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Tarawneh N, Hussein SA, Abdalla S. Repurposing Antiepileptic Drugs for Cancer: A Promising Therapeutic Strategy. J Clin Med 2025; 14:2673. [PMID: 40283503 PMCID: PMC12027853 DOI: 10.3390/jcm14082673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 03/29/2025] [Accepted: 04/10/2025] [Indexed: 04/29/2025] Open
Abstract
Epilepsy is a neurological disorder characterized by repeated convulsions. Antiepileptic drugs (AEDs) are the main course of therapy for epilepsy. These medications are given according to each patient's personal medical history and the types of seizures they suffer. They have been employed for decades to manage epilepsy, thus delivering relief from seizures through numerous mechanisms of action. Aside from their anticonvulsant attributes, current evidence suggests that certain AEDs may display potential inhibitory effects against cancer invasion and metastasis. This review explored the complicated interactions between the modes of action of AEDs and the pathways causing cancer, and the potential impact of AEDs on the invasion and metastasis of various forms of cancer, while addressing their associated side effects. For example, valproic acid inhibits histone deacetylase, causing hyperacetylation of genes, especially those regulating cell cycle, culminating in cell cycle arrest. Topiramate inhibits carbonic anhydrase, thus disrupting the acidic microenvironment needed for cancer cells to thrive. Lacosamide increases the slow inactivation of the voltage gated Na+ channel, thus inhibiting the growth, proliferation, and metastasis of many cancers. Although drug development is a complex task due to regulatory, intellectual property, and economic challenges, researchers are exploring drug repurposing tactics to overcome these challenges and to find new therapeutic alternatives for diseases like cancer. Thus, drug repurposing is considered among the most effective ways to develop drug candidates using novel properties and therapeutic characteristics, and this review also discusses these issues.
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Affiliation(s)
- Noor Tarawneh
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman 11733, Jordan;
| | - Shaymaa A. Hussein
- Department of Biological Sciences, School of Science, The University of Jordan, Amman 11942, Jordan;
| | - Shtaywy Abdalla
- Department of Biological Sciences, School of Science, The University of Jordan, Amman 11942, Jordan;
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Fan XP, Wang JR, Chen SY, Li XR, Cao JL, Wang HB, Ding LY, Che TJ, Yang L. Mechanistic insights into PROS1 inhibition of bladder cancer progression and angiogenesis via the AKT/GSK3β/β-catenin pathway. Sci Rep 2025; 15:4748. [PMID: 39922934 PMCID: PMC11807197 DOI: 10.1038/s41598-025-89217-4] [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: 08/26/2024] [Accepted: 02/04/2025] [Indexed: 02/10/2025] Open
Abstract
Bladder cancer (BLCA) is one of the ten most common cancers worldwide. However, the deregulation of PROS1 and its specific function in BLCA is not well understood. By combining proteomic and transcriptomic datasets, we discovered PROS1 expression was significantly reduced in BLCA tissues and revealed the clinical relevance of PROS1 with BLCA. Analysis of multiple BLCA datasets consistently showed the group with reduced PROS1 expression was linked to cancer-promoting pathways, more aggressive characteristics, and a greater chance of responding positively to immunotherapy. Next, various functional experiments were performed and the results revealed PROS1 overexpression inhibited the proliferation, cell cycle progression, migration, invasion, and angiogenesis of BLCA. In recovery trials, the AKT activator SC79 offered additional proof that PROS1 may influence BLCA cells via the AKT/GSK3β/β-catenin pathway. In conclusion, as an angiogenesis-related gene, PROS1 may play an inhibitory role in the biological functions of bladder cancer.
