|
1
|
Abou-Shanab AM, Gaser OA, Galal N, Mohamed A, Atta D, Kamar SS, Magdy S, Khedr MA, Elkhenany H, El-Badri N. PHD-2/HIF-1α axis mediates doxorubicin-induced angiogenesis in SH-SY5Y neuroblastoma microenvironment: a potential survival mechanism. Sci Rep 2025; 15:7487. [PMID: 40032892 DOI: 10.1038/s41598-025-89884-3] [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: 09/11/2024] [Accepted: 02/10/2025] [Indexed: 03/05/2025] Open
Abstract
The response of neuroblastoma (NB) cells to chemotherapeutics and their influence on NB microenvironment remain incompletely understood. Herein, we examined the underlying molecular mechanism via which Doxorubicin, a chemotherapeutic agent used for NB treatment, promotes proangiogenic response in the SH-SY5Y microenvironment. Doxorubicin treatment at 1 µg/ml reduced SH-SY5Y cell proliferation and primed the apoptosis pathway. Unexpectedly, SH-SY5Y cells treated with doxorubicin upregulated their expression of the pro-angiogenic factors, including vascular endothelial growth factor (VEGF), platelets-derived growth factor (PDGF), and matrix metalloprotease-2 (MMP-2) and secretion of nitric oxide. To assess the functional angiogenesis of SH-SY5Y cells pre-treated with doxorubicin, an indirect co-culture system with human umbilical vein endothelial cells (HUVEC) was established. These HUVECs acquired enhanced proliferation, migration capacity, and tube formation capability and exhibited increased nitric oxide (NO) production, in addition to upregulated α-smooth muscle actin expression, suggesting enhanced contractility. In-ovo studies of the neo-angiogenic response of SH-SY5Y pre-treated with doxorubicin further show their promoted neo-angiogenesis as indicated by the generated blood vessels and histological analysis of CD31 expression. Inhibition of PHD-2 could be a potential target for doxorubicin, as indicated by molecular docking, molecular dynamics (MD) simulation, and MM-GBSA calculations, leading to hypoxia-inducible factor-1 alpha (HIF-1α) stabilization. Bioinformatics analyses and enrichment analyses of RNA-seq data revealed activation of Pi3K pathway which is further validated in-vitro. These results provide evidence of the unexpected pro-angiogenic response of SH-SY5Y cells to doxorubicin treatment and suggest the potential use of multi-modal therapeutic regimens for a more comprehensive approach to NB treatment.
Collapse
Affiliation(s)
- Ahmed M Abou-Shanab
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Ola A Gaser
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Noha Galal
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Alaa Mohamed
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Dina Atta
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Samaa Samir Kamar
- Histology Department, Kasr Al-Ainy Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Shireen Magdy
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Mennatallah A Khedr
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Hoda Elkhenany
- Department of Surgery, Faculty of Veterinary Medicine, Alexandria University, Alexandria, 22785, Egypt
| | - Nagwa El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt.
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12578, Egypt.
| |
Collapse
|
|
2
|
Lu X, Lin W, Zheng J, Huang W, Yu S, Chen H, Wang H, Zhang Y. Sodium nitrite orchestrates macrophage mimicry of tongue squamous carcinoma cells to drive lymphatic metastasis. Br J Cancer 2025; 132:340-353. [PMID: 39799274 PMCID: PMC11833070 DOI: 10.1038/s41416-024-02923-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 11/21/2024] [Accepted: 11/28/2024] [Indexed: 01/15/2025] Open
Abstract
BACKGROUND Tongue squamous cell carcinoma (TSCC) is a malignant oral cancer with unclear pathogenesis that shows a tendency for early-stage lymphatic metastasis. This results in a poor prognosis, with a low 5-year survival rate. Dietary sodium nitrite (NaNO2) has proposed associations with disease, including cancer. However, a direct relationship between NaNO2 and TSCC has not been established. METHODS In vitro and in vivo assays were used to investigate the role of NaNO2 in TSCC. Protein expression in TSCC specimens was detected by immunohistochemistry and immunofluorescence. The molecular mechanism was determined using RT-qPCR, western blot, RNA-seq, luciferase reporter assays, migration assays, and FACS analysis. More detail of methods can be found in the Materials and methods section. RESULTS The data in this study showed that NaNO2 did not initiate carcinogenesis in the tongue but improved the lymphatic metastatic potential of TSCC cells in the specified experimental period. During metastasis to lymph nodes, monocyte-macrophage markers were upregulated in TSCC cells, whereas keratin markers were downregulated. Specifically, expression of the CD68 gene was high in TSCC cells following NaNO2-induced TSCC phenotypic switching. These phenotypic changes were associated with activation of transcription factor cyclic-AMP response binding protein (CREB1), which directly targets CD68 transcription. Furthermore, blocking CREB1 activity either through gene knockout or specific inhibitor treatment decreased the migration ability of TSCC cells and suppressed CD68 expression. CONCLUSIONS Our findings highlight the role of NaNO2 in enabling macrophage mimicry in TSCC cells through the CREB1-CD68 signaling pathway, which promotes lymphatic metastasis. Shedding light on drivers of lymphatic metastasis in TSCC and providing a new perspective on dietary strategies to improve outcomes of patients with TSCC.
Collapse
Affiliation(s)
- Xiangwan Lu
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Weifan Lin
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Junheng Zheng
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Wuheng Huang
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Shuyi Yu
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Haoxiang Chen
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Hua Wang
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, PR China.
| | - Yan Zhang
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, PR China.
| |
Collapse
|
|
3
|
Dos Reis RA, Sarkar I, Rodrigues MG, Matson JB, Seabra AB, Kashfi K. NO- and H 2S- releasing nanomaterials: A crosstalk signaling pathway in cancer. Nitric Oxide 2024; 151:17-30. [PMID: 39179197 PMCID: PMC11424202 DOI: 10.1016/j.niox.2024.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 08/13/2024] [Accepted: 08/16/2024] [Indexed: 08/26/2024]
Abstract
The gasotransmitters nitric oxide (NO) and hydrogen sulfide (H2S) play important roles not only in maintaining physiological functions, but also in pathological conditions and events. Importantly, these molecules show a complex interplay in cancer biology, demonstrating both tumor-promoting and anti-tumor activities depending on their concentration, flux, and the environmental redox state. Additionally, various cell types respond differently to NO and H2S. These gasotransmitters can be synergistically combined with traditional anticancer treatments such as radiotherapy, immunotherapy, chemotherapy, and phototherapy. Notably, NO, and more recently H2S, have been shown to reverse multidrug resistance. Nanomaterials to deliver NO donors and, to a lesser extent, H2S donors, have emerged as a promising approach for targeted delivery of these gasotransmitters. Nanotechnology has advanced the delivery of anticancer drugs, enhancing efficiency and reducing side effects on non-cancerous cells. This review highlights recent progress in the design of NO and H2S-releasing nanomaterials for anticancer effects. It also explores the interactions between NO and H2S, which are crucial for developing combined therapies and nanomedicines with minimal side effects.
Collapse
Affiliation(s)
- Roberta Albino Dos Reis
- Center for Natural and Human Sciences, Federal University of ABC, Santo André, 09210-580, SP, Brazil
| | - Ishani Sarkar
- Department of Chemistry, Virginia Tech Center for Drug Discovery, and Macromolecules Innovation Institute, Virginia Tech, Blacksburg, VA, 24061, USA
| | | | - John B Matson
- Department of Chemistry, Virginia Tech Center for Drug Discovery, and Macromolecules Innovation Institute, Virginia Tech, Blacksburg, VA, 24061, USA.
| | - Amedea Barozzi Seabra
- Center for Natural and Human Sciences, Federal University of ABC, Santo André, 09210-580, SP, Brazil
| | - 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, 10091, USA.
| |
Collapse
|
|
4
|
Feng Y, Feng X, Wan R, Luo Z, Qu L, Wang Q. Impact of exercise on cancer: mechanistic perspectives and new insights. Front Immunol 2024; 15:1474770. [PMID: 39346906 PMCID: PMC11427289 DOI: 10.3389/fimmu.2024.1474770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 08/28/2024] [Indexed: 10/01/2024] Open
Abstract
This review critically evaluates the substantial role of exercise in enhancing cancer prevention, treatment, and patient quality of life. It conclusively demonstrates that regular physical activity not only reduces cancer risk but also significantly mitigates side effects of cancer therapies. The key findings include notable improvements in fatigue management, reduction of cachexia symptoms, and enhancement of cognitive functions. Importantly, the review elucidates the profound impact of exercise on tumor behavior, modulation of immune responses, and optimization of metabolic pathways, advocating for the integration of exercise into standard oncological care protocols. This refined abstract encourages further exploration and application of exercise as a pivotal element of cancer management.
Collapse
Affiliation(s)
- Ye Feng
- School of Stomatology, Xuzhou Medical University, Xuzhou,
Jiangsu, China
| | - Xingting Feng
- Department of Sports Medicine, Huashan Hospital, Fudan University,
Shanghai, China
| | - Renwen Wan
- Department of Sports Medicine, Huashan Hospital, Fudan University,
Shanghai, China
| | - Zhiwen Luo
- Department of Sports Medicine, Huashan Hospital, Fudan University,
Shanghai, China
| | - Lijun Qu
- Department of Orthopaedics, Kunshan Hospital of Chinese Medicine,
Kunshan, Jiangsu, China
| | - Qing Wang
- Department of Orthopaedics, Kunshan Hospital of Chinese Medicine,
Kunshan, Jiangsu, China
| |
Collapse
|
|
5
|
Da J, Di X, Xie Y, Li J, Zhang L, Liu Y. Recent advances in nanomedicine for metabolism-targeted cancer therapy. Chem Commun (Camb) 2024; 60:2442-2461. [PMID: 38321983 DOI: 10.1039/d3cc05858a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2024]
Abstract
Metabolism denotes the sum of biochemical reactions that maintain cellular function. Different from most normal differentiated cells, cancer cells adopt altered metabolic pathways to support malignant properties. Typically, almost all cancer cells need a large number of proteins, lipids, nucleotides, and energy in the form of ATP to support rapid division. Therefore, targeting tumour metabolism has been suggested as a generic and effective therapy strategy. With the rapid development of nanotechnology, nanomedicine promises to have a revolutionary impact on clinical cancer therapy due to many merits such as targeting, improved bioavailability, controllable drug release, and potentially personalized treatment compared to conventional drugs. This review comprehensively elucidates recent advances of nanomedicine in targeting important metabolites such as glucose, glutamine, lactate, cholesterol, and nucleotide for effective cancer therapy. Furthermore, the challenges and future development in this area are also discussed.
Collapse
Affiliation(s)
- Jun Da
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China.
| | - XinJia Di
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China.
| | - YuQi Xie
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China.
| | - JiLi Li
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China.
| | - LiLi Zhang
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China.
| | - YanLan Liu
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China.
| |
Collapse
|
|
6
|
Yalaz C, Bridges E, Alham NK, Zois CE, Chen J, Bensaad K, Miar A, Pires E, Muschel RJ, McCullagh JSO, Harris AL. Cone photoreceptor phosphodiesterase PDE6H inhibition regulates cancer cell growth and metabolism, replicating the dark retina response. Cancer Metab 2024; 12:5. [PMID: 38350962 PMCID: PMC10863171 DOI: 10.1186/s40170-023-00326-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 11/24/2023] [Indexed: 02/15/2024] Open
Abstract
BACKGROUND PDE6H encodes PDE6γ', the inhibitory subunit of the cGMP-specific phosphodiesterase 6 in cone photoreceptors. Inhibition of PDE6, which has been widely studied for its role in light transduction, increases cGMP levels. The purpose of this study is to characterise the role of PDE6H in cancer cell growth. METHODS From an siRNA screen for 487 genes involved in metabolism, PDE6H was identified as a controller of cell cycle progression in HCT116 cells. Role of PDE6H in cancer cell growth and metabolism was studied through the effects of its depletion on levels of cell cycle controllers, mTOR effectors, metabolite levels, and metabolic energy assays. Effect of PDE6H deletion on tumour growth was also studied in a xenograft model. RESULTS PDE6H knockout resulted in an increase of intracellular cGMP levels, as well as changes to the levels of nucleotides and key energy metabolism intermediates. PDE6H knockdown induced G1 cell cycle arrest and cell death and reduced mTORC1 signalling in cancer cell lines. Both knockdown and knockout of PDE6H resulted in the suppression of mitochondrial function. HCT116 xenografts revealed that PDE6H deletion, as well as treatment with the PDE5/6 inhibitor sildenafil, slowed down tumour growth and improved survival, while sildenafil treatment did not have an additive effect on slowing the growth of PDE6γ'-deficient tumours. CONCLUSIONS Our results indicate that the changes in cGMP and purine pools, as well as mitochondrial function which is observed upon PDE6γ' depletion, are independent of the PKG pathway. We show that in HCT116, PDE6H deletion replicates many effects of the dark retina response and identify PDE6H as a new target in preventing cancer cell proliferation and tumour growth.
