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Qian C, Wang Q, Qiao Y, Xu Z, Zhang L, Xiao H, Lin Z, Wu M, Xia W, Yang H, Bai J, Geng D. Arachidonic acid in aging: New roles for old players. J Adv Res 2025; 70:79-101. [PMID: 38710468 PMCID: PMC11976421 DOI: 10.1016/j.jare.2024.05.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 04/26/2024] [Accepted: 05/03/2024] [Indexed: 05/08/2024] Open
Abstract
BACKGROUND Arachidonic acid (AA), one of the most ubiquitous polyunsaturated fatty acids (PUFAs), provides fluidity to mammalian cell membranes. It is derived from linoleic acid (LA) and can be transformed into various bioactive metabolites, including prostaglandins (PGs), thromboxanes (TXs), lipoxins (LXs), hydroxy-eicosatetraenoic acids (HETEs), leukotrienes (LTs), and epoxyeicosatrienoic acids (EETs), by different pathways. All these processes are involved in AA metabolism. Currently, in the context of an increasingly visible aging world population, several scholars have revealed the essential role of AA metabolism in osteoporosis, chronic obstructive pulmonary disease, and many other aging diseases. AIM OF REVIEW Although there are some reviews describing the role of AA in some specific diseases, there seems to be no or little information on the role of AA metabolism in aging tissues or organs. This review scrutinizes and highlights the role of AA metabolism in aging and provides a new idea for strategies for treating aging-related diseases. KEY SCIENTIFIC CONCEPTS OF REVIEW As a member of lipid metabolism, AA metabolism regulates the important lipids that interfere with the aging in several ways. We present a comprehensivereviewofthe role ofAA metabolism in aging, with the aim of relieving the extreme suffering of families and the heavy economic burden on society caused by age-related diseases. We also collected and summarized data on anti-aging therapies associated with AA metabolism, with the expectation of identifying a novel and efficient way to protect against aging.
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Affiliation(s)
- Chen Qian
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, PR China
| | - Qing Wang
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, PR China
| | - Yusen Qiao
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, PR China
| | - Ze Xu
- Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 17 Lujiang Road, Hefei, Anhui 230031, PR China
| | - Linlin Zhang
- Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 17 Lujiang Road, Hefei, Anhui 230031, PR China
| | - Haixiang Xiao
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, PR China
| | - Zhixiang Lin
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, PR China
| | - Mingzhou Wu
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, PR China
| | - Wenyu Xia
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, PR China
| | - Huilin Yang
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, PR China.
| | - Jiaxiang Bai
- Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 17 Lujiang Road, Hefei, Anhui 230031, PR China.
| | - Dechun Geng
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, PR China.
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Fu X, Ma J, Ma F, Guo S, Wang X, Li Y, Tang Y, Qi J, Zhang W, Ye L. MISP-mediated enhancement of pancreatic cancer growth through the Wnt/β-catenin signaling pathway is suppressed by Fisetin. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167515. [PMID: 39278512 DOI: 10.1016/j.bbadis.2024.167515] [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: 01/10/2024] [Revised: 09/04/2024] [Accepted: 09/10/2024] [Indexed: 09/18/2024]
Abstract
Pancreatic cancer is a highly malignant tumor characterized by high mortality and low survival rates. The mitotic interactor and substrate of Plk1 (MISP) is a cancer-associated protein that regulates mitotic spindle localization and is highly expressed in several malignant tumors, contributing to tumor development. However, the function and regulatory mechanisms of MISP in pancreatic cancer remain unclear. In this study, we analyzed RNA sequencing data related to pancreatic cancer from the TCGA and GEO databases, identifying MISP as a potential prognostic marker for the disease. MISP was significantly upregulated in pancreatic cancer cells and tissues compared to normal pancreatic cells and tissues. Notably, in pancreatic cancer cells, high MISP protein expression promoted cell proliferation and growth. Mechanistically, the upregulation of MISP facilitated the nuclear accumulation of β-catenin, thereby activating the Wnt/β-catenin signaling pathway and promoting pancreatic cancer growth. In search of effective inhibitors of MISP expression, we screened an FDA-approved drug library and identified Fisetin as a potential suppressor of MISP expression. Fisetin was found to downregulate the transcription factor MYB, thereby reducing MISP expression. Further experiments demonstrated that Fisetin effectively inhibited the in vitro and in vivo growth of pancreatic cancer by suppressing the MISP/Wnt/β-catenin signaling axis. In summary, our research has identified MISP as a novel therapeutic target in pancreatic cancer and uncovered its associated regulatory mechanisms.
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Affiliation(s)
- Xueli Fu
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Jiaqi Ma
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Fangyuan Ma
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Shiman Guo
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Xue Wang
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Ye Li
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Yanxin Tang
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Jingwei Qi
- Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90001, USA
| | - Weiying Zhang
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
| | - Lihong Ye
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
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Gajos-Michniewicz A, Czyz M. Therapeutic Potential of Natural Compounds to Modulate WNT/β-Catenin Signaling in Cancer: Current State of Art and Challenges. Int J Mol Sci 2024; 25:12804. [PMID: 39684513 DOI: 10.3390/ijms252312804] [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: 10/22/2024] [Revised: 11/22/2024] [Accepted: 11/26/2024] [Indexed: 12/18/2024] Open
Abstract
Targeted therapies and immunotherapies have improved the clinical outcome of cancer patients; however, the efficacy of treatment remains frequently limited due to low predictability of response and development of drug resistance. Therefore, novel therapeutic strategies for various cancer types are needed. Current research emphasizes the potential therapeutic value of targeting WNT/β-catenin dependent signaling that is deregulated in various cancer types. Targeting the WNT/β-catenin signaling pathway with diverse synthetic and natural agents is the subject of a number of preclinical studies and clinical trials for cancer patients. The usage of nature-derived agents is attributed to their health benefits, reduced toxicity and side effects compared to synthetic agents. The review summarizes preclinical studies and ongoing clinical trials that aim to target components of the WNT/β-catenin pathway across a diverse spectrum of cancer types, highlighting their potential to improve cancer treatment.
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Affiliation(s)
- Anna Gajos-Michniewicz
- Department of Molecular Biology of Cancer, Medical University of Lodz, 6/8 Mazowiecka Street, 92-215 Lodz, Poland
| | - Malgorzata Czyz
- Department of Molecular Biology of Cancer, Medical University of Lodz, 6/8 Mazowiecka Street, 92-215 Lodz, Poland
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Zamanian MY, Taheri N, Ramadan MF, Mustafa YF, Alkhayyat S, Sergeevna KN, Alsaab HO, Hjazi A, Molavi Vasei F, Daneshvar S. A comprehensive view on the fisetin impact on colorectal cancer in animal models: Focusing on cellular and molecular mechanisms. Animal Model Exp Med 2024; 7:591-605. [PMID: 39136058 PMCID: PMC11528395 DOI: 10.1002/ame2.12476] [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: 05/27/2024] [Revised: 06/21/2024] [Accepted: 07/09/2024] [Indexed: 11/02/2024] Open
Abstract
Flavonoids, including fisetin, have been linked to a reduced risk of colorectal cancer (CRC) and have potential therapeutic applications for the condition. Fisetin, a natural flavonoid found in various fruits and vegetables, has shown promise in managing CRC due to its diverse biological activities. It has been found to influence key cell signaling pathways related to inflammation, angiogenesis, apoptosis, and transcription factors. The results of this study demonstrate that fisetin induces colon cancer cell apoptosis through multiple mechanisms. It impacts the p53 pathway, leading to increased levels of p53 and decreased levels of murine double minute 2, contributing to apoptosis induction. Fisetin also triggers the release of important components in the apoptotic process, such as second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI and cytochrome c. Furthermore, fisetin inhibits the cyclooxygenase-2 and wingless-related integration site (Wnt)/epidermal growth factor receptor/nuclear factor kappa B signaling pathways, reducing Wnt target gene expression and hindering colony formation. It achieves this by regulating the activities of cyclin-dependent kinase 2 and cyclin-dependent kinase 4, reducing retinoblastoma protein phosphorylation, decreasing cyclin E levels, and increasing p21 levels, ultimately influencing E2 promoter binding factor 1 and cell division cycle 2 (CDC2) protein levels. Additionally, fisetin exhibits various effects on CRC cells, including inhibiting the phosphorylation of Y-box binding protein 1 and ribosomal S6 kinase, promoting the phosphorylation of extracellular signal-regulated kinase 1/2, and disrupting the repair process of DNA double-strand breaks. Moreover, fisetin serves as an adjunct therapy for the prevention and treatment of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA)-mutant CRC, resulting in a reduction in phosphatidylinositol-3 kinase (PI3K) expression, Ak strain transforming phosphorylation, mTOR activity, and downstream target proteins in CRC cells with a PIK3CA mutation. These findings highlight the multifaceted potential of fisetin in managing CRC and position it as a promising candidate for future therapy development.
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Affiliation(s)
- Mohammad Yasin Zamanian
- Department of Physiology, School of MedicineHamadan University of Medical SciencesHamadanIran
- Department of Pharmacology and Toxicology, School of PharmacyHamadan University of Medical SciencesHamadanIran
| | - Niloofar Taheri
- School of MedicineShahroud University of Medical SciencesShahroudIran
| | | | - Yasser Fakri Mustafa
- Department of Pharmaceutical ChemistryCollege of Pharmacy, University of MosulMosulIraq
| | | | - Klunko Nataliya Sergeevna
- Department of Training of Scientific and Scientific‐Pedagogical PersonnelRussian New UniversityMoscowRussian Federation
| | - Hashem O. Alsaab
- Department of Pharmaceutics and Pharmaceutical TechnologyTaif UniversityTaifSaudi Arabia
| | - Ahmed Hjazi
- Department of Medical LaboratoryCollege of Applied Medical Sciences, Prince Sattam bin Abdulaziz UniversityAl‐KharjSaudi Arabia
| | - Farnoosh Molavi Vasei
- Department of Clinical Biochemistry, School of MedicineRafsanjan University of Medical SciencesRafsanjanIran
| | - Siamak Daneshvar
- Department of Surgery, School of MedicineHamadan University of Medical SciencesHamadanIran
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Zehra K, Banu A, Can E, Hülya C. Fisetin and/or capecitabine causes changes in apoptosis pathways in capecitabine-resistant colorectal cancer cell lines. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:7913-7926. [PMID: 38748229 PMCID: PMC11449987 DOI: 10.1007/s00210-024-03145-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 05/03/2024] [Indexed: 10/04/2024]
Abstract
Capecitabine is recommended as one of the first-line chemotherapy treatments for advanced or metastatic colorectal cancer. Researches have been conducted on capecitabine's impact on the viability of human colon cancer cells and its potential to induce apoptosis. However, even in cases initially responsive to treatment, the development of acquired resistance significantly limits its efficacy. Challenges still exist in effectively treating patients with chemotherapy, and developing new cytotoxic drugs is hindered by drug resistance. Fisetin alters the cell cycle, inducing apoptosis, inhibiting cancer cell proliferation, and enhancing the therapeutic effectiveness of chemotherapy drugs. This work aims to create a plan for reversing capecitabine resistance. For this purpose, the role of capecitabine and/or fisetin combinations in cell proliferation and apoptosis has been determined in both wild-type and capecitabine-resistant HT29 cells (CR/HT29). We developed capecitabine-resistant cell line from wild-type HT29 cells. This study demonstrated the effects of capecitabine, fisetin, and their combinations on both resistant and wild-type cells through experiments including cell survival skills, cell proliferation, wound healing, colony formation, hoechst staining, and western blot analysis. We established capecitabine-resistant cell lines. P-gp expression increased in CR/HT29 cells. Capecitabine effects on a CR/HT29 cells less than wild-type HT29 cells. The combination of fisetin and capecitabine in cell proliferation caused greater reductions in wild-type HT29 cells than in capecitabine-resistant cells. Fisetin has also additive effects on the apoptotic pathway in CR/HT29 cells. This study provides new perspectives on the combination of capecitabine and/or flavonoid treatment in resistant cells.
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Affiliation(s)
- Kanli Zehra
- Institute of Health Sciences, Marmara University, Basibuyuk-Maltepe, Istanbul, 34854, Turkey
| | - Aydin Banu
- School of Medicine, Department of Biophysics, Marmara University, Basic Medical Sciences Building, Maltepe, Istanbul, 34854, Turkey
| | - Erzik Can
- School of Medicine, Department of Medical Biology, Marmara University, Basic Medical Sciences Building, Maltepe, Istanbul, 34854, Turkey
| | - Cabadak Hülya
- School of Medicine, Department of Biophysics, Marmara University, Basic Medical Sciences Building, Maltepe, Istanbul, 34854, Turkey.