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Affiliation(s)
- Xin-Peng Fan
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for urinary system disease, Lanzhou, China
| | - Ji-Rong Wang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for urinary system disease, Lanzhou, China
| | - Si-Yu Chen
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for urinary system disease, Lanzhou, China
| | - Xiao-Ran Li
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for urinary system disease, Lanzhou, China
| | - Jin-Long Cao
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for urinary system disease, Lanzhou, China
| | - Hua-Bin Wang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for urinary system disease, Lanzhou, China
| | - Li-Yun Ding
- School of Physical Science and Technology, Lanzhou University, Lanzhou, China
| | - Tuan-Jie Che
- Baiyuan Company for Gene Technology, Lanzhou, China
| | - Li Yang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China.
- Gansu Province Clinical Research Center for urinary system disease, Lanzhou, China.
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Błaszczak E, Miziak P, Odrzywolski A, Baran M, Gumbarewicz E, Stepulak A. Triple-Negative Breast Cancer Progression and Drug Resistance in the Context of Epithelial-Mesenchymal Transition. Cancers (Basel) 2025; 17:228. [PMID: 39858010 PMCID: PMC11764116 DOI: 10.3390/cancers17020228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 12/30/2024] [Accepted: 01/09/2025] [Indexed: 01/27/2025] Open
Abstract
Triple-negative breast cancer (TNBC) is one of the most difficult subtypes of breast cancer to treat due to its distinct clinical and molecular characteristics. Patients with TNBC face a high recurrence rate, an increased risk of metastasis, and lower overall survival compared to other breast cancer subtypes. Despite advancements in targeted therapies, traditional chemotherapy (primarily using platinum compounds and taxanes) continues to be the standard treatment for TNBC, often with limited long-term efficacy. TNBC tumors are heterogeneous, displaying a diverse mutation profile and considerable chromosomal instability, which complicates therapeutic interventions. The development of chemoresistance in TNBC is frequently associated with the process of epithelial-mesenchymal transition (EMT), during which epithelial tumor cells acquire a mesenchymal-like phenotype. This shift enhances metastatic potential, while simultaneously reducing the effectiveness of standard chemotherapeutics. It has also been suggested that EMT plays a central role in the development of cancer stem cells. Hence, there is growing interest in exploring small-molecule inhibitors that target the EMT process as a future strategy for overcoming resistance and improving outcomes for patients with TNBC. This review focuses on the progression and drug resistance of TNBC with an emphasis on the role of EMT in these processes. We present TNBC-specific and EMT-related molecular features, key EMT protein markers, and various signaling pathways involved. We also discuss other important mechanisms and factors related to chemoresistance in TNBC within the context of EMT, highlighting treatment advancements to improve patients' outcomes.
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Affiliation(s)
- Ewa Błaszczak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland
| | | | | | | | | | - Andrzej Stepulak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland
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Zhang J, Chen C, Geng Q, Li H, Wu M, Chan B, Wang S, Sheng W. ZNF263 cooperates with ZNF31 to promote the drug resistance and EMT of pancreatic cancer through transactivating RNF126. J Cell Physiol 2024; 239:e31259. [PMID: 38515383 DOI: 10.1002/jcp.31259] [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: 12/08/2023] [Revised: 03/05/2024] [Accepted: 03/11/2024] [Indexed: 03/23/2024]
Abstract
The poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is attribute to the aggressive local invasion, distant metastasis and drug resistance of PDAC patients, which was strongly accelerated by epithelial-mesenchymal transition (EMT). In current study, we systematically investigate the role of ZNF263/RNF126 axis in the initiation of EMT in PDAC in vitro and vivo. ZNF263 is firstly identified as a novel transactivation factor of RNF126. Both ZNF263 and RNF126 were overexpressed in PDAC tissues, which were associated with multiple advanced clinical stages and poor prognosis of PDAC patients. ZNF263 overexpression promoted cell proliferation, drug resistance and EMT in vitro via activating RNF126 following by the upregulation of Cyclin D1, N-cad, and MMP9, and the downregulation of E-cad, p21, and p27. ZNF263 silencing contributed to the opposite phenotype. Mechanistically, ZNF263 transactivated RNF126 via binding to its promoter. Further investigations revealed that ZNF263 interacted with ZNF31 to coregulate the transcription of RNF126, which in turn promoted ubiquitination-mediated degradation of PTEN. The downregulation of PTEN activated AKT/Cyclin D1 and AKT/GSK-3β/β-catenin signaling, thereby promoting the malignant phenotype of PDAC. Finally, the coordination of ZNF263 and RNF126 promotes subcutaneous tumor size and distant liver metastasis in vivo. ZNF263, as an oncogene, promotes proliferation, drug resistance and EMT of PDAC through transactivating RNF126.
