover their hidden chemotherapeutics applications, including chronic cancer pain management. Acetaminophen also represents an anti-proliferative effect in some cancer cells. Few studies also suggest that the use of Acetaminophen can trigger apoptosis and impede cellular growth. However, Acetaminophen's molecular potential and precise mechanism against improper cellular proliferation and use as an effective anti-proliferative agent still need to be better understood. Here, our current findings show that Acetaminophen induces proteasomal dysfunctions, resulting in aberrant protein accumulation and mitochondrial abnormalities, and consequently induces cell apoptosis. We observed that the Acetaminophen treatment leads to improper aggregation of ubiquitylated expanded polyglutamine proteins, which may be due to the dysfunctions of proteasome activities. Our in-silico analysis suggests the interaction of Acetaminophen and proteasome. Furthermore, we demonstrated the accumulation of proteasome substrates and the depletion of proteasome activities after treating Acetaminophen in cells. Acetaminophen induces proteasome dysfunctions and mitochondrial abnormalities, leading to pro-apoptotic morphological changes and apoptosis successively. These results suggest that Acetaminophen can induce cell death and may retain a promising anti-proliferative effect. These observations can open new possible molecular strategies in the near future for developing and designing specific and effective proteasome inhibitors, which can be helpful in conjugation with other anti-tumor drugs for their better efficiency.
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Affiliation(s)
- Yuvraj Anandrao Jagtap
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, 342037, India
| | - Prashant Kumar
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, 342037, India
| | - Ankur Rakesh Dubey
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, 342037, India
| | - Sumit Kinger
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, 342037, India
| | - Akash Choudhary
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, 342037, India
| | - Surojit Karmakar
- National Centre for Cell Science (NCCS), Ganeshkhind, Pune, Maharashtra, 411007, India
| | - Girdhari Lal
- National Centre for Cell Science (NCCS), Ganeshkhind, Pune, Maharashtra, 411007, India
| | - Awanish Kumar
- Department of Biotechnology, National Institute of Technology, Raipur, Chhattisgarh, 492010, India
| | - Amit Kumar
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, Madhya Pradesh, 453552, India
| | - Amit Prasad
- School of Biosciences and Bioengineering, Indian Institute of Technology Mandi, Mandi, Himachal Pradesh, 175005, India
| | - Amit Mishra
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, 342037, India.
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Schwab M, Dezfouli AB, Khosravi M, Alkotub B, Bauer L, Birgani MJT, Multhoff G. The radiation- and chemo-sensitizing capacity of diclofenac can be predicted by a decreased lactate metabolism and stress response. Radiat Oncol 2024; 19:7. [PMID: 38229111 DOI: 10.1186/s13014-024-02399-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 01/08/2024] [Indexed: 01/18/2024] Open
Abstract
BACKGROUND An enhanced aerobic glycolysis ("Warburg effect") associated with an increase in lactic acid in the tumor microenvironment contributes to tumor aggressiveness and resistance to radiation and chemotherapy. We investigated the radiation- and chemo-sensitizing effects of the nonsteroidal anti-inflammatory drug (NSAID) diclofenac in different cancer cell types. METHODS The effects of a non-lethal concentration of diclofenac was investigated on c-MYC and Lactate Dehydrogenase (LDH) protein expression/activity and the Heat shock Protein (HSP)/stress response in human colorectal (LS174T, LoVo), lung (A549), breast (MDA-MB-231) and pancreatic (COLO357) carcinoma cells. Radiation- and chemo-sensitization of diclofenac was determined using clonogenic cell survival assays and a murine xenograft tumor model. RESULTS A non-lethal concentration of diclofenac decreases c-MYC protein expression and LDH activity, reduces cytosolic Heat Shock Factor 1 (HSF1), Hsp70 and Hsp27 levels and membrane Hsp70 positivity in LS174T and LoVo colorectal cancer cells, but not in A549 lung carcinoma cells, MDA-MB-231 breast cancer cells and COLO357 pancreatic adenocarcinoma cells. The impaired lactate metabolism and stress response in diclofenac-sensitive colorectal cancer cells was associated with a significantly increased sensitivity to radiation and 5Fluorouracil in vitro, and in a human colorectal cancer xenograft mouse model diclofenac causes radiosensitization. CONCLUSION These findings suggest that a decrease in the LDH activity and/or stress response upon diclofenac treatment predicts its radiation/chemo-sensitizing capacity.
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Affiliation(s)
- Melissa Schwab
- Radiation Immuno-Oncology Group, Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany
| | - Ali Bashiri Dezfouli
- Radiation Immuno-Oncology Group, Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany
- Department of Otolaryngology, Head and Neck Surgery, TUM School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany
| | - Mohammad Khosravi
- Department of Pathobiology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Bayan Alkotub
- Radiation Immuno-Oncology Group, Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany
- Institute of Biological and Medical Imaging (IBMI), Helmholtz Zentrum München, Neuherberg, Germany
| | - Lisa Bauer
- Radiation Immuno-Oncology Group, Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany
| | | | - Gabriele Multhoff
- Radiation Immuno-Oncology Group, Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany.
- Department of Radiation Oncology, TUM School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany.
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Yang Y, Wang J, Ni H, Ding H, Wei L, Ke ZJ. Genetic model of selective COX2 inhibition improve learning and memory ability and brain pathological changes in 5xFAD mouse. Brain Res 2023; 1821:148566. [PMID: 37683778 DOI: 10.1016/j.brainres.2023.148566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 08/31/2023] [Accepted: 09/05/2023] [Indexed: 09/10/2023]
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease that leads to dementia. Its pathogenesis is very complex, and inflammation is one of the main pathophysiological mechanisms of AD. Non-steroidal anti-inflammatory drugs (NSAIDs), which mainly target cyclooxygenase (COX) activity, are used to reduce the risk of AD, but several side effects limit their application. Here we assess the effect of Cyclooxygenase-2 (COX2) catalytic activity on learning ability and AD pathology using 5x Familial Alzheimer's Disease (FAD) mice with COX2 inhibition (5xFAD/COX2 KO), 5xFAD mice with cyclooxygenase inactivation of COX2 (5xFAD/COX2 Y385F), and 5xFAD mice with peroxidase (POX) inactivation of COX2 (5xFAD/COX2) H374Y), respectively. Our results indicate that learning ability of COX2 KO and mutants is improved compared to 5xFAD mice, further investigations show that Aβ depositions are reduced, microglia and astrocytes homeostasis are changed in COX2 KO and mutants. Especially, there is more responsive microglia in the brain of 5xFAD/COX2 Y385F mice, and Aβ depositions are more effectively cleaned at old age. Taken together, these results identify a role of COX2 Y385F in regulating microglia function and may have important implications for future treatment of AD.
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Affiliation(s)
- Yang Yang
- The Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, PR China
| | - Jie Wang
- Endocrinology Department of Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, PR China
| | - Hong Ni
- The Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, PR China
| | - Hanqing Ding
- The Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, PR China
| | - Luyao Wei
- The Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, PR China.
| | - Zun-Ji Ke
- The Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, PR China.
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Saghi H, Mirzavi F, Afshari AR, Jalili-Nik M, Mashkani B, Soukhtanloo M. Bee venom induces anti-tumor effects in HT-29 colon cancer cells through regulation of cell proliferation and apoptosis. Biologia (Bratisl) 2022. [DOI: 10.1007/s11756-022-01201-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Hoefnagel SJ, Li S, Timmer EM, Meijer SL, Krishnadath KK. Increased PXR and Suppressed T-Cell Signaling Are Associated With Malignant Degeneration of Barrett's Esophagus. GASTRO HEP ADVANCES 2022; 2:63-71. [PMID: 39130159 PMCID: PMC11308616 DOI: 10.1016/j.gastha.2022.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 08/18/2022] [Indexed: 08/13/2024]
Abstract
Background and Aims Barrett's esophagus (BE) is the precursor lesion for esophageal adenocarcinoma (EAC). To detect EAC in early stage, patients with BE undergo endoscopic surveillance. Surveillance cohorts largely consist of nondysplastic BE (NDBE) patients with a low annual progression risk (<0.5%). Predictive biomarkers for malignant progression of NDBE could improve efficacy of surveillance. Biomarker research has mostly focused on aberrant protein expression on BE epithelial cells. Moreover, insight in cell signaling driving malignant transformation is unknown. This study uses a data-driven approach to analyze tumor-stroma interaction in NDBE which progressed to high-grade dysplasia or EAC. Methods In this case-control study, we performed RNA sequencing analysis on index NDBE biopsies from 6 patients who, during long-term follow-up, progressed and 7 who did not progress to high-grade dysplasia/EAC. For control samples, squamous and duodenum tissues from BE patients were analyzed. For validation, we used quantitative PCR. Results Significant differences in BE transcriptomic profiles between progressors and nonprogressors were found by principal component and differential expression analyses. Ingenuity pathway analysis indicated that 8 cell signaling pathways were significantly upregulated in the progressors, and 14 pathways were significantly downregulated. The most interesting finding was the upregulation of the xenobiotic metabolism pregnane X receptor signaling pathway in the progressor cohort, while of the downregulated pathways in progressors, several were related to the immune system. Conclusion These novel transcriptomic insights are fundamental for developing (chemo-)preventive therapies. These could be therapies, which protect against toxins, including biles, responsible for pregnane X receptor activation or which enhance protective immune mechanisms. The identified RNA markers are promising biomarkers for improving risk stratification in surveillance programs.
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Affiliation(s)
- Sanne J.M. Hoefnagel
- Center for Experimental and Molecular Medicine, Amsterdam UMC, Location Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Location Academic Medical Center, Amsterdam, the Netherlands
- Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Shulin Li
- Center for Experimental and Molecular Medicine, Amsterdam UMC, Location Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
- Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Eva M. Timmer
- Center for Experimental and Molecular Medicine, Amsterdam UMC, Location Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
- Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Sybren L. Meijer
- Cancer Center Amsterdam, Amsterdam, The Netherlands
- Department of Pathology, Amsterdam UMC, Location Academic Medical Center, Amsterdam, the Netherlands
| | - Kausilia K. Krishnadath
- Center for Experimental and Molecular Medicine, Amsterdam UMC, Location Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Location Academic Medical Center, Amsterdam, the Netherlands
- Cancer Center Amsterdam, Amsterdam, The Netherlands
- Laboratory of Experimental Medicine and Paediatrics, Department of Gastroenterology and Hepatology, University Hospital Antwerp, University of Antwerp, Edegem, Belgium
- Department of Gastroenterology and Hepatology, Erasmus University MC, Rotterdam, The Netherlands
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Aru B, Gümüşgöz Çelik G, Harmandar K, Şahin B, Gürek AG, Atilla D, Yanıkkaya Demirel G. Chemo-photodynamic Activity of Silicon Phthalocyanines Bearing Cyclooxygenase Inhibitors on Colorectal Cancer Cell Lines. ACS APPLIED BIO MATERIALS 2022; 5:3936-3950. [PMID: 35802827 DOI: 10.1021/acsabm.2c00461] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Colorectal cancer ranks as the third most lethal cancer worldwide, resulting in over 1 million cases and 900 000 deaths per year. According to population-based studies, administration of long-term non-steroidal anti-inflammatory drugs (NSAIDs) was proven to reduce the risk of a subject developing colorectal cancer. In the present study, the anti-cancer activity of two different NSAIDs, sulindac- (Pc-1) or diclofenac-substituted (Pc-2) asymmetric silicon phthalocyanine derivatives, was evaluated in four different colorectal cancer cell lines bearing various carcinogenic mutations. In this context, the IC50 values of each compound after 24 and 48 h were determined on HCT116, SW480, LoVo, and HT29 cell lines, and the effects of the compounds on programmed cell death pathways apoptosis and autophagy, their impact on cell cycle progression, and the effect of NSAID moieties they bear on COX-1 and COX-2 proteins were analyzed. In addition, the photophysical and photochemical properties of a synthesized Pc derivative bearing axial diclofenac and triethylene glycol groups (Pc-2) have been investigated, and the compound has been characterized by using different analytical techniques. Our results indicated that both compounds inhibit COX protein expression levels, activate apoptosis in all cell lines, and lead to cell cycle arrest in the G2/M phase, depending on the COX expression profiles of the cell lines, indicating that NSAIDs can be coupled with Pc's to achieve increased anti-cancer activity, especially on cancer cells known to have high COX activity.