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Sharma V, Chaudhary AA, Bawari S, Gupta S, Mishra R, Khan SUD, Ali MAM, Shahid M, Srivastava S, Verma D, Gupta A, Kumar S, Kumar S. Unraveling cancer progression pathways and phytochemical therapeutic strategies for its management. Front Pharmacol 2024; 15:1414790. [PMID: 39246660 PMCID: PMC11377287 DOI: 10.3389/fphar.2024.1414790] [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: 04/09/2024] [Accepted: 05/09/2024] [Indexed: 09/10/2024] Open
Abstract
Cancer prevention is currently envisioned as a molecular-based approach to prevent carcinogenesis in pre-cancerous stages, i.e., dysplasia and carcinoma in situ. Cancer is the second-leading cause of mortality worldwide, and a more than 61% increase is expected by 2040. A detailed exploration of cancer progression pathways, including the NF-kβ signaling pathway, Wnt-B catenin signaling pathway, JAK-STAT pathway, TNF-α-mediated pathway, MAPK/mTOR pathway, and apoptotic and angiogenic pathways and effector molecules involved in cancer development, has been discussed in the manuscript. Critical evaluation of these effector molecules through molecular approaches using phytomolecules can intersect cancer formation and its metastasis. Manipulation of effector molecules like NF-kβ, SOCS, β-catenin, BAX, BAK, VEGF, STAT, Bcl2, p53, caspases, and CDKs has played an important role in inhibiting tumor growth and its spread. Plant-derived secondary metabolites obtained from natural sources have been extensively studied for their cancer-preventing potential in the last few decades. Eugenol, anethole, capsaicin, sanguinarine, EGCG, 6-gingerol, and resveratrol are some examples of such interesting lead molecules and are mentioned in the manuscript. This work is an attempt to put forward a comprehensive approach to understanding cancer progression pathways and their management using effector herbal molecules. The role of different plant metabolites and their chronic toxicity profiling in modulating cancer development pathways has also been highlighted.
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Affiliation(s)
- Vikas Sharma
- Metro College of Health Sciences and Research, Greater Noida, India
- School of Pharmacy, Sharda University, Greater Noida, India
| | - Anis Ahmad Chaudhary
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia
| | - Sweta Bawari
- Amity Institute of Pharmacy, Amity University, Noida, India
| | - Saurabh Gupta
- Department of Biotechnology, GLA University, Mathura, India
| | - Richa Mishra
- Department of Computer Engineering, Parul University, Vadodara, India
| | - Salah-Ud-Din Khan
- Department of Biochemistry, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia
| | - Mohamed A M Ali
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Mohammad Shahid
- Department of Basic Medical Sciences, College of Medicine, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | | | - Devvrat Verma
- Department of Biotechnology, Graphic Era (Deemed to be University), Dehradun, Uttarakhand, India
| | - Arti Gupta
- Lloyd School of Pharmacy, Greater Noida, India
| | - Sanjay Kumar
- Biological and Bio-computational Laboratory, Department of Life Science, Sharda School of Basic Sciences and Research, Sharda University, Greater Noida, India
| | - Sandeep Kumar
- School of Pharmacy, Sharda University, Greater Noida, India
- DST-FIST Laboratory, Department of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida, India
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Klekowski J, Chabowski M. Nutritional Strategy for Cancer-From Prevention to Aftercare. Nutrients 2024; 16:1437. [PMID: 38794675 PMCID: PMC11123879 DOI: 10.3390/nu16101437] [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: 04/17/2024] [Accepted: 04/22/2024] [Indexed: 05/26/2024] Open
Abstract
In recent decades, there has been a noteworthy increase in the efficacy of oncological treatments for a variety of neoplasms, which has improved the overall results and survival rates in cancer therapy [...].
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Affiliation(s)
- Jakub Klekowski
- Department of Nursing and Obstetrics, Division of Anesthesiological and Surgical Nursing, Faculty of Health Science, Wroclaw Medical University, 50-367 Wroclaw, Poland;
- Department of Surgery, 4th Military Clinical Hospital, 50-981 Wroclaw, Poland
| | - Mariusz Chabowski
- Department of Surgery, 4th Military Clinical Hospital, 50-981 Wroclaw, Poland
- Department of Clinical Surgical Sciences, Faculty of Medicine, Wroclaw University of Science and Technology, 50-556 Wroclaw, Poland
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Sharma V, Arora A, Bansal S, Semwal A, Sharma M, Aggarwal A. Role of bio-flavonols and their derivatives in improving mitochondrial dysfunctions associated with pancreatic tumorigenesis. Cell Biochem Funct 2024; 42:e3920. [PMID: 38269510 DOI: 10.1002/cbf.3920] [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: 09/06/2023] [Revised: 11/30/2023] [Accepted: 12/27/2023] [Indexed: 01/26/2024]
Abstract
Mitochondria, a cellular metabolic center, efficiently fulfill cellular energy needs and regulate crucial metabolic processes, including cellular proliferation, differentiation, apoptosis, and generation of reactive oxygen species. Alteration in the mitochondrial functions leads to metabolic imbalances and altered extracellular matrix dynamics in the host, utilized by solid tumors like pancreatic cancer (PC) to get energy benefits for fast-growing cancer cells. PC is highly heterogeneous and remains unidentified for a longer time because of its complex pathophysiology, retroperitoneal position, and lack of efficient diagnostic approaches, which is the foremost reason for accounting for the seventh leading cause of cancer-related deaths worldwide. PC cells often respond poorly to current therapeutics because of dense stromal barriers in the pancreatic tumor microenvironment, which limit the drug delivery and distribution of antitumor immune cell populations. As an alternative approach, various natural compounds like flavonoids are reported to possess potent antioxidant and anticancerous properties and are less toxic than current chemotherapeutic drugs. Therefore, we aim to summarize the current state of knowledge regarding the pharmacological properties of flavonols in PC in this review from the perspective of mitigating mitochondrial dysfunctions associated with cancer cells. Our literature survey indicates that flavonols efficiently regulate cellular metabolism by scavenging reactive oxygen species, mitigating inflammation, and arresting the cell cycle to promote apoptosis in tumor cells via intrinsic mitochondrial pathways. In particular, flavonols proficiently inhibit the cancer-associated proliferation and inflammatory pathways such as EGFR/MAPK, PI3K/Akt, and nuclear factor κB in PC. Overall, this review provides in-depth evidence about the therapeutic potential of flavonols for future anticancer strategies against PC; still, more multidisciplinary human interventional studies are required to dissect their pharmacological effect accurately.
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Affiliation(s)
- Vinit Sharma
- Department of Anatomy, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Ankita Arora
- Department of Anatomy, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Sakshi Bansal
- Department of Anatomy, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Ankita Semwal
- Department of Anatomy, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Mayank Sharma
- Department of Anatomy, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Anjali Aggarwal
- Department of Anatomy, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
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Markowska A, Antoszczak M, Kacprzak K, Markowska J, Huczyński A. Role of Fisetin in Selected Malignant Neoplasms in Women. Nutrients 2023; 15:4686. [PMID: 37960338 PMCID: PMC10648688 DOI: 10.3390/nu15214686] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 10/31/2023] [Accepted: 11/03/2023] [Indexed: 11/15/2023] Open
Abstract
A promising therapeutic window and cost-effectiveness are just two of the potential advantages of using naturally derived drugs. Fisetin (3,3',4',7-tetrahydroxyflavone) is a natural flavonoid of the flavonol group, commonly found in fruit and vegetables. In recent years, fisetin has gained wide attention across the scientific community because of its broad spectrum of pharmacological properties, including cytotoxic activity against most abundant cancers. By stimulating or inhibiting selected molecular targets or biochemical processes, fisetin could affect the reduction of metastasis or cancer progression, which indicates its chemotherapeutic or chemopreventive role. In this review, we have summarized the results of studies on the anticancer effects of fisetin on selected female malignancies, both in in vitro and in vivo tests, i.e., breast, cervical, and ovarian cancer, published over the past two decades. Until now, no article dedicated exclusively to the action of fisetin on female malignancies has appeared. This review also describes a growing number of nanodelivery systems designed to improve the bioavailability and solubility of this natural compound. The reported low toxicity and activity of fisetin on cancer cells indicate its valuable potential, but large-scale clinical trials are urgently needed to assess real chemotherapeutic efficacy of this flavonoid.
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Affiliation(s)
- Anna Markowska
- Department of Perinatology and Women’s Health, Poznań University of Medical Sciences, 60-535 Poznań, Poland;
| | - Michał Antoszczak
- Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, 61-614 Poznań, Poland; (M.A.); (K.K.)
| | - Karol Kacprzak
- Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, 61-614 Poznań, Poland; (M.A.); (K.K.)
| | - Janina Markowska
- Gynecological Oncology Center, Poznańska 58A, 60-850 Poznań, Poland;
| | - Adam Huczyński
- Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, 61-614 Poznań, Poland; (M.A.); (K.K.)
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Gupta M, Ahmad J, Ahamad J, Kundu S, Goel A, Mishra A. Flavonoids as promising anticancer therapeutics: Contemporary research, nanoantioxidant potential, and future scope. Phytother Res 2023; 37:5159-5192. [PMID: 37668281 DOI: 10.1002/ptr.7975] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 06/30/2023] [Accepted: 07/21/2023] [Indexed: 09/06/2023]
Abstract
Flavonoids are natural polyphenolic compounds considered safe, pleiotropic, and readily available molecules. It is widely distributed in various food products such as fruits and vegetables and beverages such as green tea, wine, and coca-based products. Many studies have reported the anticancer potential of flavonoids against different types of cancers, including solid tumors. The chemopreventive effect of flavonoids is attributed to various mechanisms, including modulation of autophagy, induction of cell cycle arrest, apoptosis, and antioxidant defense. Despite of significant anticancer activity of flavonoids, their clinical translation is limited due to their poor biopharmaceutical attributes (such as low aqueous solubility, limited permeability across the biological membranes (intestinal and blood-brain barrier), and stability issue in biological systems). A nanoparticulate system is an approach that is widely utilized to improve the biopharmaceutical performance and therapeutic efficacy of phytopharmaceuticals. The present review discusses the significant anticancer potential of promising flavonoids in different cancers and the utilization of nanoparticulate systems to improve their nanoantioxidant activity further to enhance the anticancer activity of loaded promising flavonoids. Although, various plant-derived secondary metabolites including flavonoids have been recommended for treating cancer, further vigilant research is warranted to prove their translational values.
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Affiliation(s)
- Mukta Gupta
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Javed Ahmad
- Department of Pharmaceutics, College of Pharmacy, Najran University, Najran, Saudi Arabia
| | - Javed Ahamad
- Department of Pharmacognosy, Faculty of Pharmacy, Tishk International University, Erbil, Iraq
| | - Snehashis Kundu
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Assam, India
| | - Archit Goel
- All India Institute of Medical Sciences (AIIMS), Bathinda, Punjab, India
| | - Awanish Mishra
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Assam, India
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Kim N, Kwon J, Shin US, Jung J. Fisetin induces the upregulation of AKAP12 mRNA and anti-angiogenesis in a patient-derived organoid xenograft model. Biomed Pharmacother 2023; 167:115613. [PMID: 37801904 DOI: 10.1016/j.biopha.2023.115613] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 09/22/2023] [Accepted: 09/27/2023] [Indexed: 10/08/2023] Open
Abstract
Colorectal cancer (CRC) is associated with high incidence and mortality rates. Targeted therapies for CRC cause various adverse effects, necessitating the development of novel approaches to control CRC progression. In this milieu, we investigated the anti-CRC effects of fisetin, a natural plant flavonoid. Cytotoxicity was performed in CRC patient-derived organoids (30 T and 33 T). Fisetin-induced tumor growth was evaluated in a CRC patient-derived organoid xenograft (PDOX) model. RNA sequencing, immunohistochemistry, and western blotting were performed subsequently. Fisetin significantly decreased organoid viability in a dose-dependent manner. In the PDOX model, fisetin significantly delayed tumor growth, showing a decrease in Ki-67 expression and the induction of apoptosis. In tumor tissues, four genes were identified as differentially expressed between the control and fisetin-treated groups. Among these, A-kinase anchoring protein 12 (AKAP12) level was significantly increased by fisetin treatment (fold change > 2, p < 0.05). Notably, fisetin significantly inhibited vascular endothelial growth factor (VEGF) and epithelial cell adhesion molecule (EpCAM) via upregulation of AKAP12. Our results demonstrate the upregulation of AKAP12 mRNA and inhibition of angiogenesis by fisetin as a therapeutic strategy against CRC.