Collapse
Affiliation(s)
- Ceren Yalaz
- Molecular Oncology Laboratories, Department of Medical Oncology, John Radcliffe Hospital, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
| | - Esther Bridges
- Molecular Oncology Laboratories, Department of Medical Oncology, John Radcliffe Hospital, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
| | - Nasullah K Alham
- Department of Engineering Science, Institute of Biomedical Engineering (IBME), University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK
| | - Christos E Zois
- Molecular Oncology Laboratories, Department of Medical Oncology, John Radcliffe Hospital, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
| | - Jianzhou Chen
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK
| | - Karim Bensaad
- Molecular Oncology Laboratories, Department of Medical Oncology, John Radcliffe Hospital, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
| | - Ana Miar
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK
| | - Elisabete Pires
- Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
| | - Ruth J Muschel
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK
| | - James S O McCullagh
- Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
| | - Adrian L Harris
- Molecular Oncology Laboratories, Department of Medical Oncology, John Radcliffe Hospital, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
| |
Collapse
|
|
7
|
Oza PP, Kashfi K. The Triple Crown: NO, CO, and H 2S in cancer cell biology. Pharmacol Ther 2023; 249:108502. [PMID: 37517510 PMCID: PMC10529678 DOI: 10.1016/j.pharmthera.2023.108502] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 07/16/2023] [Accepted: 07/19/2023] [Indexed: 08/01/2023]
Abstract
Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) are three endogenously produced gases with important functions in the vasculature, immune defense, and inflammation. It is increasingly apparent that, far from working in isolation, these three exert many effects by modulating each other's activity. Each gas is produced by three enzymes, which have some tissue specificities and can also be non-enzymatically produced by redox reactions of various substrates. Both NO and CO share similar properties, such as activating soluble guanylate cyclase (sGC) to increase cyclic guanosine monophosphate (cGMP) levels. At the same time, H2S both inhibits phosphodiesterase 5A (PDE5A), an enzyme that metabolizes sGC and exerts redox regulation on sGC. The role of NO, CO, and H2S in the setting of cancer has been quite perplexing, as there is evidence for both tumor-promoting and pro-inflammatory effects and anti-tumor and anti-inflammatory activities. Each gasotransmitter has been found to have dual effects on different aspects of cancer biology, including cancer cell proliferation and apoptosis, invasion and metastasis, angiogenesis, and immunomodulation. These seemingly contradictory actions may relate to each gas having a dual effect dependent on its local flux. In this review, we discuss the major roles of NO, CO, and H2S in the context of cancer, with an effort to highlight the dual nature of each gas in different events occurring during cancer progression.
Collapse
Affiliation(s)
- Palak P Oza
- 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 10091, USA.
| |
Collapse
|
|
8
|
Li X, Ke Y, Hernandez AL, Yu J, Bian L, Hall SC, Nolan K, Wang JH, Young CD, Wang XJ. Inducible nitric oxide synthase (iNOS)-activated Cxcr2 signaling in myeloid cells promotes TGFβ-dependent squamous cell carcinoma lung metastasis. Cancer Lett 2023; 570:216330. [PMID: 37524225 PMCID: PMC10530117 DOI: 10.1016/j.canlet.2023.216330] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 07/17/2023] [Accepted: 07/28/2023] [Indexed: 08/02/2023]
Abstract
Transforming growth factor beta (TGFβ) activity is linked to metastasis in many cancer types, but whether TGFβ activity is necessary for squamous cell carcinoma (SCC) lung metastasis has not been studied. Here we used a lung metastatic SCC model derived from keratin 15 (K15). KrasG12D.Smad4-/- SCC and human SCC specimens to identify metastasis drivers and test therapeutic interventions. We demonstrated that a TGFβ receptor (TGFβR) inhibitor reduced lung metastasis in mouse SCC correlating with reduced CD11b+/Ly6G+ myeloid cells positive for inducible nitric oxide synthase (iNOS). Further, TGFβ activity and iNOS were higher in primary human oral SCCs with metastasis than SCCs without metastasis. Consistently, either depleting myeloid cells with anti-Gr1 antibody or inhibiting iNOS with L-N6-(1-iminoethyl)-l-lysine (L-NIL) reduced SCC lung metastasis. L-NIL treated tumor-bearing mice exhibited reductions in tumor-infiltrating myeloid cells and in plasma Cxcl5 levels, and attenuated primary tumor growth with increased apoptosis and decreased proliferation. Blocking Cxcl5 with an antagonist of its receptor Cxcr2, SB225002, also reduced SCC lung metastasis.
Collapse
Affiliation(s)
- Xing Li
- Hospital of Stomatology, Jilin University, Changchun, 130021, PR China; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Yao Ke
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Ariel L Hernandez
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Jingjing Yu
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Li Bian
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Spencer C Hall
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Kyle Nolan
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Jing H Wang
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA; UPMC Hillman Cancer Center, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Christian D Young
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
| | - Xiao-Jing Wang
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA; Department of Pathology & Laboratory Medicine, University of California Davis, Sacramento, CA, 95817, USA.
| |
Collapse
|
|
9
|
Shereef HA, Moemen YS, Elshami FI, El-Nahas AM, Shaban SY, van Eldik R. DNA Binding and Cleavage, Stopped-Flow Kinetic, Mechanistic, and Molecular Docking Studies of Cationic Ruthenium(II) Nitrosyl Complexes Containing “NS4” Core. Molecules 2023; 28:molecules28073028. [PMID: 37049792 PMCID: PMC10095794 DOI: 10.3390/molecules28073028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 03/24/2023] [Accepted: 03/24/2023] [Indexed: 03/31/2023] Open
Abstract
This work aimed to evaluate in vitro DNA binding mechanistically of cationic nitrosyl ruthenium complex [RuNOTSP]+ and its ligand (TSPH2) in detail, correlate the findings with cleavage activity, and draw conclusions about the impact of the metal center. Theoretical studies were performed for [RuNOTSP]+, TSPH2, and its anion TSP−2 using DFT/B3LYP theory to calculate optimized energy, binding energy, and chemical reactivity. Since nearly all medications function by attaching to a particular protein or DNA, the in vitro calf thymus DNA (ctDNA) binding studies of [RuNOTSP]+ and TSPH2 with ctDNA were examined mechanistically using a variety of biophysical techniques. Fluorescence experiments showed that both compounds effectively bind to ctDNA through intercalative/electrostatic interactions via the DNA helix’s phosphate backbone. The intrinsic binding constants (Kb), (2.4 ± 0.2) × 105 M−1 ([RuNOTSP]+) and (1.9 ± 0.3) × 105 M−1 (TSPH2), as well as the enhancement dynamic constants (KD), (3.3 ± 0.3) × 104 M−1 ([RuNOTSP]+) and (2.6 ± 0.2) × 104 M−1 (TSPH2), reveal that [RuNOTSP]+ has a greater binding propensity for DNA compared to TSPH2. Stopped-flow investigations showed that both [RuNOTSP]+ and TSPH2 bind through two reversible steps: a fast second-order binding, followed by a slow first-order isomerization reaction via a static quenching mechanism. For the first and second steps of [RuNOTSP]+ and TSPH2, the detailed binding parameters were established. The total binding constants for [RuNOTSP]+ (Ka = 43.7 M−1, Kd = 2.3 × 10−2 M−1, ΔG0 = −36.6 kJ mol−1) and TSPH2 (Ka = 15.1 M−1, Kd = 66 × 10−2 M, ΔG0 = −19 kJ mol−1) revealed that the relative reactivity is approximately ([RuNOTSP]+)/(TSPH2) = 3/1. The significantly negative ΔG0 values are consistent with a spontaneous binding reaction to both [RuNOTSP]+ and TSPH2, with the former being very favorable. The findings showed that the Ru(II) center had an effect on the reaction rate but not on the mechanism and that the cationic [RuNOTSP]+ was a more highly effective DNA binder than the ligand TSPH2 via strong electrostatic interaction with the phosphate end of DNA. Because of its higher DNA binding affinity, cationic [RuNOTSP]+ demonstrated higher cleavage efficiency towards the minor groove of pBR322 DNA via the hydrolytic pathway than TSPH2, revealing the synergy effect of TSPH2 in the form of the complex. Furthermore, the mode of interaction of both compounds with ctDNA has also been supported by molecular docking.
Collapse
Affiliation(s)
- Hadeer A. Shereef
- Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Kom 32512, Egypt
- Clinical Pathology Department, University Hospital, Menoufia University, Shebin El-Kom 32512, Egypt
| | - Yasmine S. Moemen
- Clinical Pathology Department, National Liver Institute, Menoufia University, Shebin El-Kom 32512, Egypt
| | - Fawzia I. Elshami
- Chemistry Department, Faculty of Science, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Ahmed M. El-Nahas
- Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Kom 32512, Egypt
| | - Shaban Y. Shaban
- Chemistry Department, Faculty of Science, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
- Correspondence: (S.Y.S.); (R.v.E.)
| | - Rudi van Eldik
- Department of Chemistry and Pharmacy, University of Erlangen-Nuremberg, 91058 Erlangen, Germany
- Faculty of Chemistry, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
- Correspondence: (S.Y.S.); (R.v.E.)
| |
Collapse
|
|
10
|
Arnau Del Valle C, Thomas P, Galindo F, Muñoz MP, Marín MJ. Gold nanoparticle-based two-photon fluorescent nanoprobe for monitoring intracellular nitric oxide levels. J Mater Chem B 2023; 11:3387-3396. [PMID: 36919860 DOI: 10.1039/d3tb00103b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
Abstract
Nitric oxide (NO) plays an important role in the regulation of the immune, cardiovascular and nervous systems. Consequently, being able to monitor and quantify intracellular NO levels would provide a greater understanding of the implications of this molecule in the different biological processes, including, for example, in cancer. Here, we report a broadly applicable two-photon excitable fluorescent nanoprobe able to detect and potentially quantify NO levels in an extensive range of cellular environments. The nanoprobe consists of a thiolated photoinduced electron transfer-based two=photon fluorescent probe attached onto the surface of 2.4 ± 0.7 nm gold nanoparticles (DANPY-NO@AuNPs). The nanoprobe, which can be synthesised in a reproducible manner and exhibits great stability when stored at room temperature, is able to selectively detect NO in solution, with a dynamic range up to 150 μM, and at pH values of biological relevance. DANPY-NO@AuNPs were able to selectively detect endogenous NO in RAW264.7γ NO- macrophages and THP-1 human leukemic cells; and endogenous and exogenous NO in endothelial cells. The nanoprobe accumulated in the acidic organelles of the tested cell lines showing negligible toxicity. Importantly, DANPY-NO@AuNPs showed potential to quantify intracellular NO concentrations in MDA-MB-231 breast cancer cells. The biological evaluation of the nanoprobe was undertaken using confocal laser scanning (images and intracellular emission spectra) and multiphoton microscopies, and flow cytometry. Based on their excellent sensitivity and stability, and outstanding versatility, DANPY-NO@AuNPs can be applied for the spatiotemporal monitoring of in vitro and in vivo NO levels.
Collapse
Affiliation(s)
- Carla Arnau Del Valle
- School of Chemistry, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
| | - Paul Thomas
- Henry Wellcome Laboratory for Cell Imaging, Faculty of Science, University of East Anglia, Norwich Research Park, Norwich, NR4 7T, UK
| | - Francisco Galindo
- Departamento de Química Inorgánica y Orgánica, Universitat Jaume I, Av. Sos Baynat s/n, Castellón de la Plana, 12071, Spain
| | - María Paz Muñoz
- School of Chemistry, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK. .,Department of Chemistry, Lancaster University, Bailrigg, Lancaster, LA1 4YB, UK
| | - María J Marín
- School of Chemistry, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
| |
Collapse
|
|
11
|
Gao D, Asghar S, Hu R, Chen S, Niu R, Liu J, Chen Z, Xiao Y. Recent advances in diverse nanosystems for nitric oxide delivery in cancer therapy. Acta Pharm Sin B 2022; 13:1498-1521. [PMID: 37139410 PMCID: PMC10149905 DOI: 10.1016/j.apsb.2022.11.016] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 10/26/2022] [Accepted: 11/04/2022] [Indexed: 11/18/2022] Open
Abstract
Gas therapy has been proven to be a promising and advantageous treatment option for cancers. Studies have shown that nitric oxide (NO) is one of the smallest structurally significant gas molecules with great potential to suppress cancer. However, there is controversy and concern about its use as it exhibits the opposite physiological effects based on its levels in the tumor. Therefore, the anti-cancer mechanism of NO is the key to cancer treatment, and rationally designed NO delivery systems are crucial to the success of NO biomedical applications. This review summarizes the endogenous production of NO, its physiological mechanisms of action, the application of NO in cancer treatment, and nano-delivery systems for delivering NO donors. Moreover, it briefly reviews challenges in delivering NO from different nanoparticles and the issues associated with its combination treatment strategies. The advantages and challenges of various NO delivery platforms are recapitulated for possible transformation into clinical applications.