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Affiliation(s)
- Başak Aru
- Faculty of Medicine, Immunology Department, Yeditepe University, 34755 Ataşehir, Istanbul, Turkey
| | - Gizem Gümüşgöz Çelik
- Department of Chemistry, Gebze Technical University, 41400 Gebze, Kocaeli, Turkey
| | - Kevser Harmandar
- Department of Chemistry, Gebze Technical University, 41400 Gebze, Kocaeli, Turkey
| | - Belgin Şahin
- Department of Chemistry, Gebze Technical University, 41400 Gebze, Kocaeli, Turkey
| | - Ayşe Gül Gürek
- Department of Chemistry, Gebze Technical University, 41400 Gebze, Kocaeli, Turkey
| | - Devrim Atilla
- Department of Chemistry, Gebze Technical University, 41400 Gebze, Kocaeli, Turkey
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Eisenstein A, Hilliard BK, Pope SD, Zhang C, Taskar P, Waizman DA, Israni-Winger K, Tian H, Luan HH, Wang A. Activation of the transcription factor NRF2 mediates the anti-inflammatory properties of a subset of over-the-counter and prescription NSAIDs. Immunity 2022; 55:1082-1095.e5. [PMID: 35588739 PMCID: PMC9205175 DOI: 10.1016/j.immuni.2022.04.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 03/08/2022] [Accepted: 04/21/2022] [Indexed: 12/21/2022]
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) enzymes and are ubiquitously used for their anti-inflammatory properties. However, COX inhibition alone fails to explain numerous clinical outcomes of NSAID usage. Screening commonly used NSAIDs in primary human and murine myeloid cells demonstrated that NSAIDs could be differentiated by their ability to induce growth/differentiation factor 15 (GDF15), independent of COX specificity. Using genetic and pharmacologic approaches, NSAID-mediated GDF15 induction was dependent on the activation of nuclear factor erythroid 2-related factor 2 (NRF2) in myeloid cells. Sensing by Cysteine 151 of the NRF2 chaperone, Kelch-like ECH-associated protein 1 (KEAP1) was required for NSAID activation of NRF2 and subsequent anti-inflammatory effects both in vitro and in vivo. Myeloid-specific deletion of NRF2 abolished NSAID-mediated tissue protection in murine models of gout and endotoxemia. This highlights a noncanonical NRF2-dependent mechanism of action for the anti-inflammatory activity of a subset of commonly used NSAIDs.
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Affiliation(s)
- Anna Eisenstein
- Department of Dermatology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Brandon K Hilliard
- Department of Internal Medicine and Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Scott D Pope
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, New Haven, CT, USA
| | - Cuiling Zhang
- Department of Internal Medicine and Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Pranali Taskar
- NGM Biopharmaceuticals, South San Francisco, CA 94080, USA
| | - Daniel A Waizman
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA
| | | | - Hui Tian
- NGM Biopharmaceuticals, South San Francisco, CA 94080, USA
| | - Harding H Luan
- NGM Biopharmaceuticals, South San Francisco, CA 94080, USA.
| | - Andrew Wang
- Department of Internal Medicine and Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
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Reetu R, Gujjarappa R, Malakar CC. Recent Advances in Synthesis and Medicinal Evaluation of 1,2‐Benzothiazine Analogues. ASIAN J ORG CHEM 2022. [DOI: 10.1002/ajoc.202200163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Reetu Reetu
- National Institute of Technology Manipur Chemistry INDIA
| | | | - Chandi C Malakar
- National Institute of Technology Manipur Department of Chemistry Langol, Imphal 795004 Imphal INDIA
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NSAIDs Induce Proline Dehydrogenase/Proline Oxidase-Dependent and Independent Apoptosis in MCF7 Breast Cancer Cells. Int J Mol Sci 2022; 23:ijms23073813. [PMID: 35409177 PMCID: PMC8998922 DOI: 10.3390/ijms23073813] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 03/11/2022] [Accepted: 03/28/2022] [Indexed: 02/06/2023] Open
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are considered in cancer therapy for their inhibitory effect on cyclooxygenase-2 (COX-2), which is overexpressed in most cancers. However, we found that NSAIDs as ligands of peroxisome proliferator-activated receptor-γ (PPARγ)-induced apoptosis independent of the COX-2 inhibition, and the process was mediated through activation of proline dehydrogenase/proline oxidase (PRODH/POX)-dependent generation of reactive oxygen species (ROS). This mitochondrial enzyme converts proline to ∆1-pyrroline-5-carboxylate (P5C) during which ATP or ROS is generated. To confirm the role of PRODH/POX in the mechanism of NSAID-induced apoptosis we obtained an MCF7 CRISPR/Cas9 PRODH/POX knockout breast cancer cell model (MCF7POK-KO). Interestingly, the studied NSAIDs (indomethacin and diclofenac) in MCF7POK-KO cells contributed to a more pronounced pro-apoptotic phenotype of the cells than in PRODH/POX-expressing MCF7 cells. The observed effect was independent of ROS generation, but it was related to the energetic disturbances in the cells as shown by an increase in the expression of AMPKα (sensor of cell energy status), GLUD1/2 (proline producing enzyme from glutamate), prolidase (proline releasing enzyme), PPARδ (growth supporting transcription factor) and a decrease in the expression of proline cycle enzymes (PYCR1, PYCRL), mammalian target of rapamycin (mTOR), and collagen biosynthesis (the main proline utilizing process). The data provide evidence that the studied NSAIDs induce PRODH/POX-dependent and independent apoptosis in MCF7 breast cancer cells.
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Kim MJ, Kawk HW, Kim SH, Lee HJ, Seo JW, Lee CY, Kim YM. The p53-Driven Anticancer Effect of Ribes fasciculatum Extract on AGS Gastric Cancer Cells. Life (Basel) 2022; 12:life12020303. [PMID: 35207590 PMCID: PMC8876336 DOI: 10.3390/life12020303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/14/2022] [Accepted: 02/15/2022] [Indexed: 12/24/2022] Open
Abstract
Cancer metastasis is directly related to the survival rate of cancer patients. Although cancer metastasis proceeds by the movement of cancer cells, it is fundamentally caused by its resistance to anoikis, a mechanism of apoptosis caused by the loss of adhesion of cancer cells. Therefore, it was found that inhibiting cancer migration and reducing anoikis resistance are important for cancer suppression, and natural compounds can effectively control it. Among them, Ribes fasciculatum, which has been used as a medicinal plant, was confirmed to have anticancer potential, and experiments were conducted to prove various anticancer effects by extracting Ribes fasciculatum (RFE). Through various experiments, it was observed that RFE induces apoptosis of AGS gastric cancer cells, arrests the cell cycle, induces oxidative stress, and reduces mobility. It was also demonstrated that anoikis resistance was attenuated through the downregulation of proteins, such as epidermal growth factor receptor (EGFR). Moreover, the anticancer effect of RFE depends upon the increase in p53 expression, suggesting that RFE is suitable for the development of p53-targeted anticancer materials. Moreover, through xenotransplantation, it was found that the anticancer effect of RFE confirmed in vitro was continued in vivo.
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12
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Kazberuk A, Chalecka M, Palka J, Surazynski A. Nonsteroidal Anti-Inflammatory Drugs as PPARγ Agonists Can Induce PRODH/POX-Dependent Apoptosis in Breast Cancer Cells: New Alternative Pathway in NSAID-Induced Apoptosis. Int J Mol Sci 2022; 23:ijms23031510. [PMID: 35163433 PMCID: PMC8835909 DOI: 10.3390/ijms23031510] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/25/2022] [Accepted: 01/26/2022] [Indexed: 02/01/2023] Open
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered to be therapeutics in cancer prevention because of their inhibitory effect on cyclooxygenases (COX), which are frequently overexpressed in many types of cancer. However, it was also demonstrated that NSAIDs provoked a proapoptotic effect in COX knocked-out cancer cells. Here, we suggest that this group of drugs may provoke antineoplastic activity through the activation of PPARγ, which induces proline dehydrogenase/proline oxidase (PRODH/POX)-dependent apoptosis. PRODH/POX is a mitochondrial enzyme that catalyzes proline degradation, during which ATP or reactive oxygen species (ROS) are generated. We have found that NSAIDs induced PRODH/POX and PPARγ expressions (as demonstrated by Western Blot or immunofluorescence analysis) and cytotoxicity (as demonstrated by MTT, cytometric assay, and DNA biosynthesis assay) in breast cancer MCF7 cells. Simultaneously, the NSAIDs inhibited collagen biosynthesis, supporting proline for PRODH/POX-induced ROS-dependent apoptosis (as demonstrated by an increase in the expression of apoptosis markers). The data suggest that targeting proline metabolism and the PRODH/POX–PPARγ axis can be considered a novel approach for breast cancer treatment.
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Kolawole OR, Kashfi K. NSAIDs and Cancer Resolution: New Paradigms beyond Cyclooxygenase. Int J Mol Sci 2022; 23:1432. [PMID: 35163356 PMCID: PMC8836048 DOI: 10.3390/ijms23031432] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 12/12/2022] Open
Abstract
Acute inflammation or resolved inflammation is an adaptive host defense mechanism and is self-limiting, which returns the body to a state of homeostasis. However, unresolved, uncontrolled, or chronic inflammation may lead to various maladies, including cancer. Important evidence that links inflammation and cancer is that nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, reduce the risk and mortality from many cancers. The fact that NSAIDs inhibit the eicosanoid pathway prompted mechanistic drug developmental work focusing on cyclooxygenase (COX) and its products. The increased prostaglandin E2 levels and the overexpression of COX-2 in the colon and many other cancers provided the rationale for clinical trials with COX-2 inhibitors for cancer prevention or treatment. However, NSAIDs do not require the presence of COX-2 to prevent cancer. In this review, we highlight the effects of NSAIDs and selective COX-2 inhibitors (COXIBs) on targets beyond COX-2 that have shown to be important against many cancers. Finally, we hone in on specialized pro-resolving mediators (SPMs) that are biosynthesized locally and, in a time, -dependent manner to promote the resolution of inflammation and subsequent tissue healing. Different classes of SPMs are reviewed, highlighting aspirin's potential in triggering the production of these resolution-promoting mediators (resolvins, lipoxins, protectins, and maresins), which show promise in inhibiting cancer growth and metastasis.