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Affiliation(s)
- Nayun Kim
- Duksung Innovative Drug Center, Duksung Women's University, Seoul 01369, the Republic of Korea; College of Pharmacy, Duksung Women's University, Seoul 01369, the Republic of Korea
| | - Junhye Kwon
- Department of Radiological & Clinical Research, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul 01812, the Republic of Korea
| | - Ui Sup Shin
- Department of Surgery, Korea Cancer Center Hospital, KIRAMS, Seoul 01812, the Republic of Korea
| | - Joohee Jung
- Duksung Innovative Drug Center, Duksung Women's University, Seoul 01369, the Republic of Korea; College of Pharmacy, Duksung Women's University, Seoul 01369, the Republic of Korea.
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12
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Qaed E, Al-Hamyari B, Al-Maamari A, Qaid A, Alademy H, Almoiliqy M, Munyemana JC, Al-Nusaif M, Alafifi J, Alyafeai E, Safi M, Geng Z, Tang Z, Ma X. Fisetin's Promising Antitumor Effects: Uncovering Mechanisms and Targeting for Future Therapies. Glob Med Genet 2023; 10:205-220. [PMID: 37565061 PMCID: PMC10412067 DOI: 10.1055/s-0043-1772219] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/12/2023] Open
Abstract
Background Cancer remains a critical global health challenge and a leading cause of mortality. Flavonoids found in fruits and vegetables have gained attention for their potential anti-cancer properties. Fisetin, abundantly present in strawberries, apples, onions, and other plant sources, has emerged as a promising candidate for cancer prevention. Epidemiological studies linking a diet rich in these foods to lower cancer risk have sparked extensive research on fisetin's efficacy. Objective This review aims to comprehensively explore the molecular mechanisms of fisetin's anticancer properties and investigate its potential synergistic effects with other anticancer drugs. Furthermore, the review examines the therapeutic and preventive effects of fisetin against various cancers. Methods A systematic analysis of the available scientific literature was conducted, including research articles, clinical trials, and review papers related to fisetin's anticancer properties. Reputable databases were searched, and selected studies were critically evaluated to extract essential information on fisetin's mechanisms of action and its interactions with other anticancer drugs. Results Preclinical trials have demonstrated that fisetin inhibits cancer cell growth through mechanisms such as cell cycle alteration, induction of apoptosis, and activation of the autophagy signaling pathway. Additionally, fisetin reduces reactive oxygen species levels, contributing to its overall anticancer potential. Investigation of its synergistic effects with other anticancer drugs suggests potential for combination therapies. Conclusion Fisetin, a bioactive flavonoid abundant in fruits and vegetables, exhibits promising anticancer properties through multiple mechanisms of action. Preclinical trials provide a foundation for further exploration in human clinical trials. Understanding fisetin's molecular mechanisms is vital for developing novel, safe, and effective cancer prevention and treatment strategies. The potential synergy with other anticancer drugs opens new avenues for combination therapies, enhancing cancer management approaches and global health outcomes.
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Affiliation(s)
- Eskandar Qaed
- State Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, People's Republic of China
| | - Bandar Al-Hamyari
- School of Pharmacy and State Key Laboratory of Applied Organic Chemistry, Lanzhou University, People's Republic of China
| | - Ahmed Al-Maamari
- The Key Laboratory of Neural and Vascular Biology, The Key Laboratory of New Drug Pharmacology and Toxicology, Department of Pharmacology, Ministry of Education, Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Abdullah Qaid
- N.I. Pirogov Russian National Research Medical University, Russia
| | - Haneen Alademy
- Taiz University Faculty of Medicine and Health Science, Yemen
| | - Marwan Almoiliqy
- Department of Pharmacy, Faculty of Medicine and Health Sciences, University of Science and Technology, Aden, Yemen
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Jean Claude Munyemana
- State Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, People's Republic of China
| | - Murad Al-Nusaif
- Department of Neurology and Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China
| | - Jameel Alafifi
- School of Pharmacy and State Key Laboratory of Applied Organic Chemistry, Lanzhou University, People's Republic of China
| | - Eman Alyafeai
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Mohammed Safi
- Department of Pharmacy, Dalian Medical University, Dalian, People's Republic of China
| | - Zhaohong Geng
- Department of Cardiology, 2nd Affiliated Hospital of Dalian Medical University, Dalian, People's Republic of China
| | - Zeyao Tang
- Department of Pharmacy, Dalian Medical University, Dalian, People's Republic of China
| | - Xiaodong Ma
- Department of Pharmacy, Dalian Medical University, Dalian, People's Republic of China
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Imtiyaz K, Husain Rahmani A, Alsahli MA, Almatroodi SA, Rizvi MMA. Fisetin induces apoptosis in human skin cancer cells through downregulating MTH1. J Biomol Struct Dyn 2023; 41:7339-7353. [PMID: 36129011 DOI: 10.1080/07391102.2022.2121323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 08/27/2022] [Indexed: 10/14/2022]
Abstract
Fisetin, a natural flavonoid molecule, has been shown to have anticancer properties against various malignancies. In this investigation, we discovered that Fisetin decreased cell viability of both the treated skin cancer cell lines A375 and A431 in a dose and time-dependent manner. The IC50 values ranging from 57.60 µM ± 6.59 to 41.70 µM ± 1.25 in A375 and 48.70 µM ± 5.49 to 33.67 µM ± 1.03 for A431 at the observed time ranging between 24 h to 72 h of treatment remained quite enthusiastic when compared with the normal HEK 293 cells. Fisetin significantly decreased colony formation and migratory ability of the cancer cells. Flow cytometry analysis revealed that Fisetin significantly restricted the progression of skin cancer cells in the G0/G1 phase of the cell cycle and induced cells to undergo apoptosis by increasing reactive oxygen species, decreasing mitochondrial membrane potential, and elevating the count of early and late apoptotic cells. Our in silico studies of molecular docking followed by molecular dynamics simulation found that the interactions and stability of MTH1 protein with Fisetin further showed a considerable binding affinity for MTH1 (-11.4 kcal/mol) and developed stable complexes maintained throughout 100 ns trajectories. Our western blot analysis endorsed this. We found that Fisetin downregulated the expression levels of MTH1 also in addition, it played a crucial role in regulation of apoptotic events in cancer cells. We therefore, conclude that Fisetin anticancer properties against skin cancer cells are mediated through MTH1 inhibition followed by ATM and P53 upregulation.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Khalid Imtiyaz
- Department of Bioscience, Genome Biology Lab, New Delhi, India
| | - Arshad Husain Rahmani
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Mohammed A Alsahli
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Saleh A Almatroodi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
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14
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Pandey A, Trigun SK. Fisetin induces apoptosis in colorectal cancer cells by suppressing autophagy and down-regulating nuclear factor erythroid 2-related factor 2 (Nrf2). J Cell Biochem 2023; 124:1289-1308. [PMID: 37450699 DOI: 10.1002/jcb.30447] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 07/04/2023] [Accepted: 07/07/2023] [Indexed: 07/18/2023]
Abstract
Modulation of autophagy is evolving as a relevant strategy in cancer pathogenesis and therapeutic intervention and hence, needs to be examined as a target for the promising anticancer agents. Fisetin, a dietary flavanol, is emerging as a potent anticancer agent, however, its tumour-specific pharmacological targets remain largely unexplored. This article describes correlative profiles of autophagy and apoptotic markers versus nuclear factor erythroid 2-related factor 2 (Nrf2) and reactive oxygen species (ROS) in the colorectal cancer (CRC) cell line SW-480. As compared to the untreated cells, significantly less number of fluorescent detected autophagic vacuoles (AVOs) in the fisetin-treated cells coincided with a similar decline of the autophagy flux markers, Beclin 1 and microtubule-associated protein-1 light chain-3 and accumulation of p62 in those cells. The significantly increased number of annexin-V/propidium iodide (+/+) positive and acridine orange/ethidium bromide-stained apoptotic cells coincided with the enhanced signals for the cleaved caspase 3 and nuclear PARP-1 in those fisetin-treated cells. This was consistent with the collapse of mitochondrial membrane potential and release of cytochrome c. The fisetin-treated cells showed increased ROS level and a significant decline in nuclear Nrf2 immunosignal versus recovery in nuclear Nrf2 due to the treatment with curcumin and resveratrol (Nrf2 activators) and thus, suggesting a role of Nrf2 suppression in fisetin-mediated apoptosis in SW-480 cells. The effect of chloroquine, an autophagy inhibitor, resulted into declined number of AVOs and enhanced apoptosis, similar to that of the fisetin effect. Also, regaining of AVOs number and reduced apoptosis of CRC cells due to the treatment with rapamycin, an autophagy inducer, could be observed. These loss and gain of functions experiments thus suggested a correlation between fisetin-mediated autophagy suppression and apoptotic induction in a colorectal cell line.
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Affiliation(s)
- Akanksha Pandey
- Department of Zoology, Biochemistry Section, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Surendra Kumar Trigun
- Department of Zoology, Biochemistry Section, Institute of Science, Banaras Hindu University, Varanasi, India
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15
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Park CR, Bae HR, Lee GY, Son CG, Cho JH, Cho CK, Lee NH. Feasibility of combination of Gun-Chil-Jung and cytokine-induced killer cells-based immunotherapy for terminal hepatocellular carcinoma patient: a case report. Front Pharmacol 2023; 14:1203379. [PMID: 37719842 PMCID: PMC10502300 DOI: 10.3389/fphar.2023.1203379] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 08/21/2023] [Indexed: 09/19/2023] Open
Abstract
Introduction: Terminal-stage hepatocellular carcinoma (HCC) is inoperable and currently has no form of adjuvant therapy. This study examined the anticancer herbal extract Gun-Chil-Jung (GCJ) combined with cytokine-induced killer (CIK)-cell-based immunotherapy as a palliative therapy for terminal HCC. We report the case of an HCC patient with extended overall survival and improved symptoms and tumor marker levels following combination therapy with GCJ and CIK cell-based immunotherapy. Baseline Characteristics: From March to July 2020, a 57-year-old man who had been diagnosed with HCC underwent combination treatment with GCJ and CIK cell-based immunotherapy. By August 2021, he was prescribed GCJ. After treatment, the patient's condition was evaluated with respect to overall survival, tumor markers, symptoms, abdominal computed tomography findings, chest x-ray results, and Eastern Cooperative Oncology Group (ECOG) grade. Results: The patient's overall survival, tumor marker levels, ECOG grade, and symptoms, including ascites, lower limb edema, jaundice, pleural effusion, and fatigue, were largely alleviated. Conclusion: We expect that this combination therapy may be an option for palliative therapy of terminal HCC.
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Affiliation(s)
- Chan-Ran Park
- Department of Hepatology and Hematology, Graduated School of Korean Medicine, Daejeon University, Daejeon, Republic of Korea
| | - Hye-Ri Bae
- Department of Hepatology and Hematology, Graduated School of Korean Medicine, Daejeon University, Daejeon, Republic of Korea
- East-West Cancer Center, Cheonan Korean Medical Hospital, Daejeon University, Daejeon, Republic of Korea
| | - Ga-Young Lee
- Department of Hepatology and Hematology, Graduated School of Korean Medicine, Daejeon University, Daejeon, Republic of Korea
| | - Chang-Gue Son
- Department of Hepatology and Hematology, Graduated School of Korean Medicine, Daejeon University, Daejeon, Republic of Korea
- Department of Internal Medicine, Daejeon Korean Medicine Hospital of Daejeon University, Daejeon, Republic of Korea
| | - Jung-Hyo Cho
- Department of Hepatology and Hematology, Graduated School of Korean Medicine, Daejeon University, Daejeon, Republic of Korea
- Department of Internal Medicine, Daejeon Korean Medicine Hospital of Daejeon University, Daejeon, Republic of Korea
| | - Chong-Kwan Cho
- Department of Hepatology and Hematology, Graduated School of Korean Medicine, Daejeon University, Daejeon, Republic of Korea
- Department of Internal Medicine, Daejeon Korean Medicine Hospital of Daejeon University, Daejeon, Republic of Korea
| | - Nam-Hun Lee
- Department of Hepatology and Hematology, Graduated School of Korean Medicine, Daejeon University, Daejeon, Republic of Korea
- East-West Cancer Center, Cheonan Korean Medical Hospital, Daejeon University, Daejeon, Republic of Korea
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Hosseinzadeh A, Poursoleiman F, Biregani AN, Esmailzadeh A. Flavonoids target different molecules of autophagic and metastatic pathways in cancer cells. Cancer Cell Int 2023; 23:114. [PMID: 37308913 DOI: 10.1186/s12935-023-02960-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 05/30/2023] [Indexed: 06/14/2023] Open
Abstract
Despite the success of cancer therapy, it has encountered a major obstacle due to the complicated nature of cancer, namely resistance. The recurrence and metastasis of cancer occur when anti-cancer therapeutic agents fail to eradicate all cancer cells. Cancer therapy aims to find the best agent that targets all cancer cells, including those sensitive or resistant to treatment. Flavonoids, natural products from our diet, show anti-cancer effects in different studies. They can inhibit metastasis and the recurrence of cancers. This review discusses metastasis, autophagy, anoikis in cancer cells, and their dynamic relationship. We present evidence that flavonoids can block metastasis and induce cell death in cancer cells. Our research suggests that flavonoids can serve as potential therapeutic agents in cancer therapy.