Collapse
Affiliation(s)
- Dan Gao
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Sajid Asghar
- Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad 38000, Pakistan
| | - Rongfeng Hu
- Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application, Hefei 230012, China
| | - Su Chen
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Ruixin Niu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Jia Liu
- Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangyin 214499, China
- Corresponding authors. Tel./fax: +86 510 86700000 (Jia Liu); +86 25 85811050 (Zhipeng Chen); +86 25 83271079 (Yanyu Xiao).
| | - Zhipeng Chen
- Department of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
- Corresponding authors. Tel./fax: +86 510 86700000 (Jia Liu); +86 25 85811050 (Zhipeng Chen); +86 25 83271079 (Yanyu Xiao).
| | - Yanyu Xiao
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
- Corresponding authors. Tel./fax: +86 510 86700000 (Jia Liu); +86 25 85811050 (Zhipeng Chen); +86 25 83271079 (Yanyu Xiao).
| |
Collapse
|
|
12
|
Liu H, Wang D, Yang Z, Li S, Wu H, Xiang J, Kan S, Hao M, Liu W. Regulation of epigenetic modifications in the head and neck tumour microenvironment. Front Immunol 2022; 13:1050982. [DOI: 10.3389/fimmu.2022.1050982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 10/14/2022] [Indexed: 12/24/2022] Open
Abstract
Head and neck tumours are common malignancies that are associated with high mortality. The low rate of early diagnosis and the high rates of local recurrence and distant metastasis are the main reasons for treatment failure. Recent studies have established that the tumour microenvironment (TME) can affect the proliferation and metastasis of head and neck tumours via several mechanisms, including altered expressions of certain genes and cytokines. Increasing evidence has shown that epigenetic modifications, such as DNA methylation, histone modification, RNA modification, and non-coding RNAs, can regulate the head and neck TME and thereby influence tumour development. Epigenetic modifications can regulate the expression of different genes and subsequently alter the TME to affect the progression of head and neck tumours. In addition, the cell components in the TME are regulated by epigenetic modifications, which, in turn, affect the behaviour of head and neck tumour cells. In this review, we have discussed the functions of epigenetic modifications in the head and neck TME. We have further examined the roles of such modifications in the malignancy and metastasis of head and neck tumours.
Collapse
|
|
13
|
Rallis KS, Corrigan AE, Dadah H, Stanislovas J, Zamani P, Makker S, Szabados B, Sideris M. IL-10 in cancer: an essential thermostatic regulator between homeostatic immunity and inflammation - a comprehensive review. Future Oncol 2022; 18:3349-3365. [PMID: 36172856 DOI: 10.2217/fon-2022-0063] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Cytokines are soluble proteins that mediate intercellular signaling regulating immune and inflammatory responses. Cytokine modulation represents a promising cancer immunotherapy approach for immune-mediated tumor regression. However, redundancy in cytokine signaling and cytokines' pleiotropy, narrow therapeutic window, systemic toxicity, short half-life and limited efficacy represent outstanding challenges for cytokine-based cancer immunotherapies. Recently, there has been interest in the paradoxical role of IL-10 in cancer, its controversial prognostic utility and novel strategies to enhance its therapeutic profile. Here, the authors review the literature surrounding the role of IL-10 within the tumor microenvironment, its prognostic correlates to cancer patient outcomes and its pro- and antitumor effects, and they assess the legitimacy of potential therapeutic strategies harnessing IL-10 by outlining the notable preclinical and clinical evidence to date.
Collapse
Affiliation(s)
- Kathrine S Rallis
- Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, E1 2AD, UK.,Barts Cancer Institute, Queen Mary University of London, London, EC1M 5PZ, UK
| | - Amber E Corrigan
- GKT School of Medicine, King's College London, London, SE1 9RT, UK
| | - Hashim Dadah
- GKT School of Medicine, King's College London, London, SE1 9RT, UK
| | - Justas Stanislovas
- Barts Cancer Institute, Queen Mary University of London, London, EC1M 5PZ, UK
| | - Parisa Zamani
- GKT School of Medicine, King's College London, London, SE1 9RT, UK
| | - Shania Makker
- Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, E1 2AD, UK
| | - Bernadett Szabados
- Barts Cancer Institute, Queen Mary University of London, London, EC1M 5PZ, UK
| | - Michail Sideris
- Women's Health Research Unit, Queen Mary University of London, London, E1 2AB, UK
| |
Collapse
|
|
14
|
The Nitric Oxide Donor [Zn(PipNONO)Cl] Exhibits Antitumor Activity through Inhibition of Epithelial and Endothelial Mesenchymal Transitions. Cancers (Basel) 2022; 14:cancers14174240. [PMID: 36077778 PMCID: PMC9454450 DOI: 10.3390/cancers14174240] [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: 08/02/2022] [Revised: 08/27/2022] [Accepted: 08/28/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Nitric oxide (NO) plays a critical pathophysiological role in cancer by modulating several processes, such as angiogenesis, tumor growth, and metastatic potential. The aim of this study was to characterize the antitumor effects of a novel NO donor, [Zn(PipNONO)Cl], on the processes of epithelial– and endothelial–mesenchymal transitions (EMT and EndMT), known to actively participate in cancer progression. Two tumor cells lines were used in this study: human lung cancer cells (A549) and melanoma cells (A375), alone and co-cultured with human endothelial cells. Our results demonstrate that both tumor and endothelial cells were targets of NO action, which impaired EMT and EndMT functional and molecular features. Further studies are needed to finalize the therapeutic use of the novel NO donor. Abstract Exogenous nitric oxide appears a promising therapeutic approach to control cancer progression. Previously, a nickel-based nonoate, [Ni(SalPipNONO)], inhibited lung cancer cells, along with impairment of angiogenesis. The Zn(II) containing derivatives [Zn(PipNONO)Cl] exhibited a protective effect on vascular endothelium. Here, we have evaluated the antitumor properties of [Zn(PipNONO)Cl] in human lung cancer (A549) and melanoma (A375) cells. Metastasis initiates with the epithelial–mesenchymal transition (EMT) process, consisting of the acquisition of invasive and migratory properties by tumor cells. At not cytotoxic levels, the nonoate significantly impaired A549 and A375 EMT induced by transforming growth factor-β1 (TGF-β1). Reduction of the mesenchymal marker vimentin, upregulated by TGF-β1, and restoration of the epithelial marker E-cadherin, reduced by TGF-β1, were detected in both tumor cell lines in the presence of Zn-nonoate. Further, the endothelial–mesenchymal transition achieved in a tumor-endothelial cell co-culture was assessed. Endothelial cells co-cultured with A549 or A375 acquired a mesenchymal phenotype with increased vimentin, alpha smooth muscle actin and Smad2/3, and reduced VE-cadherin. The presence of [Zn(PipNONO)Cl] maintained a typical endothelial phenotype. In conclusion, [Zn(PipNONO)Cl] appears a promising therapeutic tool to control tumor growth and metastasis, by acting on both tumor and endothelial cells, reprogramming the cells toward their physiologic phenotypes.
Collapse
|
|
15
|
Doman AJ, Tommasi S, Perkins MV, McKinnon RA, Mangoni AA, Nair PC. Chemical similarities and differences among inhibitors of nitric oxide synthase, arginase and dimethylarginine dimethylaminohydrolase-1: implications for the design of novel enzyme inhibitors modulating the nitric oxide pathway. Bioorg Med Chem 2022; 72:116970. [DOI: 10.1016/j.bmc.2022.116970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 08/01/2022] [Accepted: 08/18/2022] [Indexed: 11/02/2022]
|
|
16
|
Exercise in cancer prevention and anticancer therapy: Efficacy, molecular mechanisms and clinical information. Cancer Lett 2022; 544:215814. [DOI: 10.1016/j.canlet.2022.215814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/30/2022] [Accepted: 06/30/2022] [Indexed: 11/20/2022]
|
|
17
|
Salihi A, Al-Naqshabandi MA, Khudhur ZO, Housein Z, Hama HA, Abdullah RM, Hussen BM, Alkasalias T. Gasotransmitters in the tumor microenvironment: Impacts on cancer chemotherapy (Review). Mol Med Rep 2022; 26:233. [PMID: 35616143 PMCID: PMC9178674 DOI: 10.3892/mmr.2022.12749] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 04/07/2022] [Indexed: 11/23/2022] Open
Abstract
Nitric oxide, carbon monoxide and hydrogen sulfide are three endogenous gasotransmitters that serve a role in regulating normal and pathological cellular activities. They can stimulate or inhibit cancer cell proliferation and invasion, as well as interfere with cancer cell responses to drug treatments. Understanding the molecular pathways governing the interactions between these gases and the tumor microenvironment can be utilized for the identification of a novel technique to disrupt cancer cell interactions and may contribute to the conception of effective and safe cancer therapy strategies. The present review discusses the effects of these gases in modulating the action of chemotherapies, as well as prospective pharmacological and therapeutic interfering approaches. A deeper knowledge of the mechanisms that underpin the cellular and pharmacological effects, as well as interactions, of each of the three gases could pave the way for therapeutic treatments and translational research.
Collapse
Affiliation(s)
- Abbas Salihi
- Department of Biology, College of Science, Salahaddin University-Erbil, Erbil, Kurdistan Region 44001, Iraq
- Center of Research and Strategic Studies, Lebanese French University, Erbil, Kurdistan Region 44002, Iraq
- Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum, Karolinska Institutet, SE-17165 Stockholm, Sweden
| | - Mohammed A. Al-Naqshabandi
- Department of Clinical Biochemistry, College of Health Sciences, Hawler Medical University, Erbil, Kurdistan Region 44001, Iraq
| | - Zhikal Omar Khudhur
- Department of Medical Analysis, Faculty of Applied Science, Tishk International University, Erbil, Kurdistan Region 44001, Iraq
| | - Zjwan Housein
- Department of Medical Laboratory Technology, Technical Health and Medical College, Erbil Polytechnique University, Erbil, Kurdistan Region 44002, Iraq
| | - Harmand A. Hama
- Department of Biology, Faculty of Education, Tishk International University, Erbil, Kurdistan Region 44002, Iraq
| | - Ramyar M. Abdullah
- College of Medicine, Hawler Medical University, Erbil, Kurdistan Region 44002, Iraq
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan Region 44002, Iraq
| | - Twana Alkasalias
- General Directorate of Scientific Research Center, Salahaddin University-Erbil, Erbil, Kurdistan Region 44002, Iraq
- Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, SE-17176 Stockholm, Sweden
| |
Collapse
|
|
18
|
Chu LY, Huang BL, Huang XC, Peng YH, Xie JJ, Xu YW. EFNA1 in gastrointestinal cancer: Expression, regulation and clinical significance. World J Gastrointest Oncol 2022; 14:973-988. [PMID: 35646281 PMCID: PMC9124989 DOI: 10.4251/wjgo.v14.i5.973] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 09/17/2021] [Accepted: 04/04/2022] [Indexed: 02/06/2023] Open
Abstract
Ephrin-A1 is a protein that in humans is encoded by the EFNA1 gene. The ephrins and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases which play an indispensable role in normal growth and development or in the pathophysiology of various tumors. The role of EFNA1 in tumorigenesis and development is complex and depends on the cell type and microenvironment which in turn affect the expression of EFNA1. This article reviews the expression, prognostic value, regulation and clinical significance of EFNA1 in gastrointestinal tumors.