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Affiliation(s)
- Oluwafunke R. Kolawole
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY 10031, USA;
| | - Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY 10031, USA;
- Graduate Program in Biology, City University of New York Graduate Center, New York, NY 10091, USA
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Bardaweel SK, Dahabiyeh LA, Akileh BM, Shalabi DD, AlHiary AK, Pawling J, Dennis JW, Rahman AMA. Molecular and Metabolomic Investigation of Celecoxib Antiproliferative Activity in Mono-and Combination Therapy Against Breast Cancer Cell Models. Anticancer Agents Med Chem 2021; 22:1611-1621. [PMID: 34515014 DOI: 10.2174/1871520621666210910101349] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 07/18/2021] [Accepted: 07/29/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Chronic inflammation plays a crucial role in the initiation, promotion, and invasion of tumors, and thus the antiproliferative effects of numerous anti-inflammatory drugs have been frequently reported in the literature. Upregulation of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2) has been linked to various human cancers, including breast cancer. OBJECTIVES This research aims to investigate the antiproliferative activity of different Non-steroidal anti-inflammatory drugs (NSAIDs), including COX-2 selective and non-selective agents, against various breast cancer cell lines and to elucidate possible molecular pathways involved in their activity. METHODS The antiproliferative and combined effects of NSAIDs with raloxifene were evaluated by MTT assay. Cell migration was assessed using a wound-healing assay. The mechanism of cell death was determined using the Annexin V-FITC/ propidium iodide staining flow cytometry method. A mass spectrometry-based targeted metabolomics approach was used to profile the metabolomic changes induced in the T47d cells upon drug treatment. RESULTS Our results have demonstrated that celecoxib, a potent and selective COX-2 inhibitor, resulted in significant antiproliferative activity against all examined breast cancer cell lines with IC50 values of 95.44, 49.50. and 97.70 μM against MDA-MB-231, T47d, and MCF-7, respectively. Additionally, celecoxib exhibited a synergistic effect against T47d cells combined with raloxifene, a selective estrogen receptor modulator. Interestingly, celecoxib treatment increased cell apoptosis and resulted in substantial inhibition of cancer cell migration. In addition, the metabolomic analysis suggests that celecoxib may have affected metabolites (n = 43) that are involved in several pathways, including the tricarboxylic acid cycle, amino acids metabolism pathways, and energy production pathways in cancer cells. CONCLUSION Celecoxib may possess potential therapeutic utility for breast cancer treatment as monotherapy or in combination therapy. The reported metabolic changes taking place upon celecoxib treatment may shed light on possible molecular targets mediating the antiproliferative activity of celecoxib in an independent manner of its COX-2 inhibition.
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Affiliation(s)
- Sanaa K Bardaweel
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942. Jordan
| | - Lina A Dahabiyeh
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942. Jordan
| | - Bushra M Akileh
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942. Jordan
| | - Dana D Shalabi
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942. Jordan
| | - Afnan K AlHiary
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942. Jordan
| | - Judy Pawling
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue R988, Toronto, Ontario M5G 1X5. Canada
| | - James W Dennis
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue R988, Toronto, Ontario M5G 1X5. Canada
| | - Anas M Abdel Rahman
- Metabolomics Section, Department of Clinical Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Center (KFSHRC), Riyadh, 11564. Saudi Arabia
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16
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Sankaranarayanan R, Kumar DR, Altinoz MA, Bhat GJ. Mechanisms of Colorectal Cancer Prevention by Aspirin-A Literature Review and Perspective on the Role of COX-Dependent and -Independent Pathways. Int J Mol Sci 2020; 21:ijms21239018. [PMID: 33260951 PMCID: PMC7729916 DOI: 10.3390/ijms21239018] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 11/25/2020] [Accepted: 11/26/2020] [Indexed: 12/11/2022] Open
Abstract
Aspirin, synthesized and marketed in 1897 by Bayer, is one of the most widely used drugs in the world. It has a well-recognized role in decreasing inflammation, pain and fever, and in the prevention of thrombotic cardiovascular diseases. Its anti-inflammatory and cardio-protective actions have been well studied and occur through inhibition of cyclooxygenases (COX). Interestingly, a vast amount of epidemiological, preclinical and clinical studies have revealed aspirin as a promising chemopreventive agent, particularly against colorectal cancers (CRC); however, the primary mechanism by which it decreases the occurrences of CRC has still not been established. Numerous mechanisms have been proposed for aspirin’s chemopreventive properties among which the inhibition of COX enzymes has been widely discussed. Despite the wide attention COX-inhibition has received as the most probable mechanism of cancer prevention by aspirin, it is clear that aspirin targets many other proteins and pathways, suggesting that these extra-COX targets may also be equally important in preventing CRC. In this review, we discuss the COX-dependent and -independent pathways described in literature for aspirin’s anti-cancer effects and highlight the strengths and limitations of the proposed mechanisms. Additionally, we emphasize the potential role of the metabolites of aspirin and salicylic acid (generated in the gut through microbial biotransformation) in contributing to aspirin’s chemopreventive actions. We suggest that the preferential chemopreventive effect of aspirin against CRC may be related to direct exposure of aspirin/salicylic acid or its metabolites to the colorectal tissues. Future investigations should shed light on the role of aspirin, its metabolites and the role of the gut microbiota in cancer prevention against CRC.
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Affiliation(s)
- Ranjini Sankaranarayanan
- Department of Pharmaceutical Sciences and Translational Cancer Research Center, College of Pharmacy and Allied Health Professions, South Dakota State University, Brookings, SD 57007, USA;
| | - D. Ramesh Kumar
- Department of Entomology, University of Kentucky, Lexington, KY 40506, USA;
| | - Meric A. Altinoz
- Department of Biochemistry, Acibadem M.A.A. University, Istanbul, Turkey;
| | - G. Jayarama Bhat
- Department of Pharmaceutical Sciences and Translational Cancer Research Center, College of Pharmacy and Allied Health Professions, South Dakota State University, Brookings, SD 57007, USA;
- Correspondence: ; Tel.: +1-605-688-6894
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Kaur J, Chikate T, Bandyopadhyay P, Basu S, Chikate R. Cu(II) complexes of hydrazones–NSAID conjugates: synthesis, characterization and anticancer activity. J COORD CHEM 2020. [DOI: 10.1080/00958972.2020.1843160] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Jatinder Kaur
- Department of Chemistry, Post-graduate and Research Center, MES Abasaheb Garware College, Pune, India
- Department of Chemistry, Fergusson College, Pune, India
| | - Tanmayee Chikate
- Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Cancer and Translational Research Laboratory, Pune, India
- Department of Bioengineering, University of Texas, Arlington, USA
| | | | - Soumya Basu
- Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Cancer and Translational Research Laboratory, Pune, India
| | - Rajeev Chikate
- Department of Chemistry, Post-graduate and Research Center, MES Abasaheb Garware College, Pune, India
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Kazberuk A, Zareba I, Palka J, Surazynski A. A novel plausible mechanism of NSAIDs-induced apoptosis in cancer cells: the implication of proline oxidase and peroxisome proliferator-activated receptor. Pharmacol Rep 2020; 72:1152-1160. [PMID: 32710395 PMCID: PMC7550302 DOI: 10.1007/s43440-020-00140-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/19/2020] [Accepted: 07/14/2020] [Indexed: 12/12/2022]
Abstract
Although pharmaco-epidemiological studies provided evidence for the anticancer potential of non-steroidal anti-inflammatory drugs (NSAIDs), the mechanism of their anti-cancer activity is not known. Several lines of evidence suggest that proline dehydrogenase/proline oxidase (PRODH/POX) may represent a target for NSAIDs-dependent anti-cancer activity. PRODH/POX catalyzes conversion of proline into Δ1-pyrroline-5-carboxylate releasing ATP or reactive oxygen species for autophagy/apoptosis. Since NSAIDs are ligands of peroxisome proliferator-activated receptor (PPARs) and PPARs are implicated in PRODH/POX-dependent apoptosis we provided a hypothesis on the mechanism of NSAIDs-induced apoptosis in cancer cells.
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Affiliation(s)
- Adam Kazberuk
- Department of Medicinal Chemistry, Medical University of Bialystok, Mickiewicza 2D, 15-222 Białystok, Poland
| | - Ilona Zareba
- Department of Medicinal Chemistry, Medical University of Bialystok, Mickiewicza 2D, 15-222 Białystok, Poland
| | - Jerzy Palka
- Department of Medicinal Chemistry, Medical University of Bialystok, Mickiewicza 2D, 15-222 Białystok, Poland
| | - Arkadiusz Surazynski
- Department of Medicinal Chemistry, Medical University of Bialystok, Mickiewicza 2D, 15-222 Białystok, Poland
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Hartung NM, Ostermann AI, Immenschuh S, Schebb NH. Combined Targeted Proteomics and Oxylipin Metabolomics for Monitoring of the COX-2 Pathway. Proteomics 2020; 21:e1900058. [PMID: 32875715 DOI: 10.1002/pmic.201900058] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 08/25/2020] [Indexed: 12/21/2022]
Abstract
The important role of inducible cyclooxygenase-2 (COX-2) in several diseases necessitates analytical tools enabling thorough understanding of its modulation. Analysis of a comprehensive oxylipin pattern provides detailed information about changes in enzyme activities. In order to simultaneously monitor gene expression levels, a targeted proteomics method for human COX-2 is developed. With limits of detection and quantification down to 0.25 and 0.5 fmol (on column) the method enables sensitive quantitative analysis via LC-MS/MS within a linear range up to 2.5 pmol. Three housekeeping proteins are included in the method for data normalization. A tiered approach for method development comprised of in silico and experimental steps is described for choosing unique peptides and selective and sensitive SRM transitions while avoiding isobaric interferences. This method combined with a well-established targeted oxylipin metabolomics method allows to investigate the role of COX-2 in the human colon carcinoma cell lines HCT-116, HT-29, and HCA-7. Moreover, the developed methodology is used to demonstrate the time-dependent prostanoid formation and COX-2 enzyme synthesis in lipopolysaccharide-stimulated human primary macrophages. The described approach is a helpful tool which will be further used as standard operation procedure, ultimately aiming at comprehensive targeted proteomics/oxylipin metabolomics strategies to examine the entire arachidonic acid cascade.
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Affiliation(s)
- Nicole M Hartung
- Chair of Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Gaußstr. 20, Wuppertal, 42119, Germany
| | - Annika I Ostermann
- Chair of Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Gaußstr. 20, Wuppertal, 42119, Germany
| | - Stephan Immenschuh
- Institute for Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, 30625, Germany
| | - Nils Helge Schebb
- Chair of Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Gaußstr. 20, Wuppertal, 42119, Germany
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20
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Krzystek-Korpacka M, Szczęśniak-Sięga B, Szczuka I, Fortuna P, Zawadzki M, Kubiak A, Mierzchała-Pasierb M, Fleszar MG, Lewandowski Ł, Serek P, Jamrozik N, Neubauer K, Wiśniewski J, Kempiński R, Witkiewicz W, Bednarz-Misa I. L-Arginine/Nitric Oxide Pathway Is Altered in Colorectal Cancer and Can Be Modulated by Novel Derivatives from Oxicam Class of Non-Steroidal Anti-Inflammatory Drugs. Cancers (Basel) 2020; 12:E2594. [PMID: 32932854 PMCID: PMC7564351 DOI: 10.3390/cancers12092594] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/05/2020] [Accepted: 09/10/2020] [Indexed: 12/14/2022] Open
Abstract
L-arginine/nitric oxide pathway metabolites are altered in colorectal cancer (CRC). We evaluated underlying changes in pathway enzymes in 55 paired tumor/tumor-adjacent samples and 20 normal mucosa using quantitative-PCR and assessed the impact of classic and novel oxicam analogues on enzyme expression and intracellular metabolite concentration (LC-MS/MS) in Caco-2, HCT116, and HT-29 cells. Compared to normal mucosa, ARG1, PRMT1, and PRMT5 were overexpressed in both tumor and tumor-adjacent tissue and DDAH2 solely in tumor-adjacent tissue. Tumor-adjacent tissue had higher expression of ARG1, DDAH1, and DDAH2 and lower NOS2 than patients-matched tumors. The ARG1 expression in tumors increased along with tumor grade and reflected lymph node involvement. Novel oxicam analogues with arylpiperazine moiety at the thiazine ring were more effective in downregulating DDAHs and PRMTs and upregulating ARG2 than piroxicam and meloxicam. An analogue distinguished by propylene linker between thiazine's and piperazine's nitrogen atoms and containing two fluorine substituents was the strongest inhibitor of DDAHs and PRMTs expression, while an analogue containing propylene linker but no fluorine substituents was the strongest inhibitor of ARG2 expression. Metabolic reprogramming in CRC includes overexpression of DDAHs and PRMTs in addition to ARG1 and NOS2 and is not restricted to tumor tissue but can be modulated by novel oxicam analogues.