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Affiliation(s)
- Aysooda Hosseinzadeh
- Department of Immunology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Faezeh Poursoleiman
- Department of Cellular and Molecular Nutrition, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Akram Naghdipour Biregani
- Department of Nutrition, School of Health, Shahid Sadoughi University of Medical Scinences, Yazd, Iran
| | - Ahmad Esmailzadeh
- Students' Scientific Center, Tehran University of Medical Sciences, Tehran, Iran.
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran.
- Food Security Research Center, Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran.
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17
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Russo M, Moccia S, Luongo D, Russo GL. Senolytic Flavonoids Enhance Type-I and Type-II Cell Death in Human Radioresistant Colon Cancer Cells through AMPK/MAPK Pathway. Cancers (Basel) 2023; 15:cancers15092660. [PMID: 37174126 PMCID: PMC10177236 DOI: 10.3390/cancers15092660] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/04/2023] [Accepted: 05/05/2023] [Indexed: 05/15/2023] Open
Abstract
Resistance to cancer therapies remains a clinical challenge and an unsolved problem. In a previous study, we characterized a new colon cancer cell line, namely HT500, derived from human HT29 cells and resistant to clinically relevant levels of ionizing radiation (IR). Here, we explored the effects of two natural flavonoids, quercetin (Q) and fisetin (F), well-known senolytic agents that inhibit genotoxic stress by selectively removing senescent cells. We hypothesized that the biochemical mechanisms responsible for the radiosensitising effects of these natural senolytics could intercept multiple biochemical pathways of signal transduction correlated to cell death resistance. Radioresistant HT500 cells modulate autophagic flux differently than HT29 cells and secrete pro-inflammatory cytokines (IL-8), commonly associated with senescence-related secretory phenotypes (SASP). Q and F inhibit PI3K/AKT and ERK pathways, which promote p16INK4 stability and resistance to apoptosis, but they also activate AMPK and ULK kinases in response to autophagic stress at an early stage. In summary, the combination of natural senolytics and IR activates two forms of cell death: apoptosis correlated to the inhibition of ERKs and lethal autophagy dependent on AMPK kinase. Our study confirms that senescence and autophagy partially overlap, share common modulatory pathways, and reveal how senolytic flavonoids can play an important role in these processes.
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Affiliation(s)
- Maria Russo
- Institute of Food Sciences, National Research Council, 83100 Avellino, Italy
| | - Stefania Moccia
- Institute of Food Sciences, National Research Council, 83100 Avellino, Italy
| | - Diomira Luongo
- Institute of Food Sciences, National Research Council, 83100 Avellino, Italy
| | - Gian Luigi Russo
- Institute of Food Sciences, National Research Council, 83100 Avellino, Italy
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18
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Pandey P, Khan F, Seifeldin SA, Alshaghdali K, Siddiqui S, Abdelwadoud ME, Vyas M, Saeed M, Mazumder A, Saeed A. Targeting Wnt/β-Catenin Pathway by Flavonoids: Implication for Cancer Therapeutics. Nutrients 2023; 15:2088. [PMID: 37432240 DOI: 10.3390/nu15092088] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 04/17/2023] [Accepted: 04/20/2023] [Indexed: 07/12/2023] Open
Abstract
The Wnt pathway has been recognized for its crucial role in human development and homeostasis, but its dysregulation has also been linked to several disorders, including cancer. Wnt signaling is crucial for the development and metastasis of several kinds of cancer. Moreover, members of the Wnt pathway have been proven to be effective biomarkers and promising cancer therapeutic targets. Abnormal stimulation of the Wnt signaling pathway has been linked to the initiation and advancement of cancer in both clinical research and in vitro investigations. A reduction in cancer incidence rate and an improvement in survival may result from targeting the Wnt/β-catenin pathway. As a result, blocking this pathway has been the focus of cancer research, and several candidates that can be targeted are currently being developed. Flavonoids derived from plants exhibit growth inhibitory, apoptotic, anti-angiogenic, and anti-migratory effects against various malignancies. Moreover, flavonoids influence different signaling pathways, including Wnt, to exert their anticancer effects. In this review, we comprehensively evaluate the influence of flavonoids on cancer development and metastasis by focusing on the Wnt/β-catenin signaling pathway, and we provide evidence of their impact on a number of molecular targets. Overall, this review will enhance our understanding of these natural products as Wnt pathway modulators.
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Affiliation(s)
- Pratibha Pandey
- Department of Biotechnology, Noida Institute of Engineering and Technology, Greater Noida 201306, India
| | - Fahad Khan
- Department of Biotechnology, Noida Institute of Engineering and Technology, Greater Noida 201306, India
| | - Sara A Seifeldin
- Department of Medical Laboratory Science, College of Applied Medical Sciences, University of Ha'il, Hail 55476, Saudi Arabia
- Medical and Diagnostic Research Centre, University of Hail, Ha'il 55473, Saudi Arabia
| | - Khalid Alshaghdali
- Department of Medical Laboratory Science, College of Applied Medical Sciences, University of Ha'il, Hail 55476, Saudi Arabia
- Medical and Diagnostic Research Centre, University of Hail, Ha'il 55473, Saudi Arabia
| | - Samra Siddiqui
- Medical and Diagnostic Research Centre, University of Hail, Ha'il 55473, Saudi Arabia
- Department of Public Health, College of Health Sciences, University of Ha'il, Hail 55476, Saudi Arabia
| | - Mohamed Elfatih Abdelwadoud
- Department of Histopathology and Cytology, Faculty of Medical Laboratory Sciences, University of Medical Sciences & Technology, Khartoum 11115, Sudan
| | - Manish Vyas
- School of Pharmaceutical Sciences, Lovely Professional University, Punjab 144411, India
| | - Mohd Saeed
- Department of Biology, College of Sciences, University of Hail, Ha'il 34464, Saudi Arabia
| | - Avijit Mazumder
- Department of Pharmacology, Noida Institute of Engineering and Technology (Pharmacy Institute), Greater Noida 201306, India
| | - Amir Saeed
- Department of Medical Laboratory Science, College of Applied Medical Sciences, University of Ha'il, Hail 55476, Saudi Arabia
- Medical and Diagnostic Research Centre, University of Hail, Ha'il 55473, Saudi Arabia
- Department of Medical Microbiology, Faculty of Medical Laboratory Sciences, University of Medical Sciences & Technology, Khartoum 11115, Sudan
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Ibrahim TA, Hegazy MM, Maatooq GT, El-Hela AA. Ultra-performance liquid chromatography coupled with quadrupole high-resolution time-of-flight mass spectrometry for metabolite profiling and biological activity of Stellaria pallida (Dumort) Piré. Med Chem Res 2023. [DOI: 10.1007/s00044-023-03055-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2023]
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20
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Garg P, Garg R, Horne D, Awasthi S, Salgia R, Singhal SS. Prognostic significance of natural products against multidrug tumor resistance. Cancer Lett 2023; 557:216079. [PMID: 36736532 DOI: 10.1016/j.canlet.2023.216079] [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: 01/04/2023] [Revised: 01/23/2023] [Accepted: 01/29/2023] [Indexed: 02/05/2023]
Abstract
Cancer is a pervasive, constantly evolving, and significant public health concern. The number of new cancer cases has risen dramatically in the last decades, making it one of the top causes of poor health and mortality worldwide. Although various treatment strategies, including surgery, radiation, and pharmaceutical therapies, have evolved into more sophisticated, precise methods, there is not much improvement in the cancer-related death toll. Consequently, natural product-based therapeutic discoveries have recently been considered an alternative approach. According to an estimate, one-third of the top twenty medications in today's market have a natural plant-product-based origin. Accordingly, primary prevention is an essential component of worldwide cancer control. This review provides an overview of the mechanisms of action of bioactive ingredients in natural dietary products that may contribute to the prevention and management of multiple malignancies.
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Affiliation(s)
- Pankaj Garg
- Department of Chemistry, GLA University, Mathura, Uttar Pradesh, 281406, India
| | - Rachana Garg
- Department of Surgery, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA, 91010, USA
| | - David Horne
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA, 91010, USA
| | - Sanjay Awasthi
- Cayman Health, CTMH Doctors Hospital, George Town, Grand Cayman, KY1-1104, Cayman Islands
| | - Ravi Salgia
- Department of Medical Oncology & Therapeutics Research, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA, 91010, USA
| | - Sharad S Singhal
- Department of Medical Oncology & Therapeutics Research, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA, 91010, USA.
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Vélez-Vargas LC, Santa-González GA, Uribe D, Henao-Castañeda IC, Pedroza-Díaz J. In Vitro and In Silico Study on the Impact of Chlorogenic Acid in Colorectal Cancer Cells: Proliferation, Apoptosis, and Interaction with β-Catenin and LRP6. Pharmaceuticals (Basel) 2023; 16:276. [PMID: 37259421 PMCID: PMC9960681 DOI: 10.3390/ph16020276] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/23/2023] [Accepted: 02/01/2023] [Indexed: 09/12/2023] Open
Abstract
Colorectal cancer mortality rate and highly altered proteins from the Wnt/β-catenin pathway increase the scientific community's interest in finding alternatives for prevention and treatment. This study aims to determine the biological effect of chlorogenic acid (CGA) on two colorectal cancer cell lines, HT-29 and SW480, and its interactions with β-catenin and LRP6 to elucidate a possible modulatory mechanism on the Wnt/β-catenin pathway. These effects were determined by propidium iodide and DiOC6 for mitochondrial membrane permeability, MitoTracker Red for mitochondrial ROS production, DNA content for cell distribution on cell cycle phases, and molecular docking for protein-ligand interactions and binding affinity. Here, it was found that CGA at 2000 µM significantly affects cell viability and causes DNA fragmentation in SW480 cells rather than in HT-29 cells, but in both cell lines, it induces ROS production. Additionally, CGA has similar affinity and interactions for LRP6 as niclosamide but has a higher affinity for both β-catenin sites than C2 and iCRT14. These results suggest a possible modulatory role of CGA over the Wnt/β-catenin pathway in colorectal cancer.
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Affiliation(s)
- Laura Catalina Vélez-Vargas
- Grupo de Investigación e Innovación Biomédica, Facultad de Ciencias Exactas y Aplicadas, Instituto Tecnológico Metropolitano, Medellin 050012, Colombia
- Productos Naturales Marinos, Facultad de Ciencias Farmacéuticas y Alimentarias, Universidad de Antioquia, Medellin 050010, Colombia
| | - Gloria A. Santa-González
- Grupo de Investigación e Innovación Biomédica, Facultad de Ciencias Exactas y Aplicadas, Instituto Tecnológico Metropolitano, Medellin 050012, Colombia
| | - Diego Uribe
- Grupo de Investigación e Innovación Biomédica, Facultad de Ciencias Exactas y Aplicadas, Instituto Tecnológico Metropolitano, Medellin 050012, Colombia
| | - Isabel C. Henao-Castañeda
- Productos Naturales Marinos, Facultad de Ciencias Farmacéuticas y Alimentarias, Universidad de Antioquia, Medellin 050010, Colombia
| | - Johanna Pedroza-Díaz
- Grupo de Investigación e Innovación Biomédica, Facultad de Ciencias Exactas y Aplicadas, Instituto Tecnológico Metropolitano, Medellin 050012, Colombia
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22
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Rahmani AH, Almatroudi A, Allemailem KS, Khan AA, Almatroodi SA. The Potential Role of Fisetin, a Flavonoid in Cancer Prevention and Treatment. Molecules 2022; 27:9009. [PMID: 36558146 PMCID: PMC9782831 DOI: 10.3390/molecules27249009] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 12/11/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
Cancer is a main culprit and the second-leading cause of death worldwide. The current mode of treatment strategies including surgery with chemotherapy and radiation therapy may be effective, but cancer is still considered a major cause of death. Plant-derived products or their purified bioactive compounds have confirmed health-promoting effects as well as cancer-preventive effects. Among these products, flavonoids belong to polyphenols, chiefly found in fruits, vegetables and in various seeds/flowers. It has been considered to be an effective antioxidant, anti-inflammatory and to play a vital role in diseases management. Besides these activities, flavonoids have been revealed to possess anticancer potential through the modulation of various cell signaling molecules. In this regard, fisetin, a naturally occurring flavonoid, has a confirmed role in disease management through antioxidant, neuro-protective, anti-diabetic, hepato-protective and reno-protective potential. As well, its cancer-preventive effects have been confirmed via modulating various cell signaling pathways including inflammation, apoptosis, angiogenesis, growth factor, transcription factor and other cell signaling pathways. This review presents an overview of the anti-cancer potential of fisetin in different types of cancer through the modulation of cell signaling pathways based on in vivo and in vitro studies. A synergistic effect with anticancer drugs and strategies to improve the bioavailability are described. More clinical trials need to be performed to explore the anti-cancer potential and mechanism-of-action of fisetin and its optimum therapeutic dose.