Collapse
Affiliation(s)
- Ling-Yu Chu
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Bin-Liang Huang
- Department of Clinical Laboratory Medicine, The Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Xu-Chun Huang
- Department of Clinical Laboratory Medicine, The Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yu-Hui Peng
- Department of Clinical Laboratory Medicine, The Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Guangdong Esophageal Cancer Research Institute, The Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jian-Jun Xie
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yi-Wei Xu
- Department of Clinical Laboratory Medicine, The Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Guangdong Esophageal Cancer Research Institute, The Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| |
Collapse
|
|
19
|
Pavlova NN, Zhu J, Thompson CB. The hallmarks of cancer metabolism: Still emerging. Cell Metab 2022; 34:355-377. [PMID: 35123658 PMCID: PMC8891094 DOI: 10.1016/j.cmet.2022.01.007] [Citation(s) in RCA: 651] [Impact Index Per Article: 217.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 01/13/2022] [Accepted: 01/19/2022] [Indexed: 12/14/2022]
Abstract
Metabolism of cancer cells is geared toward biomass production and proliferation. Since the metabolic resources within the local tissue are finite, this can lead to nutrient depletion and accumulation of metabolic waste. To maintain growth in these conditions, cancer cells employ a variety of metabolic adaptations, the nature of which is collectively determined by the physiology of their cell of origin, the identity of transforming lesions, and the tissue in which cancer cells reside. Furthermore, select metabolites not only serve as substrates for energy and biomass generation, but can also regulate gene and protein expression and influence the behavior of non-transformed cells in the tumor vicinity. As they grow and metastasize, tumors can also affect and be affected by the nutrient distribution within the body. In this hallmark update, recent advances are incorporated into a conceptual framework that may help guide further research efforts in exploring cancer cell metabolism.
Collapse
Affiliation(s)
- Natalya N Pavlova
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Jiajun Zhu
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China
| | - Craig B Thompson
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
| |
Collapse
|
|
20
|
Mesquita A, Matsuoka M, Lopes S, Pernambuco Filho P, Cruz A, Nader H, Lopes C. Nitric oxide regulates adhesiveness, invasiveness, and migration of anoikis-resistant endothelial cells. Braz J Med Biol Res 2022; 55:e11612. [PMID: 35137850 PMCID: PMC8851903 DOI: 10.1590/1414-431x2021e11612] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 11/29/2021] [Indexed: 12/14/2022] Open
Abstract
Anoikis is a type of apoptosis that occurs in response to the loss of adhesion to the extracellular matrix (ECM). Anoikis resistance is a critical mechanism in cancer and contributes to tumor metastasis. Nitric oxide (NO) is frequently upregulated in the tumor area and is considered an important player in cancer metastasis. The aim of this study was to evaluate the effect of NO on adhesiveness, invasiveness, and migration of anoikis-resistant endothelial cells. Here, we report that anoikis-resistant endothelial cells overexpress endothelial nitric oxide synthase. The inhibition of NO release in anoikis-resistant endothelial cells was able to decrease adhesiveness to fibronectin, laminin, and collagen IV. This was accompanied by an increase in cell invasiveness and migration. Furthermore, anoikis-resistant cell lines displayed a decrease in fibronectin and collagen IV protein expression after L-NAME treatment. These alterations in adhesiveness and invasiveness were the consequence of MMP-2 up-regulation observed after NO release inhibition. The decrease in NO levels was able to down-regulate the activating transcription factor 3 (ATF3) protein expression. ATF3 represses MMP-2 gene expression by antagonizing p53-dependent trans-activation of the MMP-2 promoter. We speculate that the increased release of NO by anoikis-resistant endothelial cells acted as a response to restrict the MMP-2 action, interfering in MMP-2 gene expression via ATF3 regulation. The up-regulation of nitric oxide by anoikis-resistant endothelial cells is an important response to restrict tumorigenic behavior. Without this mechanism, invasiveness and migration potential would be even higher, as shown after L-NAME treatment.
Collapse
Affiliation(s)
| | | | - S.A. Lopes
- Universidade Federal de São Paulo, Brasil
| | | | - A.S. Cruz
- Universidade Federal de São Paulo, Brasil
| | - H.B. Nader
- Universidade Federal de São Paulo, Brasil
| | - C.C. Lopes
- Universidade Federal de São Paulo, Brasil; Universidade Federal de São Paulo, Brasil
| |
Collapse
|
|
21
|
Pros and Cons of Pharmacological Manipulation of cGMP-PDEs in the Prevention and Treatment of Breast Cancer. Int J Mol Sci 2021; 23:ijms23010262. [PMID: 35008687 PMCID: PMC8745278 DOI: 10.3390/ijms23010262] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 12/24/2022] Open
Abstract
The cyclic nucleotides, cAMP and cGMP, are ubiquitous second messengers responsible for translating extracellular signals to intracellular biological responses in both normal and tumor cells. When these signals are aberrant or missing, cells may undergo neoplastic transformation or become resistant to chemotherapy. cGMP-hydrolyzing phosphodiesterases (PDEs) are attracting tremendous interest as drug targets for many diseases, including cancer, where they regulate cell growth, apoptosis and sensitization to radio- and chemotherapy. In breast cancer, PDE5 inhibition is associated with increased intracellular cGMP levels, which is responsible for the phosphorylation of PKG and other downstream molecules involved in cell proliferation or apoptosis. In this review, we provide an overview of the most relevant studies regarding the controversial role of PDE inhibitors as off-label adjuvants in cancer therapy.
Collapse
|
|
22
|
Exploring the Pivotal Neurophysiologic and Therapeutic Potentials of Vitamin C in Glioma. JOURNAL OF ONCOLOGY 2021. [PMID: 33598702 PMCID: PMC8691980 DOI: 10.1155/2021/6141591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Gliomas represent solely primary brain cancers of glial cell or neuroepithelial origin. Gliomas are still the most lethal human cancers despite modern innovations in both diagnostic techniques as well as therapeutic regimes. Gliomas have the lowest overall survival rate compared to other cancers 5 years after definitive diagnosis. The dietary intake of vitamin C has protective effect on glioma risk. Vitamin C is an essential compound that plays a vital role in the regulation of lysyl and prolyl hydroxylase activity. Neurons store high levels of vitamin C via sodium dependent-vitamin C transporters (SVCTs) to protect them from oxidative ischemia-reperfusion injury. Vitamin C is a water-soluble enzyme, typically seen as a powerful antioxidant in plants as well as animals. The key function of vitamin C is the inhibition of redox imbalance from reactive oxygen species produced via the stimulation of glutamate receptors. Gliomas absorb vitamin C primarily via its oxidized dehydroascorbate form by means of GLUT 1, 3, and 4 and its reduced form, ascorbate, by SVCT2. Vitamin C is able to preserve prosthetic metal ions like Fe2+ and Cu+ in their reduced forms in several enzymatic reactions as well as scavenge free radicals in order to safeguard tissues from oxidative damage. Therapeutic concentrations of vitamin C are able to trigger H2O2 generation in glioma. High-dose combination of vitamin C and radiation has a much more profound cytotoxic effect on primary glioblastoma multiforme cells compared to normal astrocytes. Control trials are needed to validate the use of vitamin C and standardization of the doses of vitamin C in the treatment of patients with glioma.
Collapse
|
|
23
|
Denaro N, Merlano MC, Lo Nigro C. Further Understanding of the Immune Microenvironment in Head and Neck Squamous Cell Carcinoma: Implications for Prognosis. Cancer Manag Res 2021; 13:3973-3980. [PMID: 34040438 PMCID: PMC8139676 DOI: 10.2147/cmar.s277907] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 04/15/2021] [Indexed: 12/11/2022] Open
Abstract
Purpose We aimed to review the literature on the tumor microenvironment as a key player in tumor growth and anti-cancer treatment responses in head and neck cancer. Patients and Methods We reviewed the recent literature on this topic, using the following research words: “tumor microenvironment” and “head and neck cancer or neoplasm or head and neck squamous cell carcinoma” and “immune cells” and “stromal cells”. A search was conducted on the PubMed website and reports from international meetings, presentations and abstracts. Results The tumor microenvironment is a complex network in which myeloid cells, tumoral cells, growth factors and cytokines are involved in angiogenesis, the extracellular matrix and epithelial-to-mesenchymal transition. Conclusion Immune resistance and rapid tumor growth depend on immunosuppressive and pro-tumoral environments. Further investigations to classify and adequately treat patients with head and neck cancer are required.
Collapse
Affiliation(s)
- Nerina Denaro
- Medical Oncology, S. Croce & Carle Teaching Hospital, Cuneo, Italy
| | | | - Cristiana Lo Nigro
- Medical Oncology, S. Croce & Carle Teaching Hospital, Cuneo, Italy.,Central Laboratory, Galliera Hospital, Genoa, Italy
| |
Collapse
|
|
24
|
AboYoussef AM, Khalaf MM, Malak MN, Hamzawy MA. Repurposing of sildenafil as antitumour; induction of cyclic guanosine monophosphate/protein kinase G pathway, caspase-dependent apoptosis and pivotal reduction of Nuclear factor kappa light chain enhancer of activated B cells in lung cancer. J Pharm Pharmacol 2021; 73:1080-1091. [PMID: 33856030 DOI: 10.1093/jpp/rgab049] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 02/23/2021] [Indexed: 12/20/2022]
Abstract
OBJECTIVES Lung cancer is one of the most frequent types of cancers that lead to death. Sildenafil is a potent inhibitor of phosphodiesterase-5 and showed potential anticancer effects, which has not yet been fully evaluated. Thus, this study aims to investigate the potential anticancer effect of sildenafil in urethane-induced lung cancer in BALB/c mice. METHODS Five-week-old male BALB/c mice were treated with either (i) normal saline only, (ii) sildenafil only 50 mg kg-1/ P.O every other day for the last four successive weeks, (iii) urethane 1.5 gm kg-1 i.p (at day 1 and day 60), (iv) carboplatin after urethane induction, or (v) sildenafil after urethane induction. KEY FINDINGS It was shown that sildenafil significantly increased the levels of cGMP and Caspase-3 with a reduction of NF-κB, Bcl-2, Cyclin D1, intercellular adhesion molecule 1, matrix metalloproteinase-2 levels and normalisation of Nrf2 along with pronounced improvement in the histological patterns. CONCLUSIONS These results indicated that sildenafil markedly induces cell cycle arrest, apoptosis and inhibits the metastatic activity through activation of cyclic guanosine monophosphate/protein kinase G pathway and down-regulation of cyclin D1 and nuclear factor kappa light chain enhancer of activated B cells with downstream anti-apoptotic gene Bcl-2, which underscores the critical importance of future using sildenafil in the treatment of lung cancer.
Collapse
Affiliation(s)
- Amira M AboYoussef
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Marwa M Khalaf
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Marina N Malak
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Mohamed A Hamzawy
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Fayoum University, Fayoum, Egypt
| |
Collapse
|
|
25
|
Chatterjee S, Sinha S, Molla S, Hembram KC, Kundu CN. PARP inhibitor Veliparib (ABT-888) enhances the anti-angiogenic potentiality of Curcumin through deregulation of NECTIN-4 in oral cancer: Role of nitric oxide (NO). Cell Signal 2021; 80:109902. [PMID: 33373686 DOI: 10.1016/j.cellsig.2020.109902] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 12/22/2020] [Accepted: 12/22/2020] [Indexed: 02/08/2023]
Abstract
Concurrent use of DNA damaging agents with PARP inhibitors contribute to the effectiveness of the anticancer therapy. But there is a dearth of reports on the antiangiogenic effects of PARP inhibitors and the suppression of angiogenesis by this drug combination is not yet reported. For the successful development of cancer therapeutics, anti-cancer drugs ought to have anti-angiogenic potentiality along with their DNA damaging abilities. In this current piece of work, we investigated the in vitro and in ovo anti-angiogenic effect of Curcumin and Veliparib (a PARP inhibitor) in oral cancer. Recent evidences suggest an involvement of the NECTIN-4 in cancer angiogenesis and the exact molecular pathway of this involvement remains to be delineated. We observed that the soluble NECTIN-4 secreted from H357 oral cancer cells enhanced the angiogenesis of endothelial cells (HUVECs) and this was inhibited by Curcumin-Veliparib combination. NECTIN-4 enhanced vascularization, induced vasodilation and triggered the angiogenic sprouting via endothelial tip cell filopodia. Data indicated that NECTIN-4 mediated angiogenesis is associated with PI3K-AKT-mediated nitric oxide (NO) formation. A noticeable increase in the NO enhanced epithelial NO level through HIF-1α mediated iNOS activation. We observed that increased NO enhanced the NECTIN-4 mediated eNOS expression and thereby elicited further angiogenesis. Curcumin antagonised the NECTIN-4-induced angiogenesis through inhibition of PI3K-AKT mediated eNOS pathway and Veliparib synergized the effect of Curcumin. Our observations indicate that NO is cardinal in inducing NECTIN-4 mediated angiogenesis in H357 cells. Thus, Curcumin-Veliparib combination suppresses angiogenesis through deregulation of the PI3K-AKT-eNOS pathway downstream to the NECTIN-4.