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Affiliation(s)
- Małgorzata Krzystek-Korpacka
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.S.); (P.F.); (A.K.); (M.M.-P.); (M.G.F.); (Ł.L.); (P.S.); (N.J.); (J.W.); (I.B.-M.)
| | - Berenika Szczęśniak-Sięga
- Department of Medicinal Chemistry, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland;
| | - Izabela Szczuka
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.S.); (P.F.); (A.K.); (M.M.-P.); (M.G.F.); (Ł.L.); (P.S.); (N.J.); (J.W.); (I.B.-M.)
| | - Paulina Fortuna
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.S.); (P.F.); (A.K.); (M.M.-P.); (M.G.F.); (Ł.L.); (P.S.); (N.J.); (J.W.); (I.B.-M.)
| | - Marek Zawadzki
- Department of Oncological Surgery, Regional Specialist Hospital, 51-124 Wroclaw, Poland; (M.Z.); (W.W.)
- Department of Physiotherapy, Wroclaw Medical University, 51-618 Wroclaw, Poland
| | - Agnieszka Kubiak
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.S.); (P.F.); (A.K.); (M.M.-P.); (M.G.F.); (Ł.L.); (P.S.); (N.J.); (J.W.); (I.B.-M.)
| | - Magdalena Mierzchała-Pasierb
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.S.); (P.F.); (A.K.); (M.M.-P.); (M.G.F.); (Ł.L.); (P.S.); (N.J.); (J.W.); (I.B.-M.)
| | - Mariusz G. Fleszar
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.S.); (P.F.); (A.K.); (M.M.-P.); (M.G.F.); (Ł.L.); (P.S.); (N.J.); (J.W.); (I.B.-M.)
| | - Łukasz Lewandowski
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.S.); (P.F.); (A.K.); (M.M.-P.); (M.G.F.); (Ł.L.); (P.S.); (N.J.); (J.W.); (I.B.-M.)
| | - Paweł Serek
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.S.); (P.F.); (A.K.); (M.M.-P.); (M.G.F.); (Ł.L.); (P.S.); (N.J.); (J.W.); (I.B.-M.)
| | - Natalia Jamrozik
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.S.); (P.F.); (A.K.); (M.M.-P.); (M.G.F.); (Ł.L.); (P.S.); (N.J.); (J.W.); (I.B.-M.)
| | - Katarzyna Neubauer
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, 50-556 Wroclaw, Poland; (K.N.); (R.K.)
| | - Jerzy Wiśniewski
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.S.); (P.F.); (A.K.); (M.M.-P.); (M.G.F.); (Ł.L.); (P.S.); (N.J.); (J.W.); (I.B.-M.)
| | - Radosław Kempiński
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, 50-556 Wroclaw, Poland; (K.N.); (R.K.)
| | - Wojciech Witkiewicz
- Department of Oncological Surgery, Regional Specialist Hospital, 51-124 Wroclaw, Poland; (M.Z.); (W.W.)
- Research and Development Centre at Regional Specialist Hospital, 51-124 Wroclaw, Poland
| | - Iwona Bednarz-Misa
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.S.); (P.F.); (A.K.); (M.M.-P.); (M.G.F.); (Ł.L.); (P.S.); (N.J.); (J.W.); (I.B.-M.)
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El-Garawani IM, El-Sabbagh SM, Abbas NH, Ahmed HS, Eissa OA, Abo-Atya DM, Khalifa SAM, El-Seedi HR. A newly isolated strain of Halomonas sp. (HA1) exerts anticancer potential via induction of apoptosis and G 2/M arrest in hepatocellular carcinoma (HepG2) cell line. Sci Rep 2020; 10:14076. [PMID: 32826930 PMCID: PMC7443142 DOI: 10.1038/s41598-020-70945-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 07/28/2020] [Indexed: 12/21/2022] Open
Abstract
Marine bacterial strains are of great interest for their ability to produce secondary metabolites with anticancer potentials. Isolation, identification, characterization and anticancer activities of isolated bacteria from El-Hamra Lake, Wadi El-Natrun (Egypt) were the objectives of this study. The isolated bacteria were identified as a moderately halophilic alkaliphilic strain. Ethyl acetate extraction was performed and identified by liquid chromatography-mass spectrophotometry (LC-MS-MS) and nuclear magnetic resonance analysis (NMR). Cytotoxicity of the extract was assessed on the HepG2 cell line and normal human peripheral lymphocytes (HPBL) in vitro. Halomonas sp. HA1 extract analyses revealed anticancer potential. Many compounds have been identified including cyclo-(Leu-Leu), cyclo-(Pro-Phe), C17-sphinganine, hexanedioic acid, bis (2-ethylhexyl) ester, surfactin C14 and C15. The extract exhibited an IC50 of 68 ± 1.8 μg/mL and caused marked morphological changes in treated HepG2 cells. For mechanistic anticancer evaluation, 20 and 40 µg/mL of bacterial extract were examined. The up-regulation of apoptosis-related genes' expression, P53, CASP-3, and BAX/BCL-2 at mRNA and protein levels proved the involvement of P53-dependant mitochondrial apoptotic pathway. The anti-proliferative properties were confirmed by significant G2/M cell cycle arrest and PCNA down-regulation in the treated cells. Low cytotoxicity was observed in HPBL compared to HepG2 cells. In conclusion, results suggest that the apoptotic and anti-proliferative effects of Halomonas sp. HA1 extract on HepG2 cells can provide it as a candidate for future pharmaceutical industries.
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Affiliation(s)
- Islam M El-Garawani
- Department of Zoology, Faculty of Science, Menoufia University, Menoufia, 32511, Egypt.
| | - Sabha M El-Sabbagh
- Department of Botany and Microbiology, Faculty of Science, Menoufia University, Menoufia, 32511, Egypt
| | - Nasser H Abbas
- Department of Molecular BiologyGenetic Engineering and Biotechnology Research Institute, University of Sadat City, Sadat City, 32958, Egypt
| | - Hany S Ahmed
- Department of Botany and Microbiology, Faculty of Science, Menoufia University, Menoufia, 32511, Egypt
| | - Omaima A Eissa
- Department of Botany and Microbiology, Faculty of Science, Menoufia University, Menoufia, 32511, Egypt
| | - Doaa M Abo-Atya
- Department of Chemistry, Faculty of Science, Menoufia University, Menoufia, 32511, Egypt
| | - Shaden A M Khalifa
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 10691, Stockholm, Sweden
| | - Hesham R El-Seedi
- Department of Chemistry, Faculty of Science, Menoufia University, Menoufia, 32511, Egypt.
- Pharmacognosy Group, Department of Pharmaceutical Biosciences, Uppsala University, Biomedical Centre, 75 123, Uppsala, Sweden.
- International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang, 212013, China.
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Abstract
Tumour vasculature supports the growth and progression of solid cancers with both angiogenesis (endothelial cell proliferation) and vasculogenic mimicry (VM, the formation of vascular structures by cancer cells themselves) predictors of poor patient outcomes. Increased circulating platelet counts also predict poor outcome for cancer patients but the influence of platelets on tumour vasculature is incompletely understood. Herein, we show with in vitro assays that platelets did not influence angiogenesis but did actively inhibit VM formation by cancer cell lines. Both platelet sized beads and the releasates from platelets were partially effective at inhibiting VM formation suggesting that direct contact maximises the effect. Platelets also promoted cancer cell invasion in vitro. B16F10 melanomas in Bcl-xPlt20/Plt20 thrombocytopenic mice showed a higher content of VM than their wildtype counterparts while angiogenesis did not differ. In a xenograft mouse model of breast cancer with low-dose aspirin to inactivate the platelets, the burden of MDA-MB-231-LM2 breast cancer cells was reduced and the gene expression profile of the cancer cells was altered; but no effect on tumour vasculature was observed. Taken together, this study provides new insights into the action of platelets on VM formation and their involvement in cancer progression.
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Singh H, Kinarivala N, Sharma S. Multi-Targeting Anticancer Agents: Rational Approaches, Synthetic Routes and Structure Activity Relationship. Anticancer Agents Med Chem 2020; 19:842-874. [PMID: 30657048 DOI: 10.2174/1871520619666190118120708] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 01/04/2019] [Accepted: 01/04/2019] [Indexed: 12/21/2022]
Abstract
We live in a world with complex diseases such as cancer which cannot be cured with one-compound one-target based therapeutic paradigm. This could be due to the involvement of multiple pathogenic mechanisms. One-compound-various-targets stratagem has become a prevailing research topic in anti-cancer drug discovery. The simultaneous interruption of two or more targets has improved the therapeutic efficacy as compared to the specific targeted based therapy. In this review, six types of dual targeting agents along with some interesting strategies used for their design and synthesis are discussed. Their pharmacology with various types of the molecular interactions within their specific targets has also been described. This assemblage will reveal the recent trends and insights in front of the scientific community working in dual inhibitors and help them in designing the next generation of multi-targeted anti-cancer agents.
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Affiliation(s)
- Harbinder Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab-143005, India
| | - Nihar Kinarivala
- Program in Chemical Biology, Sloan Kettering Institute, New York, NY 10065, United States
| | - Sahil Sharma
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab-143005, India.,Program in Chemical Biology, Sloan Kettering Institute, New York, NY 10065, United States
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25
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Overcoming Resistance to Therapies Targeting the MAPK Pathway in BRAF-Mutated Tumours. JOURNAL OF ONCOLOGY 2020; 2020:1079827. [PMID: 32411231 PMCID: PMC7199609 DOI: 10.1155/2020/1079827] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 11/21/2019] [Accepted: 11/29/2019] [Indexed: 12/12/2022]
Abstract
Overactivation of the mitogen-activated protein kinase (MAPK) pathway is an important driver of many human cancers. First line, FDA-approved therapies targeting MAPK signalling, which include BRAF and MEK inhibitors, have variable success across cancers, and a significant number of patients quickly develop resistance. In recent years, a number of preclinical studies have reported alternative methods of overcoming resistance, which include promoting apoptosis, modulating autophagy, and targeting mitochondrial metabolism. This review summarizes mechanisms of resistance to approved MAPK-targeted therapies in BRAF-mutated cancers and discusses novel preclinical approaches to overcoming resistance.
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26
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Litchfield M, Wuest M, Glubrecht D, Wuest F. Radiosynthesis and Biological Evaluation of [ 18F]Triacoxib: A New Radiotracer for PET Imaging of COX-2. Mol Pharm 2019; 17:251-261. [PMID: 31816246 DOI: 10.1021/acs.molpharmaceut.9b00986] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Inducible isozyme cyclooxygenase-2 (COX-2) is upregulated under acute and chronic inflammatory conditions, including cancer, wherein it promotes angiogenesis, tissue invasion, and resistance to apoptosis. Due to its high expression in various cancers, COX-2 has become an important biomarker for molecular imaging and therapy of cancer. Recently, our group applied in situ click chemistry for the identification of the highly potent and selective COX-2 inhibitor triacoxib. In this study, we present the radiosynthesis in vitro and in vivo radiopharmacological validation of [18F]triacoxib, a novel radiotracer for PET imaging of COX-2. Radiosynthesis of [18F]triacoxib was accomplished using copper-mediated late-stage radiofluorination chemistry. The radiosynthesis, including radio-HPLC purification, of [18F]triacoxib was accomplished within 90 min in decay-corrected radiochemical yields of 72% (n = 7) at molar activities exceeding 90 GBq/μmol. Cellular uptake and inhibition studies with [18F]triacoxib were carried out in COX-2 expressing HCA-7 cells. Cellular uptake of [18F]triacoxib in HCA-7 cells reached 25% radioactivity/mg protein after 60 min. Cellular uptake was reduced by 63% upon pretreatment with 0.1 mM celecoxib, and 90% of the radiotracer remained intact in vivo after 60 min p.i. in mice. [18F]Triacoxib was further evaluated in HCA-7 tumor-bearing mice using dynamic PET imaging, radiometabolite analysis, autoradiography, and immunohistochemistry. PET imaging revealed a favorable baseline radiotracer uptake in HCA-7 tumors (SUV60min = 0.76 ± 0.02 (n = 4)), which could be blocked by 20% through i.p. pretreatment with 2 mg of celecoxib. Autoradiography and immunohistochemistry experiments further the confirmed blocking of COX-2 in vivo. [18F]Triacoxib, whose nonradioactive analogue was identified through in situ click chemistry, is a novel radiotracer for PET imaging of COX-2 in cancer. Despite a substantial amount of nonspecific uptake in vivo, [18F]triacoxib displayed specific binding to COX-2 in vivo and reinforced the feasibility of optimal structure selection by in situ click chemistry. It remains to be elucidated how this novel radiotracer would perform in first-in-human studies to detect COX-2 with PET.