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Affiliation(s)
- Arshad Husain Rahmani
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51542, Saudi Arabia
| | - Ahmad Almatroudi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51542, Saudi Arabia
| | - Khaled S. Allemailem
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51542, Saudi Arabia
| | - Amjad Ali Khan
- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah 51542, Saudi Arabia
| | - Saleh A. Almatroodi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51542, Saudi Arabia
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Islam MR, Akash S, Rahman MM, Nowrin FT, Akter T, Shohag S, Rauf A, Aljohani AS, Simal-Gandara J. Colon cancer and colorectal cancer: Prevention and treatment by potential natural products. Chem Biol Interact 2022; 368:110170. [DOI: 10.1016/j.cbi.2022.110170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 08/24/2022] [Accepted: 09/03/2022] [Indexed: 11/29/2022]
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Bhosale PB, Abusaliya A, Kim HH, Ha SE, Park MY, Jeong SH, Vetrivel P, Heo JD, Kim JA, Won CK, Kim HW, Kim GS. Apigetrin Promotes TNFα-Induced Apoptosis, Necroptosis, G2/M Phase Cell Cycle Arrest, and ROS Generation through Inhibition of NF-κB Pathway in Hep3B Liver Cancer Cells. Cells 2022; 11:cells11172734. [PMID: 36078142 PMCID: PMC9454891 DOI: 10.3390/cells11172734] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/26/2022] [Accepted: 08/31/2022] [Indexed: 11/25/2022] Open
Abstract
Apigetrin (7-(β-D-glucopyranosyloxy)-4′,5-dihydroxyflavone), a glycoside bioactive dietary flavonoid derived from Taraxacum officinale and Teucrium gnaphalodes, is known to possess anticancer, antioxidant, and anti-inflammatory effects on numerous cancers. In the present study, we examined the effect of apigetrin in Hep3B hepatocellular cancer cell line (HCC). Apigetrin inhibited cell growth and proliferation of Hep3B cells, as confirmed by MTT and colony formation assay. We used apigetrin at concentrations of 0, 50, and 100 µM for later experiments. Of these concentrations, 100 µM of apigetrin showed a significant effect on cell inhibition. In apigetrin-treated Hep3B cells, cell cycle arrest occurred at the G2/M phase. Apoptosis and necroptosis of Hep3B cells treated with apigetrin were confirmed by Annexin V/propidium iodide (PI) staining and flow cytometry results. Morphological observation through 4′,6-diamidino-2-phenylindole (DAPI) staining showed intense blue fluorescence representing chromatin condensation. Hematoxylin staining showed necroptotic features such as formation of vacuoles and swelling of organelles. Apigetrin increased reactive oxygen species (ROS) levels in cells, based on fluorescence imaging. Furthermore, the underlying mechanism involved in the apoptosis and necroptosis was elucidated through western blotting. Apigetrin up-regulated TNFα, but down-regulated phosphorylation of p-p65, and IκB. Apigetrin inhibited the expression of Bcl-xl but increased Bax levels. Up-regulation of cleaved PARP and cleaved caspase 3 confirmed the induction of apoptosis in apigetrin-treated Hep3B cells. Additionally, necroptosis markers RIP3, p-RIP3, and p-MLKL were significantly elevated by apigetrin dose-dependently, suggesting necroptotic cell death. Taken together, our findings strongly imply that apigetrin can induce apoptosis and necroptosis of Hep3B hepatocellular cancer cells. Thus, apigetrin as a natural compound might have potential for treating liver cancer.
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Affiliation(s)
- Pritam Bhagwan Bhosale
- Department of Veterinary Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea
| | - Abuyaseer Abusaliya
- Department of Veterinary Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea
| | - Hun Hwan Kim
- Department of Veterinary Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea
| | - Sang Eun Ha
- Department of Veterinary Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea
- Biological Resources Research Group, Bioenvironmental Science & Toxicology Division, Korea Institute of Toxicology (KIT), 17 Jeigok-gil, Jinju 52834, Korea
| | - Min Yeong Park
- Department of Veterinary Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea
| | - Se Hyo Jeong
- Department of Veterinary Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea
| | - Preethi Vetrivel
- Department of Pharmacy, National University of Singapore, Singapore 117643, Singapore
| | - Jeong Doo Heo
- Department of Pharmacy, National University of Singapore, Singapore 117643, Singapore
| | - Jin-A Kim
- Department of Physical Therapy, International University of Korea, Jinju 52833, Korea
| | - Chung kil Won
- Department of Veterinary Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea
| | - Hyun-Wook Kim
- Division of Animal Bioscience & Intergrated Biotechnology, Jinju 52725, Korea
| | - Gon Sup Kim
- Department of Veterinary Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea
- Correspondence: ; Tel.: +82-55-772-2346
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Li L, Wang M, Yang H, Li Y, Huang X, Guo J, Liu Z. Fisetin Inhibits Trypsin Activity and Suppresses the Growth of Colorectal Cancer in Vitro and in Vivo. Nat Prod Commun 2022. [DOI: 10.1177/1934578x221115511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Colorectal cancer (CRC) is a malignant tumor with high incidence and bad prognosis. Therapies, which are more safe and effective, are urgently needed. Trypsin is proved to be crucial to cancer proliferation and migration, therefore, it is possible to control cancers by modulating its activity. Fisetin is a flavone with trypsin inhibition properties that was screened from more than 45 compounds derived from traditional Chinese medicine (TCM). However, the effects and mechanisms of fisetin on CRC have not been well investigated. In this study, we evaluated the effects of fisetin on 2 different CRC cell lines. Fisetin remarkably inhibited CRC cell proliferation and migration, as well as induced cell apoptosis and Go/G1 phase arrest in a dose-dependent manner. Mechanistic studies revealed that these effects were mediated partially through signaling pathways involving cell cycle regulators p21, p27, cyclinD1, and NF kappa B (NF-κB) p65. Administration of fisetin also significantly suppressed the tumor growth in tumor-bearing NOD/Shi-scid-IL2R gamma (null) (NOG) mice that had been inoculated with human HCT116 cells. Fisetin at the given dosage did not induce significant acute or chronic toxicity in rats. These data provide a potential therapeutic strategy for CRC.
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Affiliation(s)
- Lin Li
- Jinan University, Guangzhou, China
| | - Min Wang
- Jinan University, Guangzhou, China
| | - Hongyan Yang
- School of Medicine, Foshan University, Foshan, China
| | | | | | - Jialiang Guo
- Jinan University, Guangzhou, China
- School of Medicine, Foshan University, Foshan, China
| | - Zheng Liu
- School of Medicine, Foshan University, Foshan, China
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26
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Kim SH, Huh CK. Isolation and Identification of Fisetin: An Antioxidative Compound Obtained from Rhus verniciflua Seeds. Molecules 2022; 27:molecules27144510. [PMID: 35889379 PMCID: PMC9318972 DOI: 10.3390/molecules27144510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/11/2022] [Accepted: 07/13/2022] [Indexed: 12/10/2022] Open
Abstract
The goal of this study was to provide basic data for the development of functional food and health materials for Rhus verniciflua (R. verniciflua) seeds. We investigated an antioxidative compound obtained from these seeds. Solvent fractionation was carried out on a 50%-ethanol extract of the seeds. The DPPH and ABTS radical-scavenging activity and superoxide dismutase (SOD) activity were measured, and high antioxidant activity was seen in the ethyl acetate fraction. The antioxidant compounds in the ethyl acetate fraction were isolated using silica-gel column chromatography by adjusting the solvent between chloroform and methanol. Fraction numbers 2–7 showed activity of more than 50%. Next, primary column chromatography was used to mix and concentrate the fractions that demonstrated antioxidant activity. The fractions were then subjected to secondary column chromatography to obtain subfraction 4, which showed high antioxidant activity. The separation of subfraction 4 was then performed using high-performance liquid chromatography (HPLC). Three peaks were identified and peak number 2 was judged to be the primary antioxidative compound, which was then isolated by pure separation. Finally, the purified subfraction peak number 2 was identified as a fisetin compound by liquid chromatography–mass spectrometry (LC–MS), nuclear magnetic resonance (NMR), and HPLC.
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Affiliation(s)
- Su-Hwan Kim
- Research Institute of Food Industry, Sunchon National University, Suncheon 57922, Korea;
| | - Chang-Ki Huh
- Department of Food Science and Technology, Sunchon National University, Suncheon 57922, Korea
- Correspondence: ; Tel.: +82-61-750-3251
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Kubina R, Krzykawski K, Kabała-Dzik A, Wojtyczka RD, Chodurek E, Dziedzic A. Fisetin, a Potent Anticancer Flavonol Exhibiting Cytotoxic Activity against Neoplastic Malignant Cells and Cancerous Conditions: A Scoping, Comprehensive Review. Nutrients 2022; 14:2604. [PMID: 35807785 PMCID: PMC9268460 DOI: 10.3390/nu14132604] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 06/21/2022] [Accepted: 06/22/2022] [Indexed: 12/10/2022] Open
Abstract
Diet plays a crucial role in homeostasis maintenance. Plants and spices containing flavonoids have been widely used in traditional medicine for thousands of years. Flavonols present in our diet may prevent cancer initiation, promotion and progression by modulating important enzymes and receptors in signal transduction pathways related to proliferation, differentiation, apoptosis, inflammation, angiogenesis, metastasis and reversal of multidrug resistance. The anticancer activity of fisetin has been widely documented in numerous in vitro and in vivo studies. This review summarizes the worldwide, evidence-based research on the activity of fisetin toward various types of cancerous conditions, while describing the chemopreventive and therapeutic effects, molecular targets and mechanisms that contribute to the observed anticancer activity of fisetin. In addition, this review synthesized the results from preclinical studies on the use of fisetin as an anticancer agent. Based on the available literature, it might be suggested that fisetin has a bioactive potential to become a complementary drug in the prevention and treatment of cancerous conditions. However, more in-depth research is required to validate current data, so that this compound or its derivatives can enter the clinical trial phase.
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Affiliation(s)
- Robert Kubina
- Department of Pathology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 30 Ostrogórska Str., 41-200 Sosnowiec, Poland;
- Silesia LabMed: Centre for Research and Implementation, Medical University of Silesia in Katowice, 18 Medyków Str., 40-752 Katowice, Poland;
| | - Kamil Krzykawski
- Silesia LabMed: Centre for Research and Implementation, Medical University of Silesia in Katowice, 18 Medyków Str., 40-752 Katowice, Poland;
| | - Agata Kabała-Dzik
- Department of Pathology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 30 Ostrogórska Str., 41-200 Sosnowiec, Poland;
| | - Robert D. Wojtyczka
- Department of Microbiology and Virology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 4 Jagiellońska Str., 41-200 Sosnowiec, Poland;
| | - Ewa Chodurek
- Department of Biopharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 8 Jedności Str., 41-208 Sosnowiec, Poland;
| | - Arkadiusz Dziedzic
- Department of Conservative Dentistry with Endodontics, Medical University of Silesia, 17 Akademicki Sq., 41-902 Bytom, Poland;
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28
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Kim SH, Lee YC. Plant-Derived Nanoscale-Encapsulated Antioxidants for Oral and Topical Uses: A Brief Review. Int J Mol Sci 2022; 23:ijms23073638. [PMID: 35409001 PMCID: PMC8998173 DOI: 10.3390/ijms23073638] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/23/2022] [Accepted: 03/24/2022] [Indexed: 02/04/2023] Open
Abstract
Several plant-based nanoscale-encapsulated antioxidant compounds (rutin, myricetin, β-carotene, fisetin, lycopene, quercetin, genkwanin, lutein, resveratrol, eucalyptol, kaempferol, glabridin, pinene, and whole-plant bio-active compounds) are briefly introduced in this paper, along with their characteristics. Antioxidants’ bioavailability has become one of the main research topics in bio-nanomedicine. Two low patient compliance drug delivery pathways (namely, the oral and topical delivery routes), are described in detail in this paper, for nanoscale colloidal systems and gel formulations. Both routes and/or formulations seek to improve bioavailability and maximize the drug agents’ efficiency. Some well-known compounds have been robustly studied, but many remain elusive. The objective of this review is to discuss recent studies and advantages of nanoscale formulations of plant-derived antioxidant compounds.