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Affiliation(s)
- Jiawei Zhang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Chuanping Chen
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Qilong Geng
- Department of Clinical Medicine, The First Clinical College, Anhui Medical University, Hefei, Anhui, China
| | - Haoyu Li
- Department of Clinical Medicine, The First Clinical College, Anhui Medical University, Hefei, Anhui, China
| | - Mengcheng Wu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Boyuan Chan
- Department of Clinical Medicine, The First Clinical College, Anhui Medical University, Hefei, Anhui, China
| | - Shiyang Wang
- Department of Geriatric Surgery, The First Hospital, China Medical University, Shenyang, China
| | - Weiwei Sheng
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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Meschi M, Khorsandi K, Kianmehr Z. The Effect of Berberine Follow by Blue Light Irradiation and Valproic Acid on the Growth Inhibition of MDA-MB-231 Breast Cancer Cells. Appl Biochem Biotechnol 2023; 195:6752-6767. [PMID: 36920717 DOI: 10.1007/s12010-023-04395-z] [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] [Accepted: 02/17/2023] [Indexed: 03/16/2023]
Abstract
Breast cancer is the second most common cancer after lung cancer in the world. Due to the anti-cancer properties of Berberine (Ber), in this study, the effect of combination therapy of Ber in the presence of blue LED irradiation and Valproic acid (Val) on the MDA-MB-231 breast cancer cell line was investigated. For this reason, after culturing the cells using different concentrations of Ber and Val, breast cancer cells were treated in both mono-treatment and combination therapy. In combination therapy, two modes were considered: (1) treatment with Val and then treatment with Ber in the dark or in presence of blue light irradiation (PDT)at a wavelength of 465 nm and energy of 30 J/cm2 for 15 min, and (2) treatment with Ber in the dark or PDT and then treated with Val. In all cases, cell viability, morphological changes, and colonization were assessed. Evaluation of apoptosis was performed by fluorescence microscope and flow cytometry. According to the results, combination therapy has a higher mortality rate compared to mono-treatment, and in combination therapy, treatment of cells first with Ber (10 µg/mL)-PDT and then treatment with Val (250 µg/mL) caused a significant reduction (P < 0/05) in the survival rate of cancer cells. According to the findings, it can be said that the use of Ber-PDT in combination with Val, in addition to reducing the dose of the drug, has shown a synergistic effect which can suggest the potential of this strategy as a new treatment.
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Affiliation(s)
- Mahdieh Meschi
- Department of Biochemistry, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Khatereh Khorsandi
- Department of Photodynamics, Medical Laser Research Center, Yara Institute, ACER, Tehran, Iran.
| | - Zahra Kianmehr
- Department of Biochemistry, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran.