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Affiliation(s)
- Marcus Litchfield
- Department of Oncology , University of Alberta , 11560 University Avenue , Edmonton , Alberta T6G 1Z2 , Canada
| | - Melinda Wuest
- Department of Oncology , University of Alberta , 11560 University Avenue , Edmonton , Alberta T6G 1Z2 , Canada.,Cancer Research Institute of Northern Alberta , University of Alberta , Edmonton , Alberta T6G 2S2 , Canada
| | - Darryl Glubrecht
- Department of Oncology , University of Alberta , 11560 University Avenue , Edmonton , Alberta T6G 1Z2 , Canada
| | - Frank Wuest
- Department of Oncology , University of Alberta , 11560 University Avenue , Edmonton , Alberta T6G 1Z2 , Canada.,Cancer Research Institute of Northern Alberta , University of Alberta , Edmonton , Alberta T6G 2S2 , Canada
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27
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Cao X, Ding L, Xie ZZ, Yang Y, Whiteman M, Moore PK, Bian JS. A Review of Hydrogen Sulfide Synthesis, Metabolism, and Measurement: Is Modulation of Hydrogen Sulfide a Novel Therapeutic for Cancer? Antioxid Redox Signal 2019; 31:1-38. [PMID: 29790379 PMCID: PMC6551999 DOI: 10.1089/ars.2017.7058] [Citation(s) in RCA: 281] [Impact Index Per Article: 46.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 05/14/2018] [Accepted: 05/22/2018] [Indexed: 02/07/2023]
Abstract
Significance: Hydrogen sulfide (H2S) has been recognized as the third gaseous transmitter alongside nitric oxide and carbon monoxide. In the past decade, numerous studies have demonstrated an active role of H2S in the context of cancer biology. Recent Advances: The three H2S-producing enzymes, namely cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3MST), have been found to be highly expressed in numerous types of cancer. Moreover, inhibition of CBS has shown anti-tumor activity, particularly in colon cancer, ovarian cancer, and breast cancer, whereas the consequence of CSE or 3MST inhibition remains largely unexplored in cancer cells. Intriguingly, H2S donation at high amounts or a long time duration has also been observed to induce cancer cell apoptosis in vitro and in vivo while sparing noncancerous fibroblast cells. Therefore, a bell-shaped model has been proposed to explain the role of H2S in cancer development. Specifically, endogenous H2S or a relatively low level of exogenous H2S may exhibit a pro-cancer effect, whereas exposure to H2S at a higher amount or for a long period may lead to cancer cell death. This indicates that inhibition of H2S biosynthesis and H2S supplementation serve as two distinct ways for cancer treatment. This paradoxical role of H2S has stimulated the enthusiasm for the development of novel CBS inhibitors, H2S donors, and H2S-releasing hybrids. Critical Issues: A clear relationship between H2S level and cancer progression remains lacking. The possibility that the altered levels of these byproducts have influenced the cell viability of cancer cells has not been excluded in previous studies when modulating H2S producing enzymes. Future Directions: The consequence of CSE or 3MST inhibition in cancer cells need to be examined in the future. Better portrayal of the crosstalk among these gaseous transmitters may not only lead to an in-depth understanding of cancer progression but also shed light on novel strategies for cancer therapy.
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Affiliation(s)
- Xu Cao
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Lei Ding
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Zhi-zhong Xie
- Institute of Pharmacy and Pharmacology, University of South China, Hengyang, China
| | - Yong Yang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, China
| | | | - Philip K. Moore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jin-Song Bian
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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28
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Wang L, Mai Z, Zhao M, Wang B, Yu S, Wang X, Chen T. Aspirin induces oncosis in tumor cells. Apoptosis 2019; 24:758-772. [PMID: 31243598 DOI: 10.1007/s10495-019-01555-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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29
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Nasry WHS, Wang H, Jones K, Tesch M, Rodriguez-Lecompte JC, Martin CK. Cyclooxygenase and CD147 expression in oral squamous cell carcinoma patient samples and cell lines. Oral Surg Oral Med Oral Pathol Oral Radiol 2019; 128:400-410.e3. [PMID: 31350224 DOI: 10.1016/j.oooo.2019.06.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 05/09/2019] [Accepted: 06/05/2019] [Indexed: 12/21/2022]
Abstract
OBJECTIVES In oral squamous cell carcinoma (OSCC), cyclooxygenases (COX-1 and COX-2) contribute to inflammation, and cluster of differentiation factor 147 (CD147) contributes to invasiveness, but their relationship has not been previously examined within a cohort of patients with OSCC or OSCC cell lines. STUDY DESIGN COX-2 and CD147 expression was determined by using immunohistochemistry on 39 surgical biopsy specimens of OSCC. Expression in tumor cells, stroma, and adjacent oral epithelium was characterized by using a visual grading system. COX-1, COX-2, and CD147 expression was determined in vitro by using OSCC cell lines (SCC25, BHY, and HN) and reverse transcriptase-quantitative polymerase chain reaction. Secretion of prostagladin E2 (PGE2) from OSCC cell lines was determined by using PGE2 enzyme-linked immunosorbent assay. RESULTS Biopsy specimens showed higher COX-2 expression in tumor cells compared with stroma and adjacent epithelium (P < .05). There was no difference in CD147 expression among the tumor cells, stroma, and adjacent epithelium. In OSCC cell lines, there was a trend for COX-2 and CD147 gene expression to be coordinated. Interestingly, PGE2 secretion was more closely related to COX-1 expression than to COX-2 expression. CONCLUSIONS COX-1, COX-2, and CD147 appear to be independently regulated in OSCC, potentially representing 2 therapeutic targets for future investigation. COX-1 expression in OSCC deserves further study because it may be an important determinant of PGE2 secretion from OSCC cells.
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Affiliation(s)
- Walaa Hamed Shaker Nasry
- Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada
| | - Haili Wang
- Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada
| | - Kathleen Jones
- Diagnostic Services, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada
| | - Marvin Tesch
- Provincial Health Services, Health PEI, Charlottetown, Prince Edward Island, Canada
| | - Juan Carlos Rodriguez-Lecompte
- Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada
| | - Chelsea K Martin
- Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada.
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30
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Nam GH, Jo KJ, Park YS, Kawk HW, Kim SY, Kim YM. In vitro and in vivo Induction of p53-Dependent Apoptosis by Extract of Euryale ferox Salisb in A549 Human Caucasian Lung Carcinoma Cancer Cells Is Mediated Through Akt Signaling Pathway. Front Oncol 2019; 9:406. [PMID: 31192119 PMCID: PMC6540844 DOI: 10.3389/fonc.2019.00406] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 04/30/2019] [Indexed: 12/21/2022] Open
Abstract
Lung cancer is one of the leading causes of death, and mortality rates have steadily been increasing. Recently, several studies were conducted to develop novel, physiologically active compounds from medicinal plant extracts. Several plant-derived extracts and molecules regulate and inhibit signaling molecules associated with the growth and proliferation of cancer cells. Euryale ferox salisb is a medicinal plant that is effective against different types of cancers. In this study, we investigated the apoptotic effects of E. ferox salisb extract (ESE) in A549 lung cancer cells, exerted by the inhibition of the Akt protein and activation of the p53 protein. Our results show that ESE induces apoptosis via the regulation of mitochondrial outer membrane potential and generation of reactive oxygen species (ROS). We demonstrate that apoptosis is induced in a p53-dependent manner when cells are treated with pifithrin-α (a p53 inhibitor) and LY294002 (an Akt inhibitor). The apoptotic effects from ESE were observed in vivo in Balb/c-nu mice bearing A549 xenografts. Altogether, these results suggest that E. ferox salisb extracts exert anti-cancer effects in a p53-dependent manner.
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Affiliation(s)
- Gun-He Nam
- Department of Biological Science and Biotechnology, College of Life Science and Nano Technology, Hannam University, Daejeon, South Korea
| | - Kyung-Jo Jo
- Department of Biological Science and Biotechnology, College of Life Science and Nano Technology, Hannam University, Daejeon, South Korea
| | - Ye-Seul Park
- Department of Biological Science and Biotechnology, College of Life Science and Nano Technology, Hannam University, Daejeon, South Korea
| | - Hye Won Kawk
- Department of Biological Science and Biotechnology, College of Life Science and Nano Technology, Hannam University, Daejeon, South Korea
| | - Sang-Yong Kim
- Department of Food Science and Bio Technology, Shinansan University, Ansan, South Korea
| | - Young-Min Kim
- Department of Biological Science and Biotechnology, College of Life Science and Nano Technology, Hannam University, Daejeon, South Korea
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31
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Xiong R, He D, Deng X, Liu J, Lei X, Xie Z, Cao X, Chen Y, Peng J, Tang G. Design, synthesis and biological evaluation of tryptamine salicylic acid derivatives as potential antitumor agents. MEDCHEMCOMM 2019; 10:573-583. [PMID: 31057737 PMCID: PMC6482410 DOI: 10.1039/c8md00484f] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 01/05/2019] [Indexed: 12/21/2022]
Abstract
A series of tryptamine salicylic acid derivatives were synthesized and their antiproliferative activity against MGC-803, MCF-7, HepG2, A549 and HeLa cell lines was evaluated. The structure-activity relationship (SAR) study revealed that different substitutions of the C5 and C3'-C5' positions have certain effects on the anti-proliferation activity. The growth assay revealed that N-[2-(5-bromo-1H-indol-3-yl)-ethyl]-2-hydroxy-3-methyl-benzamide (E20) showed the most potent and broad-spectrum anticancer inhibition of all the cell lines evaluated, and was only more potent than 5-Fu for the gastric cancer cell line. Preliminary studies indicated that compound E20 could inhibit colony formation and migration of MGC-803 cells. The flow cytometry (FCM) results showed that compound E20 arrested the cell cycle in the G2/M phase and induced apoptosis of MGC-803 cells in a concentration-dependent manner. In addition, the western blot results showed that E20 can down-regulate the expression of hexokinase 2. Our studies suggest that the framework of N-[2-(5-bromo-1H-indol-3-yl)-ethyl]-2-hydroxy-3-methyl-benzamide may be consider as a new type of chemical for designing effective anti-cancer drugs targeting gastric cancer cells.
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Affiliation(s)
- Runde Xiong
- Institute of Pharmacy and Pharmacology , Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study , University of South China , Hengyang , China .
| | - Dongxiu He
- Institute of Pharmacy and Pharmacology , Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study , University of South China , Hengyang , China .
| | - Xiangping Deng
- Institute of Pharmacy and Pharmacology , Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study , University of South China , Hengyang , China .
| | - Juan Liu
- Institute of Pharmacy and Pharmacology , Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study , University of South China , Hengyang , China .
| | - Xiaoyong Lei
- Institute of Pharmacy and Pharmacology , Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study , University of South China , Hengyang , China .
| | - Zhizhong Xie
- Institute of Pharmacy and Pharmacology , Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study , University of South China , Hengyang , China .
| | - Xuan Cao
- Institute of Pharmacy and Pharmacology , Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study , University of South China , Hengyang , China .
| | | | - Junmei Peng
- Institute of Pharmacy and Pharmacology , Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study , University of South China , Hengyang , China .
| | - Guotao Tang
- Institute of Pharmacy and Pharmacology , Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study , University of South China , Hengyang , China .