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29
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Das R, Mehta DK, Dhanawat M. Medicinal Plants in Cancer Treatment: Contribution of Nuclear Factor-Kappa B (NF-kB) Inhibitors. Mini Rev Med Chem 2022; 22:1938-1962. [PMID: 35260052 DOI: 10.2174/1389557522666220307170126] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 11/23/2021] [Accepted: 12/14/2021] [Indexed: 01/17/2023]
Abstract
Nuclear factor-kappa B (NF-κB) is one of the principal inducible proteins that is a predominant transcription factor known to control the gene expression in mammals and plays a pivotal role in regulating cell signalling in the body under certain physiological and pathological conditions. In cancer cells, such as colon, breast, pancreatic, ovarian, melanoma, and lymphoma, the NF-κB pathway has been reported to be active. In cellular proliferation, promoting angiogenesis, invasion, metastasis of tumour cells and blocking apoptosis, the constitutive activity of NF-κB signalling has been reported. Therefore, immense attention has been given to developing drugs targeting NF-κB signalling pathways to treat many types of tumours. They are a desirable therapeutic target for drugs, and many studies concentrated on recognizing compounds. They may be able to reverse or standstill the growth and spread of tumours that selectively interfere with this pathway. Recently, numerous substances derived from plants have been evaluated as possible inhibitors of the NF-κB pathway. These include various compounds, such as flavonoids, lignans, diterpenes, sesquiterpenes, polyphenols, etc. A study supported by folk medicine demonstrated that plant-derived compounds could suppress NF-κB signalling. Taking this into account, the present review revealed the anticancer potential of naturally occurring compounds which have been verified both by inhibiting the NF-κB signalling and suppressing growth and spread of cancer and highlighting their mechanism of NF-κB inhibition.
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Affiliation(s)
- Rina Das
- M.M.College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
| | - Dinesh Kumar Mehta
- M.M.College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
| | - Meenakshi Dhanawat
- M.M.College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
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30
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Fakhri S, Moradi SZ, Yarmohammadi A, Narimani F, Wallace CE, Bishayee A. Modulation of TLR/NF-κB/NLRP Signaling by Bioactive Phytocompounds: A Promising Strategy to Augment Cancer Chemotherapy and Immunotherapy. Front Oncol 2022; 12:834072. [PMID: 35299751 PMCID: PMC8921560 DOI: 10.3389/fonc.2022.834072] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 01/26/2022] [Indexed: 12/12/2022] Open
Abstract
Background Tumors often progress to a more aggressive phenotype to resist drugs. Multiple dysregulated pathways are behind this tumor behavior which is known as cancer chemoresistance. Thus, there is an emerging need to discover pivotal signaling pathways involved in the resistance to chemotherapeutic agents and cancer immunotherapy. Reports indicate the critical role of the toll-like receptor (TLR)/nuclear factor-κB (NF-κB)/Nod-like receptor pyrin domain-containing (NLRP) pathway in cancer initiation, progression, and development. Therefore, targeting TLR/NF-κB/NLRP signaling is a promising strategy to augment cancer chemotherapy and immunotherapy and to combat chemoresistance. Considering the potential of phytochemicals in the regulation of multiple dysregulated pathways during cancer initiation, promotion, and progression, such compounds could be suitable candidates against cancer chemoresistance. Objectives This is the first comprehensive and systematic review regarding the role of phytochemicals in the mitigation of chemoresistance by regulating the TLR/NF-κB/NLRP signaling pathway in chemotherapy and immunotherapy. Methods A comprehensive and systematic review was designed based on Web of Science, PubMed, Scopus, and Cochrane electronic databases. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed to include papers on TLR/NF-κB/NLRP and chemotherapy/immunotherapy/chemoresistance by phytochemicals. Results Phytochemicals are promising multi-targeting candidates against the TLR/NF-κB/NLRP signaling pathway and interconnected mediators. Employing phenolic compounds, alkaloids, terpenoids, and sulfur compounds could be a promising strategy for managing cancer chemoresistance through the modulation of the TLR/NF-κB/NLRP signaling pathway. Novel delivery systems of phytochemicals in cancer chemotherapy/immunotherapy are also highlighted. Conclusion Targeting TLR/NF-κB/NLRP signaling with bioactive phytocompounds reverses chemoresistance and improves the outcome for chemotherapy and immunotherapy in both preclinical and clinical stages.
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Affiliation(s)
- Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Seyed Zachariah Moradi
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Akram Yarmohammadi
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fatemeh Narimani
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Carly E. Wallace
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, United States
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, United States
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31
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Ullah MF, Ahmad A, Bhat SH, Abuduhier FM, Mustafa SK, Usmani S. Diet-derived small molecules (nutraceuticals) inhibit cellular proliferation by interfering with key oncogenic pathways: an overview of experimental evidence in cancer chemoprevention. Biol Futur 2022; 73:55-69. [PMID: 35040098 DOI: 10.1007/s42977-022-00110-x] [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: 08/22/2021] [Accepted: 01/07/2022] [Indexed: 10/19/2022]
Abstract
Discouraging statistics of cancer disease has projected an increase in the global cancer burden from 19.3 to 28.4 million incidences annually within the next two decades. Currently, there has been a revival of interest in nutraceuticals with evidence of pharmacological properties against human diseases including cancer. Diet is an integral part of lifestyle, and it has been proposed that an estimated one-third of human cancers can be prevented through appropriate lifestyle modification including dietary habits; hence, it is considered significant to explore the pharmacological benefits of these agents, which are easily accessible and have higher safety index. Accordingly, an impressive embodiment of evidence supports the concept that the dietary factors are critical modulators to prevent, retard, block, or reverse carcinogenesis. Such an action reflects the ability of these molecules to interfere with multitude of pathways to subdue and neutralize several oncogenic factors and thereby keep a restraint on neoplastic transformations. This review provides a series of experimental evidence based on the current literature to highlight the translational potential of nutraceuticals for the prevention of the disease through consumption of enriched diets and its efficacious management by means of novel interventions. Specifically, this review provides the current understanding of the chemopreventive pharmacology of nutraceuticals such as cucurbitacins, morin, fisetin, curcumin, luteolin and garcinol toward their potential as anticancer agents.
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Affiliation(s)
- Mohammad Fahad Ullah
- Prince Fahd Research Chair, Department of Medical Laboratory Technology, Faculty of Applied Medical Science, University of Tabuk, Tabuk, Saudi Arabia.
| | - Aamir Ahmad
- University of Alabama at Birmingham, Birmingham, AL, USA
- Interim Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | - Showket H Bhat
- Prince Fahd Research Chair, Department of Medical Laboratory Technology, Faculty of Applied Medical Science, University of Tabuk, Tabuk, Saudi Arabia
- Department of Medical Laboratory Technology and Molecular Diagnostics, Center for Vocational Studies, Islamic University of Science and Technology, Awantipora, Jammu & Kashmir, India
| | - Faisel M Abuduhier
- Prince Fahd Research Chair, Department of Medical Laboratory Technology, Faculty of Applied Medical Science, University of Tabuk, Tabuk, Saudi Arabia
| | - Syed Khalid Mustafa
- Department of Chemistry, Faculty of Science, University of Tabuk, Tabuk, Saudi Arabia
| | - Shazia Usmani
- Faculty of Pharmacy, Integral University, Lucknow, India
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Mei D, Qi Y, Xia Y, Ma J, Hu H, Ai J, Chen L, Wu N, Liao D. Microarray profile analysis identifies ETS1 as potential biomarker regulated by miR-23b and modulates TCF4 in gastric cancer. World J Surg Oncol 2021; 19:311. [PMID: 34686186 PMCID: PMC8540102 DOI: 10.1186/s12957-021-02417-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 10/03/2021] [Indexed: 12/30/2022] Open
Abstract
Background Gastric cancer (GC), a common malignancy of the human digestive system, represents the second leading cause of cancer-related deaths worldwide. Early detection of GC has a significant impact on clinical outcomes. The aim of this study was to identify potential GC biomarkers. Methods In this study, we conducted a multi-step analysis of expression profiles in GC clinical samples downloaded from TCGA database to identify differentially expressed miRNAs (DEMs) and differentially expressed mRNAs (DEGs). Potential prognostic biomarkers from the available DEMs were then established using the Cox regression method. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to investigate the biological role of the predicted target genes of the miRNA biomarkers. Then, the prognostic DEM-mediated regulatory network was constructed based on transcription factor (TF)–miRNA–target interaction. Subsequently, the consensus genes were further determined based on the overlap between DEGs and these target genes of DEMs. Besides, expression profile, co-expression analysis, immunity, and prognostic values of these prognostic genes were also investigated to further explore the roles in the mechanism of GC tumorigenesis. Results We got five miRNAs, including miR-23b, miR-100, miR-143, miR-145, and miR-409, which are associated with the overall survival of GC patients. Subsequently, enrichment analysis of the target genes of the miRNA biomarkers shown that the GO biological process terms were mainly enriched in mRNA catabolic process, nuclear chromatin, and RNA binding. In addition, the KEGG pathways were significantly enriched in fatty acid metabolism, extracellular matrix (ECM) receptor interaction, and proteoglycans in cancer pathways. The transcriptional regulatory network consisting of 68 TFs, 4 DEMs, and 58 targets was constructed based on the interaction of TFs, miRNAs, and targets. The downstream gene ETS1 of miR-23b and TCF4 regulated by ETS1 were obtained by the regulatory network construction and co-expression analysis. High expression of ETS1 and TCF4 indicated poor prognosis in GC patients, particularly in the advanced stages. The expression of ETS1 and TCF4 was correlated with CD4+ T cells, CD8+ T cells, and B cells. Conclusions miR-23b, ETS1, and TCF4 were identified as the prognostic biomarkers. ETS1 and TCF4 had potential immune function in GC, which provided a theoretical basis for molecular-targeted combined immunotherapy in the future.
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Affiliation(s)
- Dinglian Mei
- The Department of Oncology, Beijing Mentougou District Hospital, Beijing, 102300, People's Republic of China
| | - Yalong Qi
- The Department of Oncology, Beijing Mentougou District Hospital, Beijing, 102300, People's Republic of China
| | - Yuanyuan Xia
- The Department of Oncology, Beijing Mentougou District Hospital, Beijing, 102300, People's Republic of China
| | - Jun Ma
- The Department of Oncology, Beijing Mentougou District Hospital, Beijing, 102300, People's Republic of China
| | - Hao Hu
- The Department of Oncology, Beijing Mentougou District Hospital, Beijing, 102300, People's Republic of China
| | - Jun Ai
- The Department of Oncology, Beijing Mentougou District Hospital, Beijing, 102300, People's Republic of China
| | - Liqiang Chen
- The Department of Oncology, Beijing Mentougou District Hospital, Beijing, 102300, People's Republic of China
| | - Ning Wu
- Department of Oncology, Shanghai Pudong New Area Gongli Hospital, Shanghai, 200135, People's Republic of China
| | - Daixiang Liao
- The Department of Oncology, Beijing Mentougou District Hospital, Beijing, 102300, People's Republic of China.