Collapse
Affiliation(s)
- Subhajit Chatterjee
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar 751024, Odisha, India
| | - Saptarshi Sinha
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar 751024, Odisha, India
| | - Sefinew Molla
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar 751024, Odisha, India
| | - Krushna Chandra Hembram
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar 751024, Odisha, India
| | - Chanakya Nath Kundu
- Cancer Biology Division, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Campus-11, Patia, Bhubaneswar 751024, Odisha, India.
| |
Collapse
|
|
26
|
Azencot M, Lewis BS, Halon DA. Relation between Baseline Coronary Atherosclerotic Status, Cardiovascular Events, and Malignancies in Type 2 Diabetics: A Long-Term Prospective Cohort Study. Cardiology 2021; 146:419-425. [PMID: 33774635 DOI: 10.1159/000514207] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 12/29/2020] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Coronary artery disease and malignancy occur more frequently in patients with type 2 diabetes. They may share inflammation as a possible common pathogenetic mechanism, but it is unclear whether a clinical correlation exists between them. METHODS This prospective cohort study followed 735 asymptomatic diabetics, aged 63.4 ± 5.3 years (mean ± standard deviation) for 12.2 ± 0.6 years after baseline coronary artery calcium scoring and cardiac computed tomography angiography. We examined extent and nature of coronary atherosclerosis and incidence of clinical cardiovascular (CV) events (death or myocardial infarction) and sought a relation to incidence of malignancy and malignancy mortality. RESULTS Total mortality was 16.5% (121/735 patients): malignancy was cause of death in 48/121 (39.7%) of these and CV events in 44/121 (36.3%). There was no relation between extent of coronary atherosclerosis and incident malignancy (plaque volume 127 [21, 427] mm3 (median [interquartile range]) for incident malignancy versus 153 [24, 427] mm3 no malignancy, p = 0.71) or death from malignancy (plaque volume 176 [26, 646] versus 144 [22, 411] mm3, p = 0.32). There was also no relation between presence of high-risk plaque and incident malignancy (high-risk plaque in 27.1% with malignancy vs. 21.6% without, p = 0.18) or fatal malignancy (p = 0.16). Incident and fatal malignancy were not related to clinical CV events. Independent predictors of incident and fatal malignancy were age, smoking at baseline, and elevated C-reactive protein. CONCLUSION This study found no relation between extent of coronary atherosclerosis or incidence of CV events and malignancy. Malignancy surpassed CV disease as the commonest long-term cause of mortality in middle-aged and older diabetics.
Collapse
Affiliation(s)
- Mali Azencot
- Cardiovascular Clinical Research Institute, Lady Davis Carmel Medical Center, Haifa, Israel
| | - Basil S Lewis
- Cardiovascular Clinical Research Institute, Lady Davis Carmel Medical Center, Haifa, Israel.,Technion-Israel Institute of Technology, Haifa, Israel
| | - David A Halon
- Cardiovascular Clinical Research Institute, Lady Davis Carmel Medical Center, Haifa, Israel.,Technion-Israel Institute of Technology, Haifa, Israel
| |
Collapse
|
|
27
|
Studying Angiogenesis in the Rabbit Corneal Pocket Assay. Methods Mol Biol 2021. [PMID: 32754813 DOI: 10.1007/978-1-0716-0916-3_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
Abstract
The rabbit corneal micropocket assay uses the avascular cornea as a substrate to study angiogenesis in vivo. The continuous monitoring of neovascular growth in the same animal allows for the evaluation of drugs acting as suppressors or stimulators of angiogenesis. Through the use of standardized slow-release pellets, a predictable angiogenic response can be quantified over the course of 1-2 weeks. Uniform slow-release pellets are prepared by mixing purified angiogenic growth factors such as basic fibroblast growth factor (FGF) or vascular endothelial growth factor (VEGF) and a synthetic polymer to allow for their slow release. A micropocket is surgically created in the cornea thickness under anesthesia and in sterile conditions. The angiogenesis stimulus (growth factor but also tissue fragment or cell suspension) is placed into the pocket in order to induce vascular outgrowth from the limbal capillaries where vessels are preexisting. On the following days, the neovascular development and progression are measured and qualified using a slit lamp, as well as the concomitant vascular phenotype or inflammatory features. The results of the assay allow to assess the ability of potential therapeutic molecules to modulate angiogenesis in vivo, both when released locally or given by ocular formulations or through systemic treatment. In this chapter the experimental details of the avascular rabbit cornea assay, the technical challenges, advantages, and limitations are discussed.
Collapse
|
|
28
|
Prajapati N, Karan A, Khezerlou E, DeCoster MA. The Immunomodulatory Potential of Copper and Silver Based Self-Assembled Metal Organic Biohybrids Nanomaterials in Cancer Theranostics. Front Chem 2021; 8:629835. [PMID: 33585405 PMCID: PMC7873042 DOI: 10.3389/fchem.2020.629835] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 12/22/2020] [Indexed: 11/18/2022] Open
Abstract
Copper high aspect ratio structures (CuHARS) and silver cystine nanoparticles (AgCysNPs) are two unique micro/nano particles under study here that show extensive anti-cancer effects on a glioma tumor cell line. These micro/nano particles have shown potent toxicity in the presence of inflammatory stimulus (combination of tumor necrosis factor, [TNF] and lipo-polysaccharide, LPS). CuHARS with a concentration of 20 μg/ml uniquely increased the catalytic generation of nitric oxide (NO), an important contributor in the immune system. This NO was generated in a cell culture tumor microenvironment (TME) in the presence of 25 µM S-nitrosothiol (cysteine-NO) and the inflammatory stimulus. CuHARS increased the NO production by 68.75% when compared to untreated glioma cells with CysNO and inflammatory stimulus. The production of NO was significantly higher under similar circumstances in the case of normal primary structural cells like brain microvascular endothelial cells (BMVECs). The production of NO by BMVECs went up by 181.25% compared to glioma cells. This significant increase in the NO concentration could have added up to tumorigenesis but the anti-cancer effect of CuHARS was prominent enough to lower down the viability of glioma cells by approximately 20% and increased the metabolism of structural cells, BMVECs by approximately 200%. The immunomodulatory effect of NO in the TME under these circumstances in the presence of the novel micro/nano material, CuHARS has risen up compared to the effect of inflammatory stimulus alone. The potency and specific nature of these materials toward tumor cells may make them suitable candidates for cancer treatment. Successive treatment of CuHARS to glioma cells also proved to be an effective approach considering the decrease in the total count of cells by 11.84 fold in case of three successive treatments compared to a single dose which only decreased the cell count by 2.45 fold showing the dose-dependent increasing toxicity toward glioma cells. AgCysNPs are another potent nanomaterial which also proved its significant toxic nature toward tumor cell lines as demonstrated here, but their immunomodulatory response is still unclear and needs to be explored further.
Collapse
Affiliation(s)
- Neela Prajapati
- Department of Biomedical Engineering, Louisiana Tech University, Ruston, LA, United States
| | - Anik Karan
- Department of Biomedical Engineering, Louisiana Tech University, Ruston, LA, United States
| | - Elnaz Khezerlou
- Department of Biomedical Engineering, Louisiana Tech University, Ruston, LA, United States
| | - Mark A DeCoster
- Department of Biomedical Engineering, Louisiana Tech University, Ruston, LA, United States.,Institute for Micromanufacturing, Louisiana Tech University, Ruston, LA, United States
| |
Collapse
|
|
29
|
Ikeda A, Nagayama S, Sumazaki M, Konishi M, Fujii R, Saichi N, Muraoka S, Saigusa D, Shimada H, Sakai Y, Ueda K. Colorectal Cancer-Derived CAT1-Positive Extracellular Vesicles Alter Nitric Oxide Metabolism in Endothelial Cells and Promote Angiogenesis. Mol Cancer Res 2021; 19:834-846. [PMID: 33579815 DOI: 10.1158/1541-7786.mcr-20-0827] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 12/11/2020] [Accepted: 02/08/2021] [Indexed: 12/24/2022]
Abstract
Accumulating scientific evidences strongly support the importance of cancer-derived extracellular vesicles (EV) in organization of tumor microenvironment and metastatic niches, which are also considered as ideal tools for cancer liquid biopsy. To uncover the full scope of proteomic information packaged within EVs secreted directly from human colorectal cancer, we cultured surgically resected viable tissues and obtained tissue-exudative EVs (Te-EV). Our quantitative profiling of 6,307 Te-EV proteins and 8,565 tissue proteins from primary colorectal cancer and adjacent normal mucosa (n = 17) allowed identification of a specific cargo in colorectal cancer-derived Te-EVs, high-affinity cationic amino acid transporter 1 (CAT1, P = 5.0 × 10-3, fold change = 6.2), in addition to discovery of a new class of EV markers, VPS family proteins. The EV sandwich ELISA confirmed escalation of the EV-CAT1 level in plasma from patients with colorectal cancer compared with healthy donors (n = 119, P = 3.8 × 10-7). Further metabolomic analysis revealed that CAT1-overexpressed EVs drastically enhanced vascular endothelial cell growth and tubule formation via upregulation of arginine transport and downstream NO metabolic pathway. These findings demonstrate the potency of CAT1 as an EV-based biomarker for colorectal cancer and its functional significance on tumor angiogenesis. IMPLICATIONS: This study provides a proteome-wide compositional dataset for viable colorectal cancer tissue-derived EVs and especially emphasizes importance of EV-CAT1 as a key regulator of angiogenesis.
Collapse
Affiliation(s)
- Atsushi Ikeda
- Cancer Proteomics Group, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan.,Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Satoshi Nagayama
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Makoto Sumazaki
- Cancer Proteomics Group, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan.,Department of Surgery, School of Medicine, Toho University, Tokyo, Japan
| | - Makoto Konishi
- Cancer Proteomics Group, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Risa Fujii
- Cancer Proteomics Group, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Naomi Saichi
- Cancer Proteomics Group, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Satoshi Muraoka
- Cancer Proteomics Group, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Daisuke Saigusa
- Department of Integrative Genomics, Tohoku University Tohoku Medical Megabank Organization, Sendai, Japan
| | - Hideaki Shimada
- Department of Surgery, School of Medicine, Toho University, Tokyo, Japan
| | - Yoshiharu Sakai
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Koji Ueda
- Cancer Proteomics Group, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
| |
Collapse
|
|
30
|
Mintz J, Vedenko A, Rosete O, Shah K, Goldstein G, Hare JM, Ramasamy R, Arora H. Current Advances of Nitric Oxide in Cancer and Anticancer Therapeutics. Vaccines (Basel) 2021; 9:94. [PMID: 33513777 PMCID: PMC7912608 DOI: 10.3390/vaccines9020094] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 01/18/2021] [Accepted: 01/20/2021] [Indexed: 02/07/2023] Open
Abstract
Nitric oxide (NO) is a short-lived, ubiquitous signaling molecule that affects numerous critical functions in the body. There are markedly conflicting findings in the literature regarding the bimodal effects of NO in carcinogenesis and tumor progression, which has important consequences for treatment. Several preclinical and clinical studies have suggested that both pro- and antitumorigenic effects of NO depend on multiple aspects, including, but not limited to, tissue of generation, the level of production, the oxidative/reductive (redox) environment in which this radical is generated, the presence or absence of NO transduction elements, and the tumor microenvironment. Generally, there are four major categories of NO-based anticancer therapies: NO donors, phosphodiesterase inhibitors (PDE-i), soluble guanylyl cyclase (sGC) activators, and immunomodulators. Of these, NO donors are well studied, well characterized, and also the most promising. In this study, we review the current knowledge in this area, with an emphasis placed on the role of NO as an anticancer therapy and dysregulated molecular interactions during the evolution of cancer, highlighting the strategies that may aid in the targeting of cancer.
Collapse
Affiliation(s)
- Joel Mintz
- Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Davie, FL 33328, USA;
| | - Anastasia Vedenko
- John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (A.V.); (J.M.H.)
| | - Omar Rosete
- Department of Urology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
| | - Khushi Shah
- College of Arts and Sciences, University of Miami, Miami, FL 33146, USA;
| | - Gabriella Goldstein
- College of Health Professions and Sciences, University of Central Florida, Orlando, FL 32816, USA;
| | - Joshua M. Hare
- John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (A.V.); (J.M.H.)
- The Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Department of Medicine, Cardiology Division, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Ranjith Ramasamy
- Department of Urology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
- The Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Himanshu Arora
- John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (A.V.); (J.M.H.)