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32
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A cold-water soluble polysaccharide isolated from Grifola frondosa induces the apoptosis of HepG2 cells through mitochondrial passway. Int J Biol Macromol 2019; 125:1232-1241. [DOI: 10.1016/j.ijbiomac.2018.09.098] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 09/14/2018] [Accepted: 09/16/2018] [Indexed: 12/21/2022]
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33
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Xu L, Lu Y, Cong Y, Zhang P, Han J, Song G, Wang G, Chen K. Polysaccharide produced by Bacillus subtilis using burdock oligofructose as carbon source. Carbohydr Polym 2019; 206:811-819. [DOI: 10.1016/j.carbpol.2018.11.062] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Revised: 11/10/2018] [Accepted: 11/19/2018] [Indexed: 12/21/2022]
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34
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Veettil SK, Nathisuwan S, Ching SM, Jinatongthai P, Lim KG, Kew ST, Chaiyakunapruk N. Efficacy and safety of celecoxib on the incidence of recurrent colorectal adenomas: a systematic review and meta-analysis. Cancer Manag Res 2019; 11:561-571. [PMID: 30666154 PMCID: PMC6331068 DOI: 10.2147/cmar.s180261] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Celecoxib has previously been shown to be effective in reducing recurrent colorectal adenomas, but its long-term effects are unknown. In addition, safety issues are of major concern. Therefore, we examined the efficacy and safety of celecoxib as a chemopreventive agent along with its posttreatment effect. METHODS We performed a meta-analysis based on a systematic review of randomized controlled trials (RCTs) comparing celecoxib at various doses (400 mg once daily, 200 mg twice daily, and 400 mg twice daily) vs placebo in persons with history of colorectal adenomas. Several databases were searched from inception up to April 2018. Long-term follow-ups of RCTs were also included to evaluate posttreatment effect. Primary outcome was the incidence of recurrent colorectal adenomas. Various safety outcomes were evaluated, especially cardiovascular (CV) events. Risk-benefit integrated analyses were also performed. RESULTS A total of three RCTs (4,420 patients) and three post-trial studies (2,159 patients) were included in the analysis. Use of celecoxib at any dose for 1-3 years significantly reduced the incidence of recurrent advanced adenomas (risk ratio, 0.42 [95% CI, 0.34-0.53]) and any adenomas (0.67 [95% CI, 0.62-0.72]) compared with placebo. Subgroup analysis on different dosing suggested a greater effect with 400 mg twice daily. However, celecoxib 400 mg twice daily significantly increased the risk of serious adverse (1.2 [95% CI, 1.0-1.5]) and CV events (3.42 [95% CI, 1.56-7.46]), while celecoxib at 400 mg/day, especially with once daily dosing, did not increase CV risk (1.01 [95% CI, 0.70-1.46]). Analysis of post-trial studies indicated that the treatment effect disappeared (1.15 [95% CI, 0.88-1.49]) after discontinuing celecoxib for >2 years. CONCLUSION Celecoxib 400 mg once daily dosing could potentially be considered as a viable chemopreventive option in patients with high risk of adenomas but with low CV risk. Long-term trials on celecoxib at a dose of ≤400 mg either once or twice daily are warranted.
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Affiliation(s)
- Sajesh K Veettil
- Department of Pharmacy Practice, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Surakit Nathisuwan
- Clinical Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand,
| | - Siew Mooi Ching
- Department of Family Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
- Malaysian Research Institute on Ageing, Universiti Putra Malaysia, Serdang, Malaysia
- Department of Medical Sciences, School of Healthcare and Medical Sciences, Sunway University, Selangor, Malaysia
| | - Peerawat Jinatongthai
- Division of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani, Thailand
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia,
| | - Kean Ghee Lim
- Department of Surgery, Clinical School, International Medical University, Seremban, Malaysia
| | - Siang Tong Kew
- Department of Internal Medicine, School of Medicine, International Medical University, Kuala Lumpur, Malaysia
| | - Nathorn Chaiyakunapruk
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia,
- Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Center of Pharmaceutical Outcomes Research, Naresuan University, Phitsanulok, Thailand,
- School of Pharmacy, University of Wisconsin, Madison, WI, USA,
- Asian Centre for Evidence Synthesis in Population, Implementation and Clinical Outcomes (PICO), Health and Well-being Cluster, Global Asia in the 21st Century (GA21) Platform, Monash University Malaysia, Selangor, Malaysia,
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35
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Jyothish Kumar L, Sarveswari S, Vijayakumar V. DMFDMA catalyzed synthesis of 2-((Dimethylamino)methylene)-3,4-dihydro-9-arylacridin-1(2H)-ones and their derivatives: in-vitro antifungal, antibacterial and antioxidant evaluations. OPEN CHEM 2018. [DOI: 10.1515/chem-2018-0110] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
AbstractA series of 3,4-dihydro-9-arylacridin-1(2H)-ones was synthesized and enaminone function was introduced at the C-2 position using DMFDMA catalyst which in turn successfully converted into pyrazole, isoxazol, 1-phenyl-1H-pyrazole by treating it with reagents such as hydrazine, hydroxylamine and phenylhydrazine. These newly synthesized compounds were evaluated for their antibacterial activity against a series of Gram-Positive bacteria including Staphylococcusaureus, Bacilluscereus, StaphylococcusaureusMLS16 and Gram-Negative bacteria including Klebsiellaplanticol, Escherichiacoliand Pseudomonasaeruginosaand also against fungal strains including Candidaalbicans, Candidaparapsilosis, Candidaglabrata, Candidaaaseri, Aspergillusnigerand Issatchenkiahanoiensis. The compounds3aand6aexhibited considerable antifungal activity (MIC value 0.007 and 0.006 μM) against Candidaalbicansand Aspergillusnigerrespectively. The compound4ashowed excellent antibacterial activity towards EscherichiaColi(MIC = 0.003 μM) and the compound5afound to show prominent DPPH radical scavenging activity with EC50value 16.85±1.5μg mL−1.
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Affiliation(s)
- L. Jyothish Kumar
- Centre for Organic and Medicinal Chemistry, School of Advanced Sciences, VIT University, Vellore-632014, Tamil Nadu, India
| | - S. Sarveswari
- Centre for Organic and Medicinal Chemistry, School of Advanced Sciences, VIT University, Vellore-632014, Tamil Nadu, India
| | - V. Vijayakumar
- Centre for Organic and Medicinal Chemistry, School of Advanced Sciences, VIT University, Vellore-632014, Tamil Nadu, India
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El-Azab AS, Abdel-Aziz AAM, Abou-Zeid LA, El-Husseiny WM, El Morsy AM, El-Gendy MA, El-Sayed MAA. Synthesis, antitumour activities and molecular docking of thiocarboxylic acid ester-based NSAID scaffolds: COX-2 inhibition and mechanistic studies. J Enzyme Inhib Med Chem 2018; 33:989-998. [PMID: 29806488 PMCID: PMC6009944 DOI: 10.1080/14756366.2018.1474878] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
A new series of NSAID thioesters were synthesized and evaluated for their in vitro antitumor effects against a panel of four human tumor cell lines, namely: HepG2, MCF-7, HCT-116 and Caco-2, using the MTT assay. Compared to the reference drugs 5-FU, afatinib and celecoxib, compounds 2b, 3b, 6a, 7a, 7b and 8a showed potent broad-spectrum antitumor activity against the selected tumour cell lines. Accordingly, these compounds were selected for mechanistic studies about COX inhibition and kinase assays. In vitro COX-1/COX-2 enzyme inhibition assay results indicated that compounds 2b, 3b, 6a, 7a, 7b, 8a and 8 b selectively inhibited the COX-2 enzyme (IC50 = ∼0.20–0.69 μM), with SI values of (>72.5–250) compared with celecoxib (IC50 = 0.16 μM, COX-2 SI: > 312.5); however, all the tested compounds did not inhibit the COX-1 enzyme (IC50 > 50 μM). On the other hand, EGFR, HER2, HER4 and cSrc kinase inhibition assays were evaluated at a 10 μM concentration. The selected candidates displayed limited activities against the various tested kinases; the compounds 2a, 3b, 6a, 7a, 7b and 8a showed no activity to weak activity (% inhibition = ∼0–10%). The molecular docking study revealed the importance of the thioester moiety for the interaction of the drugs with the amino acids in the active sites of COX-2. The aforementioned results indicated that thioester based on NSAID scaffolds derivatives may serve as new antitumor compounds.
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Affiliation(s)
- Adel S El-Azab
- a Department of Pharmaceutical Chemistry, College of Pharmacy , King Saud University , Riyadh , Saudi Arabia.,b Department of Organic Chemistry, Faculty of Pharmacy , Al-Azhar University , Cairo , Egypt
| | - Alaa A-M Abdel-Aziz
- a Department of Pharmaceutical Chemistry, College of Pharmacy , King Saud University , Riyadh , Saudi Arabia.,c Department of Medicinal Chemistry, Faculty of Pharmacy , Mansoura University , Mansoura , Egypt
| | - Laila A Abou-Zeid
- d Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy , Mansoura University , Mansoura , Egypt
| | - Walaa M El-Husseiny
- d Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy , Mansoura University , Mansoura , Egypt
| | - Ahmad M El Morsy
- b Department of Organic Chemistry, Faculty of Pharmacy , Al-Azhar University , Cairo , Egypt
| | - Manal A El-Gendy
- a Department of Pharmaceutical Chemistry, College of Pharmacy , King Saud University , Riyadh , Saudi Arabia
| | - Magda A-A El-Sayed
- d Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy , Mansoura University , Mansoura , Egypt.,e Department of Pharmaceutical Chemistry, Faculty of pharmacy , Horus university , New Damietta , Egypt
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Mathew B, Snowden TS, Connelly MC, Guy RK, Reynolds RC. A small diversity library of α-methyl amide analogs of sulindac for probing anticancer structure-activity relationships. Bioorg Med Chem Lett 2018; 28:2136-2142. [PMID: 29776741 DOI: 10.1016/j.bmcl.2018.05.023] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 05/06/2018] [Accepted: 05/09/2018] [Indexed: 12/21/2022]
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) have a variety of potential indications that include management of pain and inflammation as well as chemoprevention and/or treatment of cancer. Furthermore, a specific form of ibuprofen, dexibuprofen or the S-(+) form, shows interesting neurological activities and has been proposed for the treatment of Alzheimer's disease. In a continuation of our work probing the anticancer activity of small sulindac libraries, we have prepared and screened a small diversity library of α-methyl substituted sulindac amides in the profen class. Several compounds of this series displayed promising activity compared with a lead sulindac analog.
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Affiliation(s)
- Bini Mathew
- Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA
| | - Timothy S Snowden
- Department of Chemistry and Biochemistry, The University of Alabama, 250 Hackberry Lane, Tuscaloosa, AL 35487, USA
| | - Michele C Connelly
- Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mailstop 1000, Memphis, TN 38105-3678, USA
| | - R Kiplin Guy
- The University of Kentucky College of Pharmacy, 214H BioPharm Complex, Lexington, KY 40536-0596, USA
| | - Robert C Reynolds
- Division of Hematology and Oncology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
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Abstract
Aim: Experimental and epidemiological studies and clinical trials suggest that nonsteroidal anti-inflammatory drugs possess antitumor potential. Sulindac, a widely used nonsteroidal anti-inflammatory drug, can prevent adenomatous colorectal polyps and colon cancer, especially in patients with familial adenomatous polyposis. Sulindac sulfide amide (SSA) is an amide-linked sulindac sulfide analog that showed in vivo antitumor activity in a human colon tumor xenograft model. Results/methodology: A new analog series with heterocyclic rings such as oxazole or thiazole at the C-2 position of sulindac was prepared and screened against prostate, colon and breast cancer cell lines to probe the effect of these novel substitutions on the activity of sulindac analogs. Conclusion: In general, replacement of the amide function of SSA analogs had a negative impact on the cell lines tested. A small number of hits incorporating rigid oxazole or thiazole groups in the sulindac scaffold in place of the amide linkage show comparable activity to our lead agent SSA.