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Estrada-Pérez AR, García-Vázquez JB, Mendoza-Figueroa HL, Rosales-Hernández MC, Fernández-Pomares C, Correa-Basurto J. Untargeted LC-MS/MS Metabolomics Study of HO-AAVPA and VPA on Breast Cancer Cell Lines. Int J Mol Sci 2023; 24:14543. [PMID: 37833990 PMCID: PMC10572250 DOI: 10.3390/ijms241914543] [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: 07/16/2023] [Revised: 09/05/2023] [Accepted: 09/06/2023] [Indexed: 10/15/2023] Open
Abstract
Breast cancer (BC) is one of the biggest health problems worldwide, characterized by intricate metabolic and biochemical complexities stemming from pronounced variations across dysregulated molecular pathways. If BC is not diagnosed early, complications may lead to death. Thus, the pursuit of novel therapeutic avenues persists, notably focusing on epigenetic pathways such as histone deacetylases (HDACs). The compound N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA), a derivative of valproic acid (VPA), has emerged as a promising candidate warranting pre-clinical investigation. HO-AAVPA is an HDAC inhibitor with antiproliferative effects on BC, but its molecular mechanism has yet to be deciphered. Furthermore, in the present study, we determined the metabolomic effects of HO-AAVPA and VPA on cells of luminal breast cancer (MCF-7) and triple-negative breast cancer (MDA-MB-231) subtypes. The LC-MS untargeted metabolomic study allowed for the simultaneous measurement of multiple metabolites and pathways, identifying that both compounds affect glycerophospholipid and sphingolipid metabolism in the MCF-7 and MDA-MB-231 cell lines, suggesting that other biological targets were different from HDACs. In addition, there are different dysregulate metabolites, possibly due to the physicochemical differences between HO-AAVPA and VPA.
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Affiliation(s)
- Alan Rubén Estrada-Pérez
- Laboratorio de Diseño y Desarrollo de Nuevos Fármacos e Innovación Biotecnológica, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Casco de Santo Tomás, Ciudad de México 11340, Mexico
| | - Juan Benjamín García-Vázquez
- Laboratorio de Diseño y Desarrollo de Nuevos Fármacos e Innovación Biotecnológica, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Casco de Santo Tomás, Ciudad de México 11340, Mexico
| | - Humberto L. Mendoza-Figueroa
- Laboratorio de Diseño y Desarrollo de Nuevos Fármacos e Innovación Biotecnológica, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Casco de Santo Tomás, Ciudad de México 11340, Mexico
| | - Martha Cecilia Rosales-Hernández
- Laboratorio de Biofísica y Biocatálisis, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Casco de Santo Tomás, Ciudad de México 11340, Mexico
| | - Cynthia Fernández-Pomares
- Laboratorio de Diseño y Desarrollo de Nuevos Fármacos e Innovación Biotecnológica, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Casco de Santo Tomás, Ciudad de México 11340, Mexico
| | - José Correa-Basurto
- Laboratorio de Diseño y Desarrollo de Nuevos Fármacos e Innovación Biotecnológica, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Casco de Santo Tomás, Ciudad de México 11340, Mexico
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Zhang J, Wei W, Zhong Q, Feng K, Yang R, Jiang Q. Budding uninhibited by benzimidazoles 1 promotes cell proliferation, invasion, and epithelial-mesenchymal transition via the Wnt/β-catenin signaling in glioblastoma. Heliyon 2023; 9:e16996. [PMID: 37342577 PMCID: PMC10277463 DOI: 10.1016/j.heliyon.2023.e16996] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 05/31/2023] [Accepted: 06/02/2023] [Indexed: 06/23/2023] Open
Abstract
The pathogenesis and progression of GBM (glioblastoma), as one of the most frequently occurring malignancies of the central nervous system, are regulated by several genes. BUB1 (budding uninhibited by benzimidazoles 1) is a mitotic checkpoint that plays an important role in chromosome segregation as well as in various tumors. However, its role in glioma is unknown. The current study discovered prominently elevated BUB1 in glioma and a significant relationship between BUB1 expression, a high World Health Organization grade, and a poor prognosis in glioma patients. Moreover, BUB1 triggered EMT (epithelial-mesenchymal transition) apart from promoting glioma cell proliferation, migration, and infiltration. Besides, BUB1 promoted EMT by activating the Wnt/β-catenin axis. As implied by our study, BUB1 probably has the potential as a target for GBM management.