- Department of Urology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
- The Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| |
Collapse
|
|
31
|
de Farias JO, de Freitas Lima SM, Rezende TMB. Physiopathology of nitric oxide in the oral environment and its biotechnological potential for new oral treatments: a literature review. Clin Oral Investig 2020; 24:4197-4212. [PMID: 33057827 DOI: 10.1007/s00784-020-03629-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 10/07/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVES A narrative review on the NO properties and their relationship with the oral environment describing NO's molecular origin, role, and perspectives regarding oral pathological, physiological, and regenerative processes for future applications and possible use as prevention or treatment in dentistry. MATERIALS AND METHODS Pubmed was searched using the word "nitric oxide." Reviews, clinical studies, and experimental studies were eligible for the screening process. Similar search procedures were then performed with the additional search words "conservative dentistry," "orthodontics," "endodontics," "implants," "periodontics," "oral cancer," "pulp revascularization," and "oral surgery." Furthermore, references of included articles were examined to identify further relevant articles. RESULTS There is a relationship between NO production and oral diseases such as caries, periodontal diseases, pulp inflammation, apical periodontitis, oral cancer, with implants, and orthodontics. Studies on this relationship and uses of NO, in diagnosis, prevention, and treatment, are being developed. Also, some NO and oral cavity patents have already registered. CONCLUSIONS The understanding of how NO can interfere in oral health maintenance or disease processes can contribute to elucidate the disease development and optimize treatment approaches. CLINICAL RELEVANCE NO has considerable biotechnological potential and can contribute to improving diagnostics and treating the oral environment. As a biomarker, NO has an important role in the early diagnosis of diseases. Regarding treatments, NO can possibly be used as a regulator of inflammation, anti-biofilm action, replacing antibiotics, inducing apoptosis of cancerous cells, and contributing to the angiogenesis. All these studies are initial considerations regarding the relationship between NO and dentistry.
Collapse
Affiliation(s)
- Jade Ormondes de Farias
- Curso de Odontologia, Universidade Católica de Brasília, QS 07 Lote 01, Brasília, DF, Brazil.,Pós-graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, SGAN 916N - Módulo B Avenida W5-Campus II -Modulo C, room C-221, Asa Norte, Brasília, DF, 70.790-160, Brazil.,Pós-graduação em Ciências da Saúde, Faculdade de Ciências de Saúde, Universidade de Brasília, Campus Darcy Ribeiro s/n-Asa Norte, Brasília, DF, Brazil
| | - Stella Maris de Freitas Lima
- Curso de Odontologia, Universidade Católica de Brasília, QS 07 Lote 01, Brasília, DF, Brazil.,Pós-graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, SGAN 916N - Módulo B Avenida W5-Campus II -Modulo C, room C-221, Asa Norte, Brasília, DF, 70.790-160, Brazil
| | - Taia Maria Berto Rezende
- Curso de Odontologia, Universidade Católica de Brasília, QS 07 Lote 01, Brasília, DF, Brazil. .,Pós-graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, SGAN 916N - Módulo B Avenida W5-Campus II -Modulo C, room C-221, Asa Norte, Brasília, DF, 70.790-160, Brazil. .,Pós-graduação em Ciências da Saúde, Faculdade de Ciências de Saúde, Universidade de Brasília, Campus Darcy Ribeiro s/n-Asa Norte, Brasília, DF, Brazil.
| |
Collapse
|
|
32
|
Mishra D, Patel V, Banerjee D. Nitric Oxide and S-Nitrosylation in Cancers: Emphasis on Breast Cancer. BREAST CANCER-BASIC AND CLINICAL RESEARCH 2020; 14:1178223419882688. [PMID: 32030066 PMCID: PMC6977095 DOI: 10.1177/1178223419882688] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 09/16/2019] [Indexed: 12/12/2022]
Abstract
Nitric oxide (NO) is a ubiquitous, endogenously produced, water-soluble signaling molecule playing critical roles in physiological processes. Nitric oxide plays pleiotropic roles in cancer and, depending on its local concentration, may lead to either tumor progression or tumor suppression. Addition of NO group to a cysteine residue within a protein, termed as S-nitrosylation, plays diverse regulatory roles and affects processes such as metabolism, apoptosis, protein phosphorylation, and regulation of transcription factors. The process of S-nitrosylation has been associated with development of different cancers, including breast cancer. The present review discusses different mechanisms through which NO acts, with special emphasis on breast cancers, and provides detailed insights into reactive nitrogen species, posttranslational modifications of proteins mediated by NO, dual nature of NO in cancers, and the implications of S-nitrosylation in cancers. Our review will generate interest in exploring molecular regulation by NO in different cancers and will have significant therapeutic implications in the management and treatment of breast cancer.
Collapse
Affiliation(s)
- Deepshikha Mishra
- Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Vaibhav Patel
- Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.,School of Graduate Studies, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Debabrata Banerjee
- Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.,School of Graduate Studies, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| |
Collapse
|
|
33
|
Hulin JA, Gubareva EA, Jarzebska N, Rodionov RN, Mangoni AA, Tommasi S. Inhibition of Dimethylarginine Dimethylaminohydrolase (DDAH) Enzymes as an Emerging Therapeutic Strategy to Target Angiogenesis and Vasculogenic Mimicry in Cancer. Front Oncol 2020; 9:1455. [PMID: 31993367 PMCID: PMC6962312 DOI: 10.3389/fonc.2019.01455] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 12/05/2019] [Indexed: 01/01/2023] Open
Abstract
The small free radical gas nitric oxide (NO) plays a key role in various physiological and pathological processes through enhancement of endothelial cell survival and proliferation. In particular, NO has emerged as a molecule of interest in carcinogenesis and tumor progression due to its crucial role in various cancer-related events including cell invasion, metastasis, and angiogenesis. The dimethylarginine dimethylaminohydrolase (DDAH) family of enzymes metabolize the endogenous nitric oxide synthase (NOS) inhibitors, asymmetric dimethylarginine (ADMA) and monomethyl arginine (L-NMMA), and are thus key for maintaining homeostatic control of NO. Dysregulation of the DDAH/ADMA/NO pathway resulting in increased local NO availability often promotes tumor growth, angiogenesis, and vasculogenic mimicry. Recent literature has demonstrated increased DDAH expression in tumors of different origins and has also suggested a potential ADMA-independent role for DDAH enzymes in addition to their well-studied ADMA-mediated influence on NO. Inhibition of DDAH expression and/or activity in cell culture models and in vivo studies has indicated the potential therapeutic benefit of this pathway through inhibition of both angiogenesis and vasculogenic mimicry, and strategies for manipulating DDAH function in cancer are currently being actively pursued by several research groups. This review will thus provide a timely discussion on the expression, regulation, and function of DDAH enzymes in regard to angiogenesis and vasculogenic mimicry, and will offer insight into the therapeutic potential of DDAH inhibition in cancer based on preclinical studies.
Collapse
Affiliation(s)
- Julie-Ann Hulin
- Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Ekaterina A Gubareva
- N.N. Petrov National Medical Research Center of Oncology, Saint Petersburg, Russia
| | - Natalia Jarzebska
- Division of Angiology, Department of Internal Medicine III, University Center for Vascular Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,Department of Anesthesiology and Intensive Care Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Roman N Rodionov
- Division of Angiology, Department of Internal Medicine III, University Center for Vascular Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Arduino A Mangoni
- Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Sara Tommasi
- Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| |
Collapse
|
|
34
|
Sumatriptan Increases Skin Flap Survival through Activation of 5-Hydroxytryptamine 1b/1d Receptors in Rats: The Mediating Role of the Nitric Oxide Pathway. Plast Reconstr Surg 2019; 144:70e-77e. [PMID: 31246821 DOI: 10.1097/prs.0000000000005740] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND Random pattern skin flaps are applicable for reconstructing any defect in plastic surgery. However, they are difficult to apply because of necrosis. Sumatriptan, a selective 5-hydroxytryptamine 1b/1d agonist, is routinely used to offset acute migraine attacks. Recent studies have suggested that sumatriptan may induce vasodilation at lower concentrations. The authors' aim is to investigate the effect of sumatriptan on skin flap survival and the role of nitric oxide in this phenomenon. METHODS Seventy-two male Sprague-Dawley rats were divided into eight groups. Increasing doses of sumatriptan (0.1, 0.3, and 1 mg/kg) were given intraperitoneally to three different groups after dorsal random pattern skin flaps were performed. To assess the exact role of 5-hydroxytryptamine 1b/1d receptors, GR-127935 was administered solely and with sumatriptan. N-ω-nitro-L-arginine methyl ester (L-NAME, a nonselective nitric oxide synthase inhibitor) was used to evaluate any possible involvement of nitric oxide in this study. All rats were examined 7 days later. RESULTS The authors' results demonstrated that flap survival was increased by lower doses of sumatriptan compared to a control group for both 0.3 mg/kg (p = 0.03, mean difference = 32, SE = 8) and 0.1 mg/kg (p = 0.02, mean difference = 26, SE = 8). This protective effect was eliminated by coadministration of GR-127935 or N-ω-nitro-L-arginine methyl ester with sumatriptan. Histopathologic studies revealed a significant increase in capillary count and collagen deposition and a decreased amount of edema, inflammation, and degeneration. CONCLUSIONS Sumatriptan in lower concentration increases skin flap survival by means of activation of 5-hydroxytryptamine 1b/1d receptors. This effect is mediated through the nitric oxide synthase pathway.
Collapse
|
|
35
|
Kacar S, Kar F, Hacioglu C, Kanbak G, Sahinturk V. The effects of L-NAME on DU145 human prostate cancer cell line: A cytotoxicity-based study. Hum Exp Toxicol 2019; 39:182-193. [PMID: 31610702 DOI: 10.1177/0960327119880591] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Of all cancer types, prostate cancer is the second most common one with an age-standardized incidence rate of 29.3 per 100,000 men worldwide. Nitric oxide (NO) is both a radical and versatile messenger molecule involved in many physiological activities. NO was documented to be highly secreted and utilized by cancer cells. Nω-nitro-L-arginine methyl ester (L-NAME) is utilized for inhibiting NO synthase. Its worst long-term side effect is reported to be hypertension, hence less cytotoxic than chemotherapeutic agents. Herein, we carried out a cytotoxicity study on how different doses of L-NAME affect DU145 human prostate cancer cells. First, toxic doses of L-NAME were determined. Then, while antioxidant capacity was determined by glutathione and total antioxidant status, oxidative stress was evaluated by quantifying malondialdehyde, NO, and total oxidant status levels. Inflammatory effects of L-NAME were investigated by measuring tumor necrosis factor-α and interleukin-6 (IL-6) levels. Apoptotic effects of L-NAME were evaluated by measuring cytochrome C somatic and caspase 3 levels and by staining Bax protein. Finally, morphological analysis was performed. IC50 of L-NAME against DU145 cells was 12.2 mM. In L-NAME-treated DU145 cells, a dose-dependent increase in oxidative stress, inflammatory, and apoptotic marker proteins and decrease in antioxidant capacity were observed. While at the moderate dose of L-NAME, apoptotic changes were commonly observed, at higher doses, vacuolated and swollen cells were also recorded. We believe that the present study will encourage future studies by providing insights about dose and effects of L-NAME.