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Hao W, Shen Y, Feng M, Wang H, Lin M, Fang Y, Tan L. Aspirin acts in esophageal cancer: a brief review. J Thorac Dis 2018; 10:2490-2497. [PMID: 29850157 DOI: 10.21037/jtd.2018.03.110] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Improved survival in esophageal cancer patients with regular aspirin use have been reported. However, with conflicting experimental results existed, an explicit definition on the role of aspirin as an adjuvant chemotherapy of esophageal cancer remains unestablished. We have summarized the current epidemiologic trials evidence over antitumor effect of aspirin in esophageal cancer in the past decades, and most of the clinical data supports that long-term regular aspirin use could reduce the mortality and improve the survival in patients with esophageal cancer. Although most of the clinical trials of aspirin on esophageal cancer are designed focusing on the prediagnosed chemo-preventive role, other than the post-diagnosed therapeutic role, it has been suggested by some studies that aspirin use as an adjuvant treatment after the standard surgery in esophageal cancer may benefit more. In the meanwhile, post diagnosed aspirin use may lead to lower risk of hemorrhage and other side effects of NSAIDs. Potential involved molecular pathways in the antitumor activities of aspirin are under studied worldwide for years and the possible mechanisms so far are reviewed in this article as cyclooxygenase (COX)-dependent pathways and COX-independent pathways, involving anti-inflammatory activity, apoptosis, platelet deactivation, PIK3CA mutation specificity and heparanase-related microenvironment changes of tumor cells. NOSH-aspirin has been developed as a succedaneum of aspirin with a wider application ranges by reducing the risk of hemorrhage in aspirin users. Further clinical and basic studies are suggested focusing on whether regular aspirin use as an adjuvant treatment prolongs survival and prevents recurrence in patients with esophageal cancer.
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Affiliation(s)
- Weiming Hao
- Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Yaxing Shen
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Mingxiang Feng
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Hao Wang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Miao Lin
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yong Fang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Lijie Tan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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Gao J, Mfuh A, Amako Y, Woo CM. Small Molecule Interactome Mapping by Photoaffinity Labeling Reveals Binding Site Hotspots for the NSAIDs. J Am Chem Soc 2018. [PMID: 29543447 DOI: 10.1021/jacs.7b11639] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Jinxu Gao
- Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford St., Cambridge, Massachusetts 02138, United States
| | - Adelphe Mfuh
- Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford St., Cambridge, Massachusetts 02138, United States
| | - Yuka Amako
- Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford St., Cambridge, Massachusetts 02138, United States
| | - Christina M. Woo
- Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford St., Cambridge, Massachusetts 02138, United States
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Mathew B, Hobrath JV, Connelly MC, Guy RK, Reynolds RC. Amine Containing Analogs of Sulindac for Cancer Prevention. THE OPEN MEDICINAL CHEMISTRY JOURNAL 2018; 12:1-12. [PMID: 29492166 PMCID: PMC5817852 DOI: 10.2174/1874104501812010001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 01/17/2018] [Accepted: 01/21/2018] [Indexed: 11/22/2022]
Abstract
Background: Sulindac belongs to the chemically diverse family of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) that effectively prevent adenomatous colorectal polyps and colon cancer, especially in patients with familial adenomatous polyposis. Sulindac sulfide amide (SSA), an amide analog of sulindac sulfide, shows insignificant COX-related activity and toxicity while enhancing anticancer activity in vitro and demonstrating in vivo xenograft activity. Objective: Develop structure-activity relationships in the sulindac amine series and identify analogs with promising anticancer activities. Method: A series of sulindac amine analogs were designed and synthesized and then further modified in a “libraries from libraries” approach to produce amide, sulfonamide and N,N-disubstituted sulindac amine sub-libraries. All analogs were screened against three cancer cell lines (prostate, colon and breast). Results: Several active compounds were identified viain vitro cancer cell line screening with the most potent compound (26) in the nanomolar range. Conclusion: Compound 26 and analogs showing the most potent inhibitory activity may be considered for further design and optimization efforts as anticancer hit scaffolds.
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Affiliation(s)
- Bini Mathew
- Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA
| | - Judith V Hobrath
- Drug Discovery Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom
| | - Michele C Connelly
- Department of Chemical Biology & Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Mailstop 1000, Memphis, TN 38105-3678, USA
| | - R Kiplin Guy
- The University of Kentucky College of Pharmacy, 214H BioPharm Complex, Lexington, KY 40536-0596, USA
| | - Robert C Reynolds
- Division of Hematology and Oncology, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
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Celecoxib inhibits proliferation and survival of chronic myelogeous leukemia (CML) cells via AMPK-dependent regulation of β-catenin and mTORC1/2. Oncotarget 2018; 7:81555-81570. [PMID: 27835591 PMCID: PMC5348412 DOI: 10.18632/oncotarget.13146] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 10/19/2016] [Indexed: 12/21/2022] Open
Abstract
CML is effectively treated with tyrosine kinase inhibitors (TKIs). However, the efficacy of these drugs is confined to the chronic phase of the disease and development of resistance to TKIs remains a pressing issue. The anti-inflammatory COX2 inhibitor celecoxib has been utilized as anti-tumour drug due to its anti-proliferative activity. However, its effects in hematological malignancies, in particular CML, have not been investigated yet. Thus, we tested biological effects and mechanisms of action of celecoxib in Philadelphia-positive (Ph+) CML and ALL cells. We show here that celecoxib suppresses the growth of Ph+ cell lines by increasing G1-phase and apoptotic cells and reducing S- and G2-phase cells. These effects were independent of COX2 inhibition but required the rapid activation of AMP-activated protein kinase (AMPK) and the consequent inhibition mTORC1 and 2. Treatment with celecoxib also restored GSK3β function and led to down-regulation of β-catenin activity through transcriptional and post-translational mechanisms, two effects likely to contribute to Ph+ cell growth suppression by celecoxib. Celecoxib inhibited colony formation of TKI-resistant Ph+ cell lines including those with the T315I BCR-ABL mutation and acted synergistically with imatinib in suppressing colony formation of TKI-sensitive Ph+ cell lines. Finally, it suppressed colony formation of CD34+ cells from CML patients, while sparing most CD34+ progenitors from healthy donors, and induced apoptosis of primary Ph+ ALL cells. Together, these findings indicate that celecoxib may serve as a COX2-independent lead compound to simultaneously target the mTOR and β-catenin pathways, key players in the resistance of CML stem cells to TKIs.
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Wang Y, Du C, Zhang N, Li M, Liu Y, Zhao M, Wang F, Luo F. TGF-β1 mediates the effects of aspirin on colonic tumor cell proliferation and apoptosis. Oncol Lett 2018; 15:5903-5909. [PMID: 29552221 DOI: 10.3892/ol.2018.8047] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 03/23/2017] [Indexed: 02/05/2023] Open
Abstract
Previous studies have demonstrated that aspirin serves an important role in chemoprevention and the suppression of colorectal cancer (CRC); however, the underlying mechanisms for this inhibition by aspirin remain unclear. Aspirin is capable of promoting apoptosis through prostaglandin-dependent orprostaglandin-independent signaling pathways. In the prostaglandin-dependent pathways, inhibition of cyclooxygenase (COX), particularly COX-2, is the primary mechanism known to be involved in aspirin-induced CRC suppression. Previous studies have implicated prostaglandin-independent signaling pathways and certain associated proteins, including SOX7, in aspirin-induced CRC suppression. In the present study, a newly-characterized association between aspirin, transforming growth factor (TGF)-β1 and CRC inhibition was identified. Specifically, aspirin triggers CRC cell apoptosis by inducing the secretion of TGF-β1, and the increased TGF-β1 then leads to apoptosis and proliferation inhibition in CRC cells.
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Affiliation(s)
- Yuyi Wang
- Department of Medical Oncology, Lung Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Chi Du
- Department of Medical Oncology, Lung Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China.,Department of Oncology, The Second People's Hospital of Neijiang, Neijiang, Sichuan 641000, P.R. China
| | - Nan Zhang
- Department of Medical Oncology, Lung Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Mei Li
- Department of Medical Oncology, Lung Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yanyang Liu
- Department of Medical Oncology, Lung Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Maoyuan Zhao
- Department of Medical Oncology, Lung Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Feng Wang
- Department of Medical Oncology, Lung Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Feng Luo
- Department of Medical Oncology, Lung Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
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Shrimp JH, Garlick JM, Tezil T, Sorum AW, Worth AJ, Blair IA, Verdin E, Snyder NW, Meier JL. Defining Metabolic and Nonmetabolic Regulation of Histone Acetylation by NSAID Chemotypes. Mol Pharm 2017; 15:729-736. [PMID: 29240439 DOI: 10.1021/acs.molpharmaceut.7b00943] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are well-known for their effects on inflammatory gene expression. Although NSAIDs are known to impact multiple cellular signaling mechanisms, a recent finding is that the NSAID salicylate can disrupt histone acetylation, in part through direct inhibition of the lysine acetyltransferase (KAT) p300/CBP. While salicylate is a relatively weak KAT inhibitor, its CoA-linked metabolite is more potent; however, the ability of NSAID metabolites to inhibit KAT enzymes biochemically and in cells remains relatively unexplored. Here we define the role of metabolic and nonmetabolic mechanisms in inhibition of KAT activity by NSAID chemotypes. First, we screen a small panel of NSAIDs for biochemical inhibition of the prototypical KAT p300, leading to the finding that many carboxylate-containing NSAIDs, including ibuprofen, are able to function as weak inhibitors. Assessing the inhibition of p300 by ibuprofen-CoA, a known NSAID metabolite, reveals that linkage of ibuprofen to CoA increases its biochemical potency toward p300 and other KAT enzymes. In cellular studies, we find that carboxylate-containing NSAIDs inhibit histone acetylation. Finally, we exploit the stereoselective metabolism of ibuprofen to assess the role of its acyl-CoA metabolite in regulation of histone acetylation. This unique strategy reveals that formation of ibuprofen-CoA and histone acetylation are poorly correlated, suggesting metabolism may not be required for ibuprofen to inhibit histone acetylation. Overall, these studies provide new insights into the ability of NSAIDs to alter histone acetylation, and illustrate how selective metabolism may be leveraged as a tool to explore the influence of metabolic acyl-CoAs on cellular enzyme activity.