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Kaur J, Gulati M, Gowthamarajan K, Vishwas S, Kumar Chellappan D, Gupta G, Dua K, Pandey NK, Kumar B, Singh SK. Combination therapy of vanillic acid and oxaliplatin co-loaded in polysaccharide based functionalized polymeric micelles could offer effective treatment for colon cancer: A hypothesis. Med Hypotheses 2021; 156:110679. [PMID: 34555619 DOI: 10.1016/j.mehy.2021.110679] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 09/06/2021] [Accepted: 09/12/2021] [Indexed: 02/07/2023]
Abstract
Colon cancer is characterised by the persistent change in bowel habits due to the formation of polyps (cancerous) in the inner lining of the colon. Clinically, there are several anticancer drugs available to treat colon cancer. Oxaliplatin (third generation platinum drug) is widely prescribed anticancer drug due to its broad range anticancer properties and low toxicities over cisplatin and carboplatin. Currently, use of oxaliplatin as adjuvant chemotherapy represents a standard care for the treatment of advanced colon cancer. Despite this, its rapid degradation in systemic circulations upon administration, lack of tumor specificity, and low bioavailability limits its anticancer potential. On the other hand, vanillic acid (VA) has shown anticancer potential in colon cancer by targeting mTOR/Ras pathway, HIF-1α inhibition, NF-ĸB, and Nrf2 that regulate cell growth, cell survival, proliferation and adaptation to cancer microenvironment. Normal oral delivery of these two drugs offers non-specific drug release in gastrointestinal tract that leads to unwanted toxicity and very less amount of drug become available for colonic site. Therefore, loading of these two drugs in polysaccharide based functionalized polymeric micelles (FPMs) can offer selective targeting at colonic site and could offer better therapeutic efficacy at much lesser doses of drugs. Therefore, a new hypothesis has been proposed that the combination of vanillic acid with oxaliplatin co-loaded in FPMs could provide colon targeting ability with enhanced potency and safety profile by targeting multiple pathways than current adjuvant chemotherapies available in the market for the treatment of colon cancer.
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Affiliation(s)
- Jaskiran Kaur
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - Monica Gulati
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - K Gowthamarajan
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India; Centre of Excellence in Nanoscience & Technology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India
| | - Sukriti Vishwas
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Mahal Road, Jagatpura, Jaipur, India
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Narendra Kumar Pandey
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - Bimlesh Kumar
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India.
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Chi X, Liu Z, Wei W, Hu X, Wang Y, Wang H, Xu B. Selenium-rich royal jelly inhibits hepatocellular carcinoma through PI3K/AKT and VEGF pathways in H22 tumor-bearing mice. Food Funct 2021; 12:9111-9127. [PMID: 34397053 DOI: 10.1039/d1fo01070k] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Royal jelly (RJ) and selenium (Se)-rich foods have well-known health benefits that are attributable to a broad range of pharmacological effects including antioxidant, anti-tumor, and immunoregulatory activities. However, the physiological effects of Se-rich RJ, which is produced by feeding Apis mellifera (Hymenoptera: Apidae) sodium selenite sucrose solution, are not well understood. The anti-hepatoma activity and mechanism of Se-rich RJ in H22 tumor-bearing mice were investigated in the current study. The findings showed that the content of organic and inorganic Se in Se-rich RJ was significantly higher than that in RJ. Furthermore, interleukin-2 (IL-2) levels and tumor necrosis factor-α (TNF-α) production in serum were increased and the malondialdehyde (MDA) content in liver was decreased in mice fed RJ and Se-rich RJ. 16SrRNA sequencing and serum untargeted metabolomics showed that RJ and Se-rich RJ could modulate the gut microbiota, and fisetin and l-glutathione oxidized were the main anti-tumor components in RJ and Se-rich RJ. Further analysis showed 11-deoxy prostaglandin F1β was the specific anti-tumor metabolite in mice treated with Se-rich RJ compared with RJ. The results indicated that RJ and Se-rich RJ could inhibit the expression of PI3K and phosphorylation of AKT, induce cell apoptosis through the activation of caspase-9 and caspase-3, and regulate Bcl-2/Bax expression. RJ and Se-rich RJ also inhibited the expression of COX-2 and VEGF. To summarize, the findings clearly demonstrate that Se-rich RJ could inhibit tumor growth by inducing apoptosis and inhibiting angiogenesis as well as exhibit anti-tumor effects by improving immune function and antioxidant activities. The results indicated that Se-rich RJ could be a potential functional food for the management and prevention of cancer.
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Affiliation(s)
- Xuepeng Chi
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai' an, Shandong 271018, China.
| | - Zhenguo Liu
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai' an, Shandong 271018, China.
| | - Wei Wei
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai' an, Shandong 271018, China.
| | - Xiyi Hu
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai' an, Shandong 271018, China.
| | - Ying Wang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai' an, Shandong 271018, China.
| | - Hongfang Wang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai' an, Shandong 271018, China.
| | - Baohua Xu
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai' an, Shandong 271018, China.
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Data Mining, Network Pharmacology, and Molecular Docking Explore the Effects of Core Traditional Chinese Medicine Prescriptions in Patients with Rectal Cancer and Qi and Blood Deficiency Syndrome. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:1353674. [PMID: 34394377 PMCID: PMC8360715 DOI: 10.1155/2021/1353674] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/18/2021] [Accepted: 07/08/2021] [Indexed: 11/28/2022]
Abstract
Background “Zheng” (syndrome) is the basic unit and the basis of traditional Chinese medicine (TCM) treatment. In clinical practice, we have been able to improve the survival time and quality of life for patients with rectal cancer through the treatment of “FuZhengXiaoJi” (strengthening the Qi and reducing accumulation). Purpose In this study, we elucidated the core prescriptions for patients with rectal cancer and Qi and blood deficiency syndrome, and we explored the potential mechanisms of the prescriptions using an integrated strategy that coupled data mining with network pharmacology. Methods A Bron–Kerbosch (BK) algorithm was applied to find the core prescriptions. The active ingredients, targets, activated signaling pathways, and biological functions of core prescriptions were analyzed using network pharmacology and directly associated proteins were docked using molecular docking technology to elucidate the multicomponent, multitarget, and inter-related components associated with TCM systematically. Results Data mining identified 3 core prescriptions, and most of the herbs consisted of “FuZhengXiaoJi” Fang. Network pharmacology identified 15 high-degree active ingredients among the 3 core prescriptions and 16 high-degree hub genes linked with both rectal cancer and the 3 core prescriptions. Additional Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses of these 16 targets showed that the most significant pathways were MAPK, interleukin-17, tumor necrosis factor (TNF), and vascular endothelial growth factor (VEGF) pathways. From the 16 genes, TGFB1, IL1B, IL10, IL6, PTGS2, and PPARG closely interacted with the tumor microenvironment, and PPARG, MYC, and ERBB2 were closely linked to survival. In molecular docking, quercetin, kaempferol, and lauric acid showed good binding energy to each target. Conclusion Data mining, network pharmacology, and molecular docking may help identify core prescriptions, high-degree ingredients, and high-degree hub genes to apply to diseases and treatments. Furthermore, these studies may help discover hub genes that affect the tumor microenvironment and survival. The combination of these tools may help elucidate the relationship between herbs acting on “Zheng” (syndrome) and diseases, thus expanding the understanding of TCM mechanisms.
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Cancer chemopreventive role of fisetin: Regulation of cell signaling pathways in different cancers. Pharmacol Res 2021; 172:105784. [PMID: 34302980 DOI: 10.1016/j.phrs.2021.105784] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 07/04/2021] [Accepted: 07/20/2021] [Indexed: 12/12/2022]
Abstract
It is becoming progressively more understandable that pharmaceutical targeting of drug-resistant cancers is challenging because of intra- and inter-tumor heterogeneity. Interestingly, naturally derived bioactive compounds have unique ability to modulate wide-ranging deregulated oncogenic cell signaling pathways. In this review, we have focused on the available evidence related to regulation of PI3K/AKT/mTOR, Wnt/β-catenin, NF-κB and TRAIL/TRAIL-R by fisetin in different cancers. Fisetin has also been shown to inhibit the metastatic spread of cancer cells in tumor-bearing mice. We have also summarized how fisetin regulated autophagy in different cancers. In addition, this review also covers fisetin-mediated regulation of VEGF/VEGFR, EGFR, necroptosis and Hippo pathway. Fisetin has entered into clinical trials particularly in context of COVID19-associated inflammations. Furthermore, fisetin mediated effects are also being tested in clinical trials with reference to osteoarthritis and senescence. These developments will surely pave the way for full-fledge and well-designed clinical trials of fisetin in different cancers. However, we still have to comprehensively analyze and fully unlock pharmacological potential of fisetin against different oncogenic signaling cascades and non-coding RNAs. Fisetin has remarkable potential as chemopreventive agent and future studies must converge on the identification of additional regulatory roles of fisetin for inhibition and prevention of cancers.
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Hossain R, Islam MT, Mubarak MS, Jain D, Khan R, Saikat AS. Natural-Derived Molecules as a Potential Adjuvant in Chemotherapy: Normal Cell Protectors and Cancer Cell Sensitizers. Anticancer Agents Med Chem 2021; 22:836-850. [PMID: 34165416 DOI: 10.2174/1871520621666210623104227] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/18/2021] [Accepted: 04/18/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Cancer is a global threat to humans and a leading cause of death worldwide. Cancer treatment includes, among other things, the use of chemotherapeutic agents, compounds that are vital for treating and preventing cancer. However, chemotherapeutic agents produce oxidative stress along with other side effects that would affect the human body. OBJECTIVE To reduce the oxidative stress of chemotherapeutic agents in cancer and normal cells by naturally derived compounds with anti-cancer properties, and protect normal cells from the oxidation process. Therefore, the need to develop more potent chemotherapeutics with fewer side effects has become increasingly important. METHOD Recent literature dealing with the antioxidant and anticancer activities of the naturally naturally-derived compounds: morin, myricetin, malvidin, naringin, eriodictyol, isovitexin, daidzein, naringenin, chrysin, and fisetin has been surveyed and examined in this review. For this, data were gathered from different search engines, including Google Scholar, ScienceDirect, PubMed, Scopus, Web of Science, Scopus, and Scifinder, among others. Additionally, several patient offices such as WIPO, CIPO, and USPTO were consulted to obtain published articles related to these compounds. RESULT Numerous plants contain flavonoids and polyphenolic compounds such as morin, myricetin, malvidin, naringin, eriodictyol, isovitexin, daidzein, naringenin, chrysin, and fisetin, which exhibit antioxidant, anti-inflammatory, and anti-carcinogenic actions via several mechanisms. These compounds show sensitizers of cancer cells and protectors of healthy cells. Moreover, these compounds can reduce oxidative stress, which is accelerated by chemotherapeutics and exhibit a potent anticancer effect on cancer cells. CONCLUSIONS Based on these findings, more research is recommended to explore and evaluate such flavonoids and polyphenolic compounds.
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Affiliation(s)
- Rajib Hossain
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj-8100, Bangladesh
| | - Muhammad Torequl Islam
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj-8100, Bangladesh
| | | | - Divya Jain
- Department of Bioscience and Biotechnology, Banasthali Vidyapith, Rajasthan-304022, India
| | - Rasel Khan
- Pharmacy Discipline, Life Science School, Khulna University, Khulna-9280, Bangladesh
| | - Abu Saim Saikat
- Department of Biochemistry and Molecular Biology, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh
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Abstract
Colorectal cancer has served as a genetic and biological paradigm for the evolution of solid tumors, and these insights have illuminated early detection, risk stratification, prevention, and treatment principles. Employing the hallmarks of cancer framework, we provide a conceptual framework to understand how genetic alterations in colorectal cancer drive cancer cell biology properties and shape the heterotypic interactions across cells in the tumor microenvironment. This review details research advances pertaining to the genetics and biology of colorectal cancer, emerging concepts gleaned from immune and single-cell profiling, and critical advances and remaining knowledge gaps influencing the development of effective therapies for this cancer that remains a major public health burden.
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Affiliation(s)
- Jiexi Li
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Xingdi Ma
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Deepavali Chakravarti
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Shabnam Shalapour
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Ronald A DePinho
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
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Hosseinzadeh E, Hassanzadeh A, Marofi F, Alivand MR, Solali S. Flavonoid-Based Cancer Therapy: An Updated Review. Anticancer Agents Med Chem 2021; 20:1398-1414. [PMID: 32324520 DOI: 10.2174/1871520620666200423071759] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 10/27/2019] [Accepted: 11/06/2019] [Indexed: 12/24/2022]
Abstract
As cancers are one of the most important causes of human morbidity and mortality worldwide, researchers try to discover novel compounds and therapeutic approaches to decrease survival of cancer cells, angiogenesis, proliferation and metastasis. In the last decade, use of special phytochemical compounds and flavonoids was reported to be an interesting and hopeful tactic in the field of cancer therapy. Flavonoids are natural polyphenols found in plant, fruits, vegetables, teas and medicinal herbs. Based on reports, over 10,000 flavonoids have been detected and categorized into several subclasses, including flavonols, anthocyanins, flavanones, flavones, isoflavones and chalcones. It seems that the anticancer effect of flavonoids is mainly due to their antioxidant and anti inflammatory activities and their potential to modulate molecular targets and signaling pathways involved in cell survival, proliferation, differentiation, migration, angiogenesis and hormone activities. The main aim of this review is to evaluate the relationship between flavonoids consumption and cancer risk, and discuss the anti-cancer effects of these natural compounds in human cancer cells. Hence, we tried to collect and revise important recent in vivo and in vitro researches about the most effective flavonoids and their main mechanisms of action in various types of cancer cells.