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Meng L, Hu YT, Xu AM. F-box and leucine-rich repeat 6 promotes gastric cancer progression via the promotion of epithelial-mesenchymal transition. World J Gastrointest Oncol 2023; 15:490-503. [PMID: 37009323 PMCID: PMC10052668 DOI: 10.4251/wjgo.v15.i3.490] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 01/06/2023] [Accepted: 02/15/2023] [Indexed: 03/14/2023] Open
Abstract
BACKGROUND F-box and leucine-rich repeat 6 (FBXL6) have reportedly been associated with several cancer types. However, the role and mechanisms of FBXL6 in gastric cancer (GC) require further elucidation.
AIM To investigate the effect of FBXL6 in GC tissues and cells and the underlying mechanisms.
METHODS TCGA and GEO database analysis was performed to evaluate the expression of FBXL6 in GC tissues and adjacent normal tissues. Reverse transcription-quantitative polymerase chain reaction, immunofluorescence, and western blotting were used to detect the expression of FBXL6 in GC tissue and cell lines. Cell clone formation, 5-ethynyl-2’-deoxyuridine (EdU) assays, CCK-8, transwell migration assay, and wound healing assays were performed to evaluate the malignant biological behavior in GC cell lines after transfection with FBXL6-shRNA and the overexpression of FBXL6 plasmids. Furthermore, in vivo tumor assays were performed to prove whether FBXL6 promoted cell proliferation in vivo.
RESULTS FBXL6 expression was upregulated more in tumor tissues than in adjacent normal tissues and positively associated with clinicopathological characteristics. The outcomes of CCK-8, clone formation, and Edu assays demonstrated that FBXL6 knockdown inhibited cell proliferation, whereas upregulation of FBXL6 promoted proliferation in GC cells. Additionally, the transwell migration assay revealed that FBXL6 knockdown suppressed migration and invasion, whereas the overexpression of FBXL6 showed the opposite results. Through the subcutaneous tumor implantation assay, it was evident that the knockdown of FBXL6 inhibited GC graft tumor growth in vivo. Western blotting showed that the effects of FBXL6 on the expression of the proteins associated with the epithelial-mesenchymal transition-associated proteins in GC cells.
CONCLUSION Silencing of FBXL6 inactivated the EMT pathway to suppress GC malignancy in vitro. FBXL6 can potentially be used for the diagnosis and targeted therapy of patients with GC.
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Affiliation(s)
- Lei Meng
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China
| | - Yu-Ting Hu
- Department of Immunology, College of Basic Medicine, Anhui Medical University, Hefei 230022, Anhui Province, China
| | - A-Man Xu
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China
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Effects and Mechanisms of Action of Preussin, a Marine Fungal Metabolite, against the Triple-Negative Breast Cancer Cell Line, MDA-MB-231, in 2D and 3D Cultures. Mar Drugs 2023; 21:md21030166. [PMID: 36976215 PMCID: PMC10053333 DOI: 10.3390/md21030166] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 03/01/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
Triple-negative breast cancer (TNBC) represents an aggressive subtype of breast cancer (BC) with a typically poorer prognosis than other subtypes of BC and limited therapeutic options. Therefore, new drugs would be particularly welcome to help treat TNBC. Preussin, isolated from the marine sponge-associated fungus, Aspergillus candidus, has shown the potential to reduce cell viability and proliferation as well as to induce cell death and cell cycle arrest in 2D cell culture models. However, studies that better mimic the tumors in vivo, such as 3D cell cultures, are needed. Here, we studied the effects of preussin in the MDA-MB-231 cell line, comparing 2D and 3D cell cultures, using ultrastructural analysis and the MTT, BrdU, annexin V-PI, comet (alkaline and FPG modified versions), and wound healing assays. Preussin was found to decrease cell viability, both in 2D and 3D cell cultures, in a dose-dependent manner, impair cell proliferation, and induce cell death, therefore excluding the hypothesis of genotoxic properties. The cellular impacts were reflected by ultrastructural alterations in both cell culture models. Preussin also significantly inhibited the migration of MDA-MB-231 cells. The new data expanded the knowledge on preussin actions while supporting other studies, highlighting its potential as a molecule or scaffold for the development of new anticancer drugs against TNBC.