Collapse
Affiliation(s)
- S Kacar
- Department of Histology and Embryology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - F Kar
- Department of Medical Biochemistry, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - C Hacioglu
- Department of Medical Biochemistry, Faculty of Medicine, Duzce University, Duzce, Turkey
| | - G Kanbak
- Department of Medical Biochemistry, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - V Sahinturk
- Department of Histology and Embryology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
| |
Collapse
|
|
36
|
Hays E, Bonavida B. Nitric Oxide-Mediated Enhancement and Reversal of Resistance of Anticancer Therapies. Antioxidants (Basel) 2019; 8:E407. [PMID: 31533363 PMCID: PMC6769868 DOI: 10.3390/antiox8090407] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 09/11/2019] [Accepted: 09/13/2019] [Indexed: 12/13/2022] Open
Abstract
In the last decade, immune therapies against human cancers have emerged as a very effective therapeutic strategy in the treatment of various cancers, some of which are resistant to current therapies. Although the clinical responses achieved with many therapeutic strategies were significant in a subset of patients, another subset remained unresponsive initially, or became resistant to further therapies. Hence, there is a need to develop novel approaches to treat those unresponsive patients. Several investigations have been reported to explain the underlying mechanisms of immune resistance, including the anti-proliferative and anti-apoptotic pathways and, in addition, the increased expression of the transcription factor Yin-Yang 1 (YY1) and the programmed death ligand 1 (PD-L1). We have reported that YY1 leads to immune resistance through increasing HIF-1α accumulation and PD-L1 expression. These mechanisms inhibit the ability of the cytotoxic T-lymphocytes to mediate their cytotoxic functions via the inhibitory signal delivered by the PD-L1 on tumor cells to the PD-1 receptor on cytotoxic T-cells. Thus, means to override these resistance mechanisms are needed to sensitize the tumor cells to both cell killing and inhibition of tumor progression. Treatment with nitric oxide (NO) donors has been shown to sensitize many types of tumors to chemotherapy, immunotherapy, and radiotherapy. Treatment of cancer cell lines with NO donors has resulted in the inhibition of cancer cell activities via, in part, the inhibition of YY1 and PD-L1. The NO-mediated inhibition of YY1 was the result of both the inhibition of the upstream NF-κB pathway as well as the S-nitrosylation of YY1, leading to both the downregulation of YY1 expression as well as the inhibition of YY1-DNA binding activity, respectively. Also, treatment with NO donors induced the inhibition of YY1 and resulted in the inhibition of PD-L1 expression. Based on the above findings, we propose that treatment of tumor cells with the combination of NO donors, at optimal noncytotoxic doses, and anti-tumor cytotoxic effector cells or other conventional therapies will result in a synergistic anticancer activity and tumor regression.
Collapse
Affiliation(s)
- Emily Hays
- Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, CA 90095, USA.
| | - Benjamin Bonavida
- Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, CA 90095, USA.
| |
Collapse
|
|
37
|
Ahmed Alshwafy RY, Dahy AA, Warad I, Mahfouz RM. Synthesis and DFT calculations of new ruthenium(II) nitrosyl complexes using cis-fac-dichlorotetrakis(dimethylsulfoxide)ruthenium(II) precursor and different oximes as sources of nitrosyl ligand. J COORD CHEM 2019. [DOI: 10.1080/00958972.2019.1647340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
| | | | - Ismail Warad
- Chemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Refaat M. Mahfouz
- Chemistry Department, Faculty of Science, Assiut University, Assiut, Egypt
| |
Collapse
|
|
38
|
Deryagina VP, Reutov VP. Modulation of the formation of active forms of nitrogen by ingredients of plant products in the inhibition of carcinogenesis. ADVANCES IN MOLECULAR ONCOLOGY 2019. [DOI: 10.17650/2313-805x-2019-6-1-18-36] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2023]
Affiliation(s)
- V. P. Deryagina
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - V. P. Reutov
- Institute of Higher Nervous Activity and Neurophysiology of the Russian Academy of Sciences
| |
Collapse
|
|
39
|
Serum prolidase activity, total oxidant/antioxidant, and nitric oxide levels in patients with esophageal squamous cell carcinoma. TURK GOGUS KALP DAMAR CERRAHISI DERGISI-TURKISH JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY 2019; 27:206-211. [PMID: 32082854 DOI: 10.5606/tgkdc.dergisi.2019.16888] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 09/01/2018] [Indexed: 01/14/2023]
Abstract
Background This study aims to assess the prolidase activity, nitric oxide levels, and oxidative status in patients with esophageal squamous cell carcinoma. Methods The study included 30 patients with esophageal squamous cell carcinoma (11 males, 19 females; mean age 61±3 years; range, 28 to 77 years) and 30 healthy controls (10 males, 20 females; mean age 58±5 years; range, 31 to 73 years). Serum prolidase activity, total antioxidant capacity, total oxidant status, and nitric oxide levels were measured. In addition, the oxidative stress index was calculated. Results Prominently elevated serum prolidase activity, oxidative stress index values, total oxidant status, and nitric oxide levels were detected in the patient group (p<0.05). Lower total antioxidant capacity levels were observed in the patient group (p<0.05). Conclusion Increased oxidant status with increased nitric oxide levels and prolidase activity were found in esophageal squamous cell carcinoma patients. Impairment of antioxidant mechanism with increased prolidase activity and nitric oxide levels may have a crucial role in the etiopathogenesis of esophageal squamous cell carcinoma.
Collapse
|
|
40
|
Li H, Wang D, Zhao X, Lu LN, Liu C, Gong LD, Zhao DX, Yang ZZ. Reaction mechanism of NO with hydrolysates of NAMI-A: an MD simulation by combining the QM/MM(ABEEM) with the MD-FEP method. J Comput Chem 2019; 40:1141-1150. [PMID: 30375671 DOI: 10.1002/jcc.25734] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 09/27/2018] [Accepted: 09/28/2018] [Indexed: 11/06/2022]
Abstract
Nitrosylation reaction mechanisms of the hydrolysates of NAMI-A and hydrolysis reactions of ruthenium nitrosyl complexes were investigated in the triplet state and the singlet state. Activation free energies were calculated by combining the QM/MM(ABEEM) method with free energy perturbation theory, and the explicit solvent environment was simulated by an ABEEMσπ polarizable force field. Our results demonstrate that nitrosylation reactions of the hydrolysates of NAMI-A occur in both the triplet and the singlet states. The Ru-N-O angle of the triplet ruthenium nitrosyl complexes is in the range of 132.0°-138.2°. However, all the ruthenium nitrosyl complexes at the singlet state show an almost linear Ru-N-O angle. The nitrosylation reaction happens prior to the hydrolysis reaction for the first-step hydrolysates. The activation free energies of the nitrosylation reactions show that the H2 O-NO exchange reaction of [RuCl4 (Im)(H2 O)] in the singlet spin sate is the most likely one. Comparing with the activation free energies of the hydrolysis reactions of the ruthenium nitrosyl complexes, the results indicate that the rate of the DMSO-H2 O exchange reaction of [RuCl3 (NO)(Im)(DMSO)] is faster than that of [RuCl3 (H2 O)(Im)(DMSO)] in both the triplet spin state and the singlet spin state. © 2018 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Hui Li
- School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian 116029, People's Republic of China.,Department of Chemistry, Bohai University, Jinzhou 121013, China
| | - Di Wang
- School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian 116029, People's Republic of China
| | - Xin Zhao
- School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian 116029, People's Republic of China
| | - Li-Nan Lu
- School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian 116029, People's Republic of China
| | - Cui Liu
- School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian 116029, People's Republic of China
| | - Li-Dong Gong
- School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian 116029, People's Republic of China
| | - Dong-Xia Zhao
- School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian 116029, People's Republic of China
| | - Zhong-Zhi Yang
- School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian 116029, People's Republic of China
| |
Collapse
|
|
41
|
Design, synthesis and crystal structure of six macrocyclic complexes as efficient and effective nitric oxide scavengers. Polyhedron 2018. [DOI: 10.1016/j.poly.2018.08.061] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
|
|
42
|
Roshandel D, Eslani M, Baradaran-Rafii A, Cheung AY, Kurji K, Jabbehdari S, Maiz A, Jalali S, Djalilian AR, Holland EJ. Current and emerging therapies for corneal neovascularization. Ocul Surf 2018; 16:398-414. [PMID: 29908870 DOI: 10.1016/j.jtos.2018.06.004] [Citation(s) in RCA: 130] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 06/10/2018] [Accepted: 06/12/2018] [Indexed: 02/08/2023]
Abstract
The cornea is unique because of its complete avascularity. Corneal neovascularization (CNV) can result from a variety of etiologies including contact lens wear; corneal infections; and ocular surface diseases due to inflammation, chemical injury, and limbal stem cell deficiency. Management is focused primarily on the etiology and pathophysiology causing the CNV and involves medical and surgical options. Because inflammation is a key factor in the pathophysiology of CNV, corticosteroids and other anti-inflammatory medications remain the mainstay of treatment. Anti-VEGF therapies are gaining popularity to prevent CNV in a number of etiologies. Surgical options including vessel occlusion and ocular surface reconstruction are other options depending on etiology and response to medical therapy. Future therapies should provide more effective treatment options for the management of CNV.
Collapse
Affiliation(s)
- Danial Roshandel
- Ocular Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Medi Eslani
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA; Cincinnati Eye Institute, Edgewood, KY/ University of Cincinnati, Department of Ophthalmology, Cincinnati, OH, USA
| | - Alireza Baradaran-Rafii
- Ocular Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Albert Y Cheung
- Cincinnati Eye Institute, Edgewood, KY/ University of Cincinnati, Department of Ophthalmology, Cincinnati, OH, USA
| | - Khaliq Kurji
- Cincinnati Eye Institute, Edgewood, KY/ University of Cincinnati, Department of Ophthalmology, Cincinnati, OH, USA
| | - Sayena Jabbehdari
- Ocular Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Alejandra Maiz
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Setareh Jalali
- Ocular Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali R Djalilian
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA.
| | - Edward J Holland
- Cincinnati Eye Institute, Edgewood, KY/ University of Cincinnati, Department of Ophthalmology, Cincinnati, OH, USA.
| |
Collapse
|
|
43
|
Sheikhbahaei F, Khazaei M, Nematollahi-Mahani SN. Teucrium polium Extract Enhances the Anti-Angiogenesis Effect of Tranilast on Human Umbilical Vein Endothelial Cells. Adv Pharm Bull 2018; 8:131-139. [PMID: 29670848 PMCID: PMC5896388 DOI: 10.15171/apb.2018.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 02/26/2018] [Accepted: 02/28/2018] [Indexed: 12/17/2022] Open
Abstract
Purpose: Angiogenesis plays an important role in numerous pathophysiological events like cancer. As a result of this, tranilast as an anti-fibrotic drug induces the promising antitumor activities through the inhibition of angiogenesis. Further, Teucrium polium (TP) is a herbal medicine (family Lamaceae) with antitumor properties. This study was conducted to investigate the combination effects of tranilast and T. polium on human umbilical vein endothelial cells (HUVECs) viability and apoptotic genes expression. Methods: The HUVECs line was treated using different doses of tranilast and T. polium alone or their combination. The cell cytotoxicity was evaluated using MTT and LDH assays; apoptosis was examined using acridine orange/ethidium bromide staining, nitric oxide (NO) production was evaluated using Griess reaction and the expression of BAX and BCL-2 genes were detected using real-time RT-PCR. One-way analysis of variance (ANOVA) test was used to compare the data in different groups. Results: The survival rate of HUVECs was significantly reduced (p<0.05) in a dose dependent manner by tranilast and T. polium. However, T. polium and tranilast combination significantly (p<0.001) reduced cell viability and increased apoptotic cells as compared to each drug alone. Also, HUVECs treated with Tranilast / T. polium combination showed a reduced level of NO as regards to cells exposed only to Tranilast or T. polium (p<0.05). Furthermore, a significant increase in BAX and a decrease in BCL-2 mRNA expression were observed in combination group (p<0.001). Conclusion: T. polium synergistically increased the antiangiogenic effect of tranilast on in vitro angiogenic model of HUVECs.
Collapse
Affiliation(s)
- Fatemeh Sheikhbahaei
- Department of Anatomy, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Mozafar Khazaei
- Fertility and Infertility Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | | |
Collapse
|
|
44
|
Ziche M, Sorriso C, Parenti A, Brogelli L, Tricarico C, Villari D, Pazzagli M. Biological Parameters for the Choice of Antiangiogenic Therapy and Efficacy Monitoring. Int J Biol Markers 2018; 14:214-7. [PMID: 10669949 DOI: 10.1177/172460089901400404] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Angiogenesis is a tightly controlled process which depends on the balance between stimulating and inhibiting factors. When this balance is disrupted, angiogenesis acquires a pathological meaning. The list of molecules able to induce angiogenesis is heterogeneous with respect to their chemical characteristics and biological properties. Quantitative measurement of tumor angiogenesis is necessary for the choice of therapeutic strategies and as an endpoint for antiangiogenic therapy. We are developing a quantitative RT-PCR which measures the expression of specific factors in real time. With the use of this rapid technique, measurement of the expression of the angiogenic factors and inhibitors is also possible in specimens as small as biopsies.