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Affiliation(s)
- Jonathan H Shrimp
- Chemical Biology Laboratory , National Cancer Institute , Frederick , Maryland 21702 , United States
| | - Julie M Garlick
- Chemical Biology Laboratory , National Cancer Institute , Frederick , Maryland 21702 , United States
| | - Tugsan Tezil
- Buck Institute for Research on Aging, Novato , California 94945 , United States
| | - Alexander W Sorum
- Chemical Biology Laboratory , National Cancer Institute , Frederick , Maryland 21702 , United States
| | - Andrew J Worth
- Penn SRP Center, Center of Excellence in Environmental Toxicology , University of Pennsylvania , Philadelphia Pennsylvania 19104 , United States
| | - Ian A Blair
- Penn SRP Center, Center of Excellence in Environmental Toxicology , University of Pennsylvania , Philadelphia Pennsylvania 19104 , United States
| | - Eric Verdin
- Buck Institute for Research on Aging, Novato , California 94945 , United States
| | - Nathaniel W Snyder
- Drexel University, A.J. Drexel Autism Institute , 3020 Market Street , Philadelphia Pennsylvania 19104 , United States
| | - Jordan L Meier
- Chemical Biology Laboratory , National Cancer Institute , Frederick , Maryland 21702 , United States
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45
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Veettil SK, Lim KG, Ching SM, Saokaew S, Phisalprapa P, Chaiyakunapruk N. Effects of aspirin and non-aspirin nonsteroidal anti-inflammatory drugs on the incidence of recurrent colorectal adenomas: a systematic review with meta-analysis and trial sequential analysis of randomized clinical trials. BMC Cancer 2017; 17:763. [PMID: 29137605 PMCID: PMC5686945 DOI: 10.1186/s12885-017-3757-8] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 11/06/2017] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Beneficial effects of aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) against recurrent colorectal adenomas have been documented in systematic reviews; however, the results have not been conclusive. Uncertainty remains about the appropriate dose of aspirin for adenoma prevention. The persistence of the protective effect of NSAIDs against recurrent adenomas after treatment cessation is yet to be established. METHODS Our objective was to update and systematically evaluate the evidence for aspirin and other NSAIDs on the incidence of recurrent colorectal adenomas taking into consideration the risks of random error and to appraise the quality of evidence using GRADE (The Grading of Recommendations, Assessment, Development and Evaluation) approach. Retrieved trials were evaluated using Cochrane risk of bias instrument. Meta-analytic estimates were calculated with random-effects model and random errors were evaluated with trial sequential analysis (TSA). RESULTS In patients with a previous history of colorectal cancer or adenomas, low-dose aspirin (80-160 mg/day) compared to placebo taken for 2 to 4 years reduces the risk of recurrent colorectal adenomas (relative risk (RR), 0.80 [95% CI (confidence interval), 0.70-0.92]). TSA indicated a firm evidence for this beneficial effect. The evidence indicated moderate GRADE quality. Low-dose aspirin also reduces the recurrence of advanced adenomas (RR, 0.66 [95% CI, 0.44-0.99]); however, TSA indicated lack of firm evidence for a beneficial effect. High-dose aspirin (300-325 mg/day) did not statistically reduce the recurrent adenomas (RR, 0.90 [95% CI, 0.68-1.18]). Cyclooxygenase-2 (COX-2) inhibitors (e.g. celecoxib 400 mg/day) were associated with a significant decrease in the recurrence of both adenomas (RR, 0.66 [95% CI, 0.59-0.72]) and advanced adenomas (RR, 0.45 [95% CI, 0.33-0.57]); however, this association did not persist and there was a trend of an increased risk of recurrent adenomas observed 2 years after the withdrawal. CONCLUSION Our findings confirm the beneficial effect of low-dose aspirin on recurrence of any adenomas; however, effect on advanced adenomas was inconclusive. COX-2 inhibitors seem to be more effective in preventing recurrence of adenomas; however, there was a trend of an increased risk of recurrence of adenomas observed after discontinuing regular use.
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Affiliation(s)
- Sajesh K Veettil
- School of Pharmacy/School of Postgraduate Studies, International Medical University, Kuala Lumpur, Malaysia
| | - Kean Ghee Lim
- Clinical School, Department of Surgery, International Medical University, Seremban, Negeri Sembilan, Malaysia
| | - Siew Mooi Ching
- Department of Family Medicine, Faculty of Medicine and Health Sciences, Serdang, Malaysia.,Malaysian Research Institute on Ageing, Universiti Putra Malaysia, Serdang, Malaysia
| | - Surasak Saokaew
- Center of Health Outcomes Research and Therapeutic Safety (Cohorts), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand.,School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, 46150, Bandar Sunway, Selangor, Malaysia.,Center of Pharmaceutical Outcomes Research, Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Naresuan University, Phitsanulok, Thailand.,Unit of Excellence on Herbal Medicine, School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
| | - Pochamana Phisalprapa
- Division of Ambulatory Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Nathorn Chaiyakunapruk
- School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, 46150, Bandar Sunway, Selangor, Malaysia. .,Center of Pharmaceutical Outcomes Research, Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Naresuan University, Phitsanulok, Thailand. .,School of Pharmacy, University of Wisconsin, Madison, USA. .,Asian Centre for Evidence Synthesis in Population, Implementation and Clinical Outcomes (PICO), Health and Well-being Cluster, Global Asia in the 21st Century (GA21) Platform, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia.
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Ong SM, Saeki K, Kok MK, Tanaka Y, Choisunirachon N, Yoshitake R, Nishimura R, Nakagawa T. Anti-tumour efficacy of etoposide alone and in combination with piroxicam against canine osteosarcoma in a xenograft model. Res Vet Sci 2017; 113:130-135. [PMID: 28957780 DOI: 10.1016/j.rvsc.2017.09.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 09/14/2017] [Accepted: 09/16/2017] [Indexed: 12/21/2022]
Abstract
Osteosarcoma (OSA) in dogs is locally invasive and highly malignant. Distant metastasis is the most common cause of death. To date, the survival rate in dogs with OSA remains poor. The cytotoxic effects of etoposide against canine OSA cell lines, either alone or in combination with piroxicam, have been previously demonstrated in vitro. The aim of this study was to evaluate the anti-tumour effect of etoposide alone and in combination with piroxicam on canine OSA using murine models. Etoposide single agent treatment significantly delayed tumour progression with a marked reduction in Ki-67 immunoreactivity in tumour tissue. Concomitant treatment with piroxicam did not enhance the anti-tumour efficacy of etoposide. Etoposide single agent treatment and combination treatment with piroxicam down-regulated survivin expression, but was not followed by increased apoptotic activity. These findings indicate that etoposide might be a promising novel therapeutic for canine OSA. Further investigations into its potential for clinical application in veterinary oncology are warranted.
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Affiliation(s)
- S M Ong
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - K Saeki
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
| | - M K Kok
- Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Y Tanaka
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - N Choisunirachon
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
| | - R Yoshitake
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - R Nishimura
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
| | - T Nakagawa
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
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47
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Mathew B, Hobrath JV, Connelly MC, Kiplin Guy R, Reynolds RC. Diverse amide analogs of sulindac for cancer treatment and prevention. Bioorg Med Chem Lett 2017; 27:4614-4621. [PMID: 28935266 DOI: 10.1016/j.bmcl.2017.09.022] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 09/04/2017] [Accepted: 09/11/2017] [Indexed: 12/21/2022]
Abstract
Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that has shown significant anticancer activity. Sulindac sulfide amide (1) possessing greatly reduced COX-related inhibition relative to sulindac displayed in vivo antitumor activity that was comparable to sulindac in a human colon tumor xenograft model. Inspired by these observations, a panel of diverse sulindac amide derivatives have been synthesized and their activity probed against three cancer cell lines (prostate, colon and breast). A neutral analog, compound 79 was identified with comparable potency relative to lead 1 and activity against a panel of lymphoblastic leukemia cell lines. Several new series also show good activity relative to the parent (1), including five analogs that also possess nanomolar inhibitory potencies against acute lymphoblastic leukemia cells. Several new analogs identified may serve as anticancer lead candidates for further development.
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Affiliation(s)
- Bini Mathew
- Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA
| | - Judith V Hobrath
- Drug Discovery Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom
| | - Michele C Connelly
- Department of Chemical Biology & Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Mailstop 1000, Memphis, TN 38105-3678, USA
| | - R Kiplin Guy
- The University of Kentucky College of Pharmacy, 214H BioPharm Complex, Lexington, KY 40536-0596, USA
| | - Robert C Reynolds
- Division of Hematology and Oncology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
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48
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Mathew B, Hobrath JV, Lu W, Li Y, Reynolds RC. Synthesis and preliminary assessment of the anticancer and Wnt/β-catenin inhibitory activity of small amide libraries of fenamates and profens. Med Chem Res 2017; 26:3038-3045. [PMID: 29104411 PMCID: PMC5656725 DOI: 10.1007/s00044-017-2001-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 07/20/2017] [Indexed: 12/21/2022]
Abstract
As part of an ongoing program to study the anticancer activity of non-steroidal anti-inflammatory drugs (NSAIDs) through generating diversity libraries of multiple NSAID scaffolds, we synthesized a series of NSAID amide derivatives and screened these sets against three cancer cell lines (prostate, colon and breast) and Wnt/β-catenin signaling. The evaluated amide analog libraries show significant anticancer activity/cell proliferation inhibition, and specific members of the sets show inhibition of Wnt/β-catenin signaling.
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Affiliation(s)
- Bini Mathew
- Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205 USA
| | - Judith V. Hobrath
- Drug Discovery Unit, College of Life Sciences, University of Dundee, Dundee, DD1 5EH UK
| | - Wenyan Lu
- Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205 USA
| | - Yonghe Li
- Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205 USA
| | - Robert C. Reynolds
- Division of Hematology and Oncology, The University of Alabama at Birmingham, Birmingham, Alabama 35294 USA
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Song B, Shu ZB, Du J, Ren JC, Feng Y. Anti-cancer effect of low dose of celecoxib may be associated with lnc-SCD-1:13 and lnc-PTMS-1:3 but not COX-2 in NCI-N87 cells. Oncol Lett 2017; 14:1775-1779. [PMID: 28789408 PMCID: PMC5529947 DOI: 10.3892/ol.2017.6316] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2015] [Accepted: 02/23/2017] [Indexed: 12/21/2022] Open
Abstract
In order to investigate the mechanism of celecoxib and whether long non-coding RNAs (lncRNAs) were involved in the effects of celecoxib treatment in NCI-N87 cells, NCI-N87 cells were treated with 15, 30 and 60 µM celecoxib and an MTT assay was performed to assess cell viability. Following treatment with 15 µM celecoxib, the cell cycle and apoptosis were analyzed by flow cytometry, and the mRNA levels of lnc-SCD-1:13, lnc-PTMS-1:3, cyclooxygenase-2 (COX-2), integrin α3 (ITGA3) and DSH homolog 1 (DVL1) were detected by reverse transcription quantitative PCR (RT-qPCR) in NCI-N87 cells. MTT analysis demonstrated that celecoxib significantly inhibited cell viability in treated cells compared with untreated cells. Flow cytometry analysis revealed that, compared with untreated cells, the percentage of cells in the G0/G1 phase was significantly increased, and the percentage of cells in the S and G2 phase was decreased. In addition, the percentage of early and late apoptotic cells was increased in cells treated with 15 µM celecoxib compared with the control. RT-qPCR analysis also demonstrated that the mRNA levels of lnc-SCD-1:13, lnc-PTMS-1:3, ITGA3 and DVL1 were increased following treatment with celecoxib (15 µM; P<0.05). However, there were no significant differences in the expression of COX-2 mRNA between cells treated with celecoxib (15 µM) and untreated cells. The present study demonstrated that a low dose of celecoxib may be involved in regulating cell growth independent of COX-2 in NCI-N87 cells. Furthermore, ITGA3 and/or DVL1 co-expressed with lnc-SCD-1:13 and lnc-PTMS-1:3 may be associated with the effects of treatment with a low dose of celecoxib in NCI-N87 cells.
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Affiliation(s)
- Bin Song
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Zhen-Bo Shu
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Juan Du
- Internal Medicine 2, The Tumor Hospital of Jilin, Changchun, Jilin 130012, P.R. China
| | - Ji-Chen Ren
- Internal Medicine 2, The Tumor Hospital of Jilin, Changchun, Jilin 130012, P.R. China
| | - Ye Feng
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
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Catarro M, Serrano J, Cavalheiro E, Ramos S, Santos AO, Silvestre S, Almeida P. Novel 4-acetamide-2-alkylthio- N -acetanilides resembling nimesulide: Synthesis, cell viability evaluation and in silico studies. Bioorg Med Chem 2017; 25:4304-4313. [DOI: 10.1016/j.bmc.2017.06.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 05/31/2017] [Accepted: 06/08/2017] [Indexed: 12/11/2022]
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