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Antioxidant Properties of Hemp Proteins: From Functional Food to Phytotherapy and Beyond. Molecules 2022; 27:molecules27227924. [PMID: 36432024 PMCID: PMC9693028 DOI: 10.3390/molecules27227924] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 11/10/2022] [Accepted: 11/14/2022] [Indexed: 11/18/2022] Open
Abstract
As one of the oldest plants cultivated by humans, hemp used to be banned in the United States but returned as a legal crop in 2018. Since then, the United States has become the leading hemp producer in the world. Currently, hemp attracts increasing attention from consumers and scientists as hemp products provide a wide spectrum of potential functions. Particularly, bioactive peptides derived from hemp proteins have been proven to be strong antioxidants, which is an extremely hot research topic in recent years. However, some controversial disputes and unknown issues are still underway to be explored and verified in the aspects of technique, methodology, characteristic, mechanism, application, caution, etc. Therefore, this review focusing on the antioxidant properties of hemp proteins is necessary to discuss the multiple critical issues, including in vitro structure-modifying techniques and antioxidant assays, structure-activity relationships of antioxidant peptides, pre-clinical studies on hemp proteins and pathogenesis-related molecular mechanisms, usage and potential hazard, and novel advanced techniques involving bioinformatics methodology (QSAR, PPI, GO, KEGG), proteomic analysis, and genomics analysis, etc. Taken together, the antioxidant potential of hemp proteins may provide both functional food benefits and phytotherapy efficacy to human health.
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Singh T, Kaur P, Singh P, Singh S, Munshi A. Differential molecular mechanistic behavior of HDACs in cancer progression. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 39:171. [PMID: 35972597 DOI: 10.1007/s12032-022-01770-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 06/10/2022] [Indexed: 12/13/2022]
Abstract
Genetic aberration including mutation in oncogenes and tumor suppressor genes transforms normal cells into tumor cells. Epigenetic modifications work concertedly with genetic factors in controlling cancer development. Histone acetyltransferases (HATs), histone deacetylases (HDACs), DNA methyltransferases (DNMTs) and chromatin structure modifier are prospective epigenetic regulators. Specifically, HDACs are histone modifiers regulating the expression of genes implicated in cell survival, growth, apoptosis, and metabolism. The majority of HDACs are highly upregulated in cancer, whereas some have a varied function and expression in cancer progression. Distinct HDACs have a positive and negative role in controlling cancer progression. HDACs are also significantly involved in tumor cells acquiring metastatic and angiogenic potential in order to withstand the anti-tumor microenvironment. HDACs' role in modulating metabolic genes has also been associated with tumor development and survival. This review highlights and discusses the molecular mechanisms of HDACs by which they regulate cell survival, apoptosis, metastasis, invasion, stemness potential, angiogenesis, and epithelial to mesenchymal transitions (EMT) in tumor cells. HDACs are the potential target for anti-cancer drug development and various inhibitors have been developed and FDA approved for a variety of cancers. The primary HDAC inhibitors with proven anti-cancer efficacy have also been highlighted in this review.
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Affiliation(s)
- Tashvinder Singh
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151401, India
| | - Prabhsimran Kaur
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151401, India
| | | | - Sandeep Singh
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151401, India.
| | - Anjana Munshi
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151401, India.