Collapse
Affiliation(s)
- M Ziche
- Interuniversity Center of Molecular Medicine and Applied Biophysics, Medical School, University of Firenze, Italy.
| | | | | | | | | | | | | |
Collapse
|
|
45
|
Kashfi K. The dichotomous role of H 2S in cancer cell biology? Déjà vu all over again. Biochem Pharmacol 2018; 149:205-223. [PMID: 29397935 PMCID: PMC5866221 DOI: 10.1016/j.bcp.2018.01.042] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 01/17/2018] [Indexed: 02/09/2023]
Abstract
Nitric oxide (NO) a gaseous free radical is one of the ten smallest molecules found in nature, while hydrogen sulfide (H2S) is a gas that bears the pungent smell of rotten eggs. Both are toxic yet they are gasotransmitters of physiological relevance. There appears to be an uncanny resemblance between the general actions of these two gasotransmitters in health and disease. The role of NO and H2S in cancer has been quite perplexing, as both tumor promotion and inflammatory activities as well as anti-tumor and antiinflammatory properties have been described. These paradoxes have been explained for both gasotransmitters in terms of each having a dual or biphasic effect that is dependent on the local flux of each gas. In this review/commentary, I have discussed the major roles of NO and H2S in carcinogenesis, evaluating their dual nature, focusing on the enzymes that contribute to this paradox and evaluate the pros and cons of inhibiting or inducing each of these enzymes.
Collapse
Affiliation(s)
- Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, NY, USA.
| |
Collapse
|
|
46
|
Treatment with the nitric oxide synthase inhibitor L-NAME provides a survival advantage in a mouse model of Kras mutation-positive, non-small cell lung cancer. Oncotarget 2018; 7:42385-42392. [PMID: 27285753 PMCID: PMC5173142 DOI: 10.18632/oncotarget.9874] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 05/12/2016] [Indexed: 01/09/2023] Open
Abstract
Oncogenic mutations in the gene KRAS are commonly detected in non-small cell lung cancer (NSCLC). This disease is inherently difficult to treat, and combinations involving platinum-based drugs remain the therapeutic mainstay. In terms of novel, pharmacologically actionable targets, nitric oxide synthases (NOS) have been implicated in the etiology of KRAS-driven cancers, including lung cancer, and small molecular weight NOS inhibitors have been developed for the treatment of other diseases. Thus, we evaluated the anti-neoplastic activity of the oral NOS inhibitor L-NAME in a randomized preclinical trial using a genetically engineered mouse model of Kras and p53 mutation-positive NSCLC. We report here that L-NAME decreased lung tumor growth in vivo, as assessed by sequential radiological imaging, and provided a survival advantage, perhaps the most difficult clinical parameter to improve upon. Moreover, L-NAME enhanced the therapeutic benefit afforded by carboplatin chemotherapy, provided it was administered as maintenance therapy after carboplatin. Collectively, these results support the clinical evaluation of L-NAME for the treatment of KRAS mutation-positive NSCLC.
Collapse
|
|
47
|
Solomon I, Voiculescu VM, Caruntu C, Lupu M, Popa A, Ilie MA, Albulescu R, Caruntu A, Tanase C, Constantin C, Neagu M, Boda D. Neuroendocrine Factors and Head and Neck Squamous Cell Carcinoma: An Affair to Remember. DISEASE MARKERS 2018; 2018:9787831. [PMID: 29854027 PMCID: PMC5966665 DOI: 10.1155/2018/9787831] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 03/21/2018] [Accepted: 04/15/2018] [Indexed: 02/07/2023]
Abstract
Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive malignancies. Therefore, the major goal of cancer treatment is inhibition of tumor cell growth and of metastasis development. In order to choose the best management option for HNSCC patients, we need to identify reliable prognostic factors and to develop new molecular techniques in order to obtain a better understanding of therapy resistance. By acting as neurohormones, neurotransmitters, or neuromodulators, the neuroendocrine factors are able to signal the maintenance of physiological homeostasis or progression to malignant disease. Certain neuropeptides possess strong antitumor properties acting as tumor suppressors and immunomodulators, providing additional benefits for future potential therapeutic strategies. In light of the current understanding, cancer starts as a localized disease that can be effectively treated if discovered on proper time. Unfortunately, more than often cancer cells migrate to the surrounding tissues generating distant metastases, thus making the prognosis and survival in this stage much worse. As cellular migration is mandatory for tumor invasion and metastasis development, searching for alternate controllers of these processes, such as the neuroendocrine factors, it is an active tremendous task.
Collapse
Affiliation(s)
- Iulia Solomon
- 1Department of Dermatology and Allergology, Elias Emergency University Hospital, Bucharest, Romania
| | - Vlad Mihai Voiculescu
- 1Department of Dermatology and Allergology, Elias Emergency University Hospital, Bucharest, Romania
- 2Department of Dermatology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Constantin Caruntu
- 3Department of Physiology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- 4Department of Dermatology, “Prof. N. C. Paulescu” National Institute of Diabetes, Nutrition and Metabolic Diseases, Bucharest, Romania
| | - Mihai Lupu
- 5Department of Dermatology, MEDAS Titan Medical Center, Bucharest, Romania
| | - Alexandra Popa
- 1Department of Dermatology and Allergology, Elias Emergency University Hospital, Bucharest, Romania
| | - Mihaela Adriana Ilie
- 6Dermatology Research Laboratory, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- 7Department of Biochemistry, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Radu Albulescu
- 8Chemical and Pharmaceutical National Institute, Bucharest, Romania
| | - Ana Caruntu
- 9Department of Oral and Maxillofacial Surgery, Carol Davila Central Military Emergency Hospital, Bucharest, Romania
- 10Faculty of Medicine, Titu Maiorescu University, Bucharest, Romania
| | - Cristiana Tanase
- 10Faculty of Medicine, Titu Maiorescu University, Bucharest, Romania
- 11Victor Babes National Institute of Pathology, Bucharest, Romania
| | - Carolina Constantin
- 11Victor Babes National Institute of Pathology, Bucharest, Romania
- 12Colentina Clinical Hospital, Bucharest, Romania
| | - Monica Neagu
- 11Victor Babes National Institute of Pathology, Bucharest, Romania
- 12Colentina Clinical Hospital, Bucharest, Romania
- 13Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Daniel Boda
- 6Dermatology Research Laboratory, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| |
Collapse
|
|
48
|
Identification of the functional alteration signatures across different cancer types with support vector machine and feature analysis. Biochim Biophys Acta Mol Basis Dis 2017; 1864:2218-2227. [PMID: 29277326 DOI: 10.1016/j.bbadis.2017.12.026] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 12/04/2017] [Accepted: 12/15/2017] [Indexed: 12/13/2022]
Abstract
Cancers are regarded as malignant proliferations of tumor cells present in many tissues and organs, which can severely curtail the quality of human life. The potential of using plasma DNA for cancer detection has been widely recognized, leading to the need of mapping the tissue-of-origin through the identification of somatic mutations. With cutting-edge technologies, such as next-generation sequencing, numerous somatic mutations have been identified, and the mutation signatures have been uncovered across different cancer types. However, somatic mutations are not independent events in carcinogenesis but exert functional effects. In this study, we applied a pan-cancer analysis to five types of cancers: (I) breast cancer (BRCA), (II) colorectal adenocarcinoma (COADREAD), (III) head and neck squamous cell carcinoma (HNSC), (IV) kidney renal clear cell carcinoma (KIRC), and (V) ovarian cancer (OV). Based on the mutated genes of patients suffering from one of the aforementioned cancer types, patients they were encoded into a large number of numerical values based upon the enrichment theory of gene ontology (GO) terms and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. We analyzed these features with the Monte-Carlo Feature Selection (MCFS) method, followed by the incremental feature selection (IFS) method to identify functional alteration features that could be used to build the support vector machine (SVM)-based classifier for distinguishing the five types of cancers. Our results showed that the optimal classifier with the selected 344 features had the highest Matthews correlation coefficient value of 0.523. Sixteen decision rules produced by the MCFS method can yield an overall accuracy of 0.498 for the classification of the five cancer types. Further analysis indicated that some of these features and rules were supported by previous experiments. This study not only presents a new approach to mapping the tissue-of-origin for cancer detection but also unveils the specific functional alterations of each cancer type, providing insight into cancer-specific functional aberrations as potential therapeutic targets. This article is part of a Special Issue entitled: Accelerating Precision Medicine through Genetic and Genomic Big Data Analysis edited by Yudong Cai & Tao Huang.
Collapse
|
|
49
|
Vitamins and regulation of angiogenesis: [A, B1, B2, B3, B6, B9, B12, C, D, E, K]. J Funct Foods 2017. [DOI: 10.1016/j.jff.2017.09.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
|
|
50
|
Lupu M, Caruntu A, Caruntu C, Papagheorghe LML, Ilie MA, Voiculescu V, Boda D, Constantin C, Tanase C, Sifaki M, Drakoulis N, Mamoulakis C, Tzanakakis G, Neagu M, Spandidos DA, Izotov BN, Tsatsakis AM. Neuroendocrine factors: The missing link in non‑melanoma skin cancer (Review). Oncol Rep 2017; 38:1327-1340. [PMID: 28713981 PMCID: PMC5549028 DOI: 10.3892/or.2017.5817] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 06/29/2017] [Indexed: 02/06/2023] Open
Abstract
Non‑melanoma skin cancer (NMSC) is the most common form of cancer worldwide, comprising 95% of all cutaneous malignancies and approximately 40% of all cancers. In spite of intensive efforts aimed towards awareness campaigns and sun‑protective measures, epidemiological data indicate an increase in the incidence of NMSC. This category of skin cancers has many common environmental triggers. Arising primarily on sun‑exposed skin, it has been shown that ultraviolet radiation is, in the majority of cases, the main trigger involved in the pathogenesis of NMSC. Aside from the well‑known etiopathogenic factors, studies have indicated that several neuroactive factors are involved in the carcinogenesis of two of the most common types of NMSC, namely basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), with the exception of penile SCC, for which a paucity of specific data on their pathogenic role exists. The complex interaction between the peripheral nervous system and target cells in the skin appears to be mediated by locally released neuroendocrine factors, such as catecholamines, substance P, calcitonin gene‑related peptide and somatostatin, as well as neurohormones, such as proopiomelanocortin and its derived peptides, α‑melanocyte‑stimulating hormone and adrenocorticotropin. All these factors have been, at least at some point, a subject of debate regarding their precise role in the pathogenesis of NMSC. There is also a significant body of evidence indicating that psychological stress is a crucial impact factor influencing the course of skin cancers, including SCC and BCC. Numerous studies have suggested that neuroendocrine factor dysregulation, as observed in stress reactions, may be involved in tumorigenesis, accelerating the development and progression, and suppressing the regression of NMSC. Further studies are required in order to elucidate the exact mechanisms through which neuroactive molecules promote or inhibit cutaneous carcinogenesis, as this could lead to the development of more sophisticated and tailored treatment protocols, as well as open new perspectives in skin cancer research.
Collapse
Affiliation(s)
- Mihai Lupu
- Department of Dermatology, MEDAS Medical Center, 030442 Bucharest, Romania
| | - Ana Caruntu
- Department of Oral and Maxillofacial Surgery, ‘Carol Davila’ Central Military Emergency Hospital, 010825 Bucharest, Romania
- ‘Titu Maiorescu’ University, Faculty of Medicine, 031593 Bucharest, Romania
| | - Constantin Caruntu
- Department of Physiology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Dermatology, ‘Prof. N. Paulescu’ National Institute of Diabetes, Nutrition and Metabolic Diseases, 011233 Bucharest, Romania
| | | | - Mihaela Adriana Ilie
- Dermatology Research Laboratory, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Vlad Voiculescu
- Department of Dermatology and Allergology, Elias Emergency University Hospital, 011461 Bucharest, Romania
| | - Daniel Boda
- Dermatology Research Laboratory, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Carolina Constantin
- ‘Victor Babes’ National Institute of Pathology, 050096 Bucharest, Romania
- Colentina University Hospital, 020125 Bucharest, Romania
| | - Cristiana Tanase
- ‘Titu Maiorescu’ University, Faculty of Medicine, 031593 Bucharest, Romania
- ‘Victor Babes’ National Institute of Pathology, 050096 Bucharest, Romania
| | - Maria Sifaki
- Laboratory of Toxicology, Faculty of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Nikolaos Drakoulis
- Research Group of Clinical Pharmacology and Pharmacogenomics, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, 15771 Athens, Greece
| | - Charalampos Mamoulakis
- Department of Urology, University General Hospital of Heraklion, University of Crete Medical School, 71003 Heraklion, Greece
| | - George Tzanakakis
- Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Monica Neagu
- ‘Victor Babes’ National Institute of Pathology, 050096 Bucharest, Romania
- Colentina University Hospital, 020125 Bucharest, Romania
| | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Boris N. Izotov
- Department of Analytical Toxicology, Pharmaceutical Chemistry and Pharmacognosy, Sechenov University, 119991 Moscow, Russia
| | - Aristides M. Tsatsakis
- Laboratory of Toxicology, Faculty of Medicine, University of Crete, 71003 Heraklion, Greece
| |
Collapse
|