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12
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Mirzaei S, Saghari S, Bassiri F, Raesi R, Zarrabi A, Hushmandi K, Sethi G, Tergaonkar V. NF-κB as a regulator of cancer metastasis and therapy response: A focus on epithelial-mesenchymal transition. J Cell Physiol 2022; 237:2770-2795. [PMID: 35561232 DOI: 10.1002/jcp.30759] [Citation(s) in RCA: 128] [Impact Index Per Article: 42.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 03/24/2022] [Accepted: 04/19/2022] [Indexed: 12/13/2022]
Abstract
Metastasis of tumor cells is a complex challenge and significantly diminishes the overall survival and prognosis of cancer patients. The epithelial-to-mesenchymal transition (EMT) is a well-known mechanism responsible for the invasiveness of tumor cells. A number of molecular pathways can regulate the EMT mechanism in cancer cells and nuclear factor-kappaB (NF-κB) is one of them. The nuclear translocation of NF-κB p65 can induce the transcription of several genes involved in EMT induction. The present review describes NF-κB and EMT interaction in cancer cells and their association in cancer progression. Due to the oncogenic role NF-κB signaling, its activation enhances metastasis of tumor cells via EMT induction. This has been confirmed in various cancers including brain, breast, lung and gastric cancers, among others. The ZEB1/2, transforming growth factor-β, and Slug as inducers of EMT undergo upregulation by NF-κB to promote metastasis of tumor cells. After EMT induction driven by NF-κB, a significant decrease occurs in E-cadherin levels, while N-cadherin and vimentin levels undergo an increase. The noncoding RNAs can potentially also function as upstream mediators and modulate NF-κB/EMT axis in cancers. Moreover, NF-κB/EMT axis is involved in mediating drug resistance in tumor cells. Thus, suppressing NF-κB/EMT axis can also promote the sensitivity of cancer cells to chemotherapeutic agents.
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Affiliation(s)
- Sepideh Mirzaei
- Department of Biology, Faculty of Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Sam Saghari
- Department of Health Services Management, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Farzaneh Bassiri
- Department of Biology, Fars Science and Research Branch, Islamic Azad University, Fars, Iran.,Department of Biology, Shiraz Branch, Islamic Azad University, Shiraz, Iran
| | - Rasoul Raesi
- PhD in Health Services Management, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, Turkey
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology and Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Yong Loo Lin School of Medicine, NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore, Singapore
| | - Vinay Tergaonkar
- Laboratory of NF-κB Signaling, Institute of Molecular and Cell Biology (IMCB), 61 Biopolis Drive, Proteos, Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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Kong F, Ma L, Wang X, You H, Zheng K, Tang R. Regulation of epithelial-mesenchymal transition by protein lysine acetylation. Cell Commun Signal 2022; 20:57. [PMID: 35484625 PMCID: PMC9052664 DOI: 10.1186/s12964-022-00870-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 03/20/2022] [Indexed: 01/01/2023] Open
Abstract
The epithelial-mesenchymal transition (EMT) is a vital driver of tumor progression. It is a well-known and complex trans-differentiation process in which epithelial cells undergo morphogenetic changes with loss of apical-basal polarity, but acquire spindle-shaped mesenchymal phenotypes. Lysine acetylation is a type of protein modification that favors reversibly altering the structure and function of target molecules via the modulation of lysine acetyltransferases (KATs), as well as lysine deacetylases (KDACs). To date, research has found that histones and non-histone proteins can be acetylated to facilitate EMT. Interestingly, histone acetylation is a type of epigenetic regulation that is capable of modulating the acetylation levels of distinct histones at the promoters of EMT-related markers, EMT-inducing transcription factors (EMT-TFs), and EMT-related long non-coding RNAs to control EMT. However, non-histone acetylation is a post-translational modification, and its effect on EMT mainly relies on modulating the acetylation of EMT marker proteins, EMT-TFs, and EMT-related signal transduction molecules. In addition, several inhibitors against KATs and KDACs have been developed, some of which can suppress the development of different cancers by targeting EMT. In this review, we discuss the complex biological roles and molecular mechanisms underlying histone acetylation and non-histone protein acetylation in the control of EMT, highlighting lysine acetylation as potential strategy for the treatment of cancer through the regulation of EMT.
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