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Affiliation(s)
- Elham Hosseinzadeh
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Hassanzadeh
- Department of Immunology, Division of Hematology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Faroogh Marofi
- Department of Immunology, Division of Hematology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Reza Alivand
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saeed Solali
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Lorthongpanich C, Charoenwongpaiboon T, Supakun P, Klaewkla M, Kheolamai P, Issaragrisil S. Fisetin Inhibits Osteogenic Differentiation of Mesenchymal Stem Cells via the Inhibition of YAP. Antioxidants (Basel) 2021; 10:antiox10060879. [PMID: 34070903 PMCID: PMC8226865 DOI: 10.3390/antiox10060879] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/27/2021] [Accepted: 05/27/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are self-renewal and capable of differentiating to various functional cell types, including osteocytes, adipocytes, myoblasts, and chondrocytes. They are, therefore, regarded as a potential source for stem cell therapy. Fisetin is a bioactive flavonoid known as an active antioxidant molecule that has been reported to inhibit cell growth in various cell types. Fisetin was shown to play a role in regulating osteogenic differentiation in animal-derived MSCs; however, its molecular mechanism is not well understood. We, therefore, studied the effect of fisetin on the biological properties of human MSCs derived from chorion tissue and its role in human osteogenesis using MSCs and osteoblast-like cells (SaOs-2) as a model. We found that fisetin inhibited proliferation, migration, and osteogenic differentiation of MSCs as well as human SaOs-2 cells. Fisetin could reduce Yes-associated protein (YAP) activity, which results in downregulation of osteogenic genes and upregulation of fibroblast genes. Further analysis using molecular docking and molecular dynamics simulations suggests that fisetin occupied the hydrophobic TEAD pocket preventing YAP from associating with TEA domain (TEAD). This finding supports the potential application of flavonoids like fisetin as a protein–protein interaction disruptor and also suggesting an implication of fisetin in regulating human osteogenesis.
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Affiliation(s)
- Chanchao Lorthongpanich
- Siriraj Center of Excellence for Stem Cell Research, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; (P.S.); (S.I.)
- Correspondence:
| | | | - Prapasri Supakun
- Siriraj Center of Excellence for Stem Cell Research, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; (P.S.); (S.I.)
| | - Methus Klaewkla
- Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand;
| | - Pakpoom Kheolamai
- Division of Cell Biology, Faculty of Medicine, Thammasat University, Pathum Thani 10120, Thailand;
| | - Surapol Issaragrisil
- Siriraj Center of Excellence for Stem Cell Research, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; (P.S.); (S.I.)
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Cotoraci C, Ciceu A, Sasu A, Miutescu E, Hermenean A. Bioactive Compounds from Herbal Medicine Targeting Multiple Myeloma. APPLIED SCIENCES 2021; 11:4451. [DOI: 10.3390/app11104451] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Multiple myeloma (MM) is one of the most widespread hematological cancers. It is characterized by a clonal proliferation of malignant plasma cells in the bone marrow and by the overproduction of monoclonal proteins. In recent years, the survival rate of patients with multiple myeloma has increased significantly due to the use of transplanted stem cells and of the new therapeutic agents that have significantly increased the survival rate, but it still cannot be completely cured and therefore the development of new therapeutic products is needed. Moreover, many patients have various side effects and face the development of drug resistance to current therapies. The purpose of this review is to highlight the bioactive active compounds (flavonoids) and herbal extracts which target dysregulated signaling pathway in MM, assessed by in vitro and in vivo experiments or clinical studies, in order to explore their healing potential targeting multiple myeloma. Mechanistically, they demonstrated the ability to promote cell cycle blockage and apoptosis or autophagy in cancer cells, as well as inhibition of proliferation/migration/tumor progression, inhibition of angiogenesis in the tumor vascular network. Current research provides valuable new information about the ability of flavonoids to enhance the apoptotic effects of antineoplastic drugs, thus providing viable therapeutic options based on combining conventional and non-conventional therapies in MM therapeutic protocols.
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Affiliation(s)
- Coralia Cotoraci
- Department of Hematology, Faculty of Medicine, Vasile Goldis Western University of Arad, Rebreanu 86, 310414 Arad, Romania
| | - Alina Ciceu
- “Aurel Ardelean” Institute of Life Sciences, Vasile Godis Western University of Arad, Rebreanu 86, 310414 Arad, Romania
| | - Alciona Sasu
- Department of Hematology, Faculty of Medicine, Vasile Goldis Western University of Arad, Rebreanu 86, 310414 Arad, Romania
| | - Eftimie Miutescu
- Department of Gastroenterology, Faculty of Medicine, Vasile Goldis Western University of Arad, Rebreanu 86, 310414 Arad, Romania
| | - Anca Hermenean
- “Aurel Ardelean” Institute of Life Sciences, Vasile Godis Western University of Arad, Rebreanu 86, 310414 Arad, Romania
- Department of Histology, Faculty of Medicine, Vasile Goldis Western University of Arad, Rebreanu 86, 310414 Arad, Romania
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Cui J, Fan J, Li H, Zhang J, Tong J. Neuroprotective potential of fisetin in an experimental model of spinal cord injury: via modulation of NF-κB/IκBα pathway. Neuroreport 2021; 32:296-305. [PMID: 33470764 PMCID: PMC7886366 DOI: 10.1097/wnr.0000000000001596] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 12/08/2020] [Indexed: 01/19/2023]
Abstract
AIM To evaluate neuroprotective efficacy of fisetin against the experimental model of spinal cord injury (SCI). MATERIALS AND METHODS SCI was induced in male Sprague-Dawley rats by placing an aneurysm clip extradurally. Rats were treated either with vehicle or fisetin for 28 days after SCI. RESULTS Treatment with fisetin significantly attenuated SCI-induced alternations in mechano-tactile and thermal allodynia, hyperalgesia and nerve conduction velocities. SCI-induced upregulated tumor necrosis factor-alpha, interleukins, inducible nitric oxide synthase, cyclooxygenase-II, Bcl-2-associated X protein and caspase-3 mRNA expressions in the spinal cord and these were markedly reduced by fisetin. Spinal nuclear factor kappa B and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha protein levels were also significantly downregulated by fisetin. Hematoxylin and eosin staining of spinal cord suggested that fisetin significantly ameliorated histological aberrations such as neuronal degeneration, necrosis and inflammatory infiltration induced in it. CONCLUSION Fisetin exerts neuroprotection via modulation of nuclear factor kappa B/nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha pathway by inhibiting release of inflammatory mediators (inducible nitric oxide synthase and cyclooxygenase-II), proinflammatory cytokines (tumor necrosis factor-alpha and interleukins), apoptotic mediators (Bcl-2-associated X protein and caspase-3).
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Affiliation(s)
| | - Jingshi Fan
- Department of Pathology, Baoding First Central Hospital, Baoding, Hebei Province, China
| | | | - Jinku Zhang
- Department of Pathology, Baoding First Central Hospital, Baoding, Hebei Province, China
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Imran M, Saeed F, Gilani SA, Shariati MA, Imran A, Afzaal M, Atif M, Tufail T, Anjum FM. Fisetin: An anticancer perspective. Food Sci Nutr 2021; 9:3-16. [PMID: 33473265 PMCID: PMC7802565 DOI: 10.1002/fsn3.1872] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 08/17/2020] [Accepted: 08/21/2020] [Indexed: 12/18/2022] Open
Abstract
Despite the provision of safe and cost-effective chemopreventive cancer approaches, still there are requirements to enhance their efficiency. The use of dietary agents as phytochemicals plays an imperative role against different human cancer cell lines. Among these novel dietary agents, fisetin (3,3',4',7-tetrahydroxyflavone) is present in different fruits and vegetables such as apple, persimmon, grape, strawberry, cucumber, and onion. Being a potent anticancer agent, fisetin has been used to inhibit stages in the cancer cells (proliferation, invasion), prevent cell cycle progression, inhibit cell growth, induce apoptosis, cause polymerase (PARP) cleavage, and modulate the expressions of Bcl-2 family proteins in different cancer cell lines (HT-29, U266, MDA-MB-231, BT549, and PC-3M-luc-6), respectively. Further, fisetin also suppresses the activation of the PKCα/ROS/ERK1/2 and p38 MAPK signaling pathways, reduces the NF-κB activation, and down-regulates the level of the oncoprotein securin. Fisetin also inhibited cell division and proliferation and invasion as well as lowered the TET1 expression levels. The current review article highlights and discusses the anticancer role of fisetin in cell cultures and animal and human studies. Conclusively, fisetin as a polyphenol with pleiotropic pharmacological properties showed promising anticancer activity in a wide range of cancers. Fisetin suppresses the cancer cell stages, prevents progression in cell cycle and cell growth, and induces apoptosis.
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Affiliation(s)
- Muhammad Imran
- Faculty of Allied Health SciencesUniversity Institute of Diet and Nutritional SciencesThe University of LahoreLahorePakistan
| | - Farhan Saeed
- Institute of Home & Food SciencesGovernment College UniversityFaisalabadPakistan
| | - Syed Amir Gilani
- Faculty of Allied Health SciencesUniversity Institute of Diet and Nutritional SciencesThe University of LahoreLahorePakistan
| | - Mohammad Ali Shariati
- Laboratory of Biocontrol and Antimicrobial ResistanceOrel StateUniversity Named After I.S. TurgenevOrelRussia
| | - Ali Imran
- Institute of Home & Food SciencesGovernment College UniversityFaisalabadPakistan
| | - Muhammad Afzaal
- Institute of Home & Food SciencesGovernment College UniversityFaisalabadPakistan
| | - Muhammad Atif
- Department of Clinical Laboratory SciencesCollege of Applied Medical SciencesJouf UniversitySakakaSaudi Arabia
| | - Tabussam Tufail
- Faculty of Allied Health SciencesUniversity Institute of Diet and Nutritional SciencesThe University of LahoreLahorePakistan
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Li G, Ding K, Qiao Y, Zhang L, Zheng L, Pan T, Zhang L. Flavonoids Regulate Inflammation and Oxidative Stress in Cancer. Molecules 2020; 25:E5628. [PMID: 33265939 PMCID: PMC7729519 DOI: 10.3390/molecules25235628] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/12/2020] [Accepted: 11/16/2020] [Indexed: 12/13/2022] Open
Abstract
Cancer is the second leading cause of death globally. Millions of persons die due to cancer each year. In the last two decades, the anticancer effects of natural flavonoids have become a hot topic in many laboratories. Meanwhile, flavonoids, of which over 8000 molecules are known to date, are potential candidates for the discovery of anticancer drugs. The current review summarizes the major flavonoid classes of anticancer efficacy and discusses the potential anti-cancer mechanisms through inflammation and oxidative stress action, which were based on database and clinical studies within the past years. The results showed that flavonoids could regulate the inflammatory response and oxidative stress of tumor through some anti-inflammatory mechanisms such as NF-κB, so as to realize the anti-tumor effect.
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Affiliation(s)
| | | | | | | | | | | | - Lin Zhang
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian 116044, China; (G.L.); (K.D.); (Y.Q.); (L.Z.); (L.Z.); (T.P.)
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Majumder M, Sharma M, Maiti S, Mukhopadhyay R. Edible Tuber Amorphophallus paeoniifolius (Dennst.) Extract Induces Apoptosis and Suppresses Migration of Breast Cancer Cells. Nutr Cancer 2020; 73:2477-2490. [PMID: 33034216 DOI: 10.1080/01635581.2020.1830127] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Medicinal plants offer enormous possibilities in the quest of novel bioactive formulation for cancer therapy. Here, we studied the anticancer efficacy of the extract of edible tuber Amorphophallus paeoniifolius (Dennst.) (APTE) against estrogen positive MCF-7 and triple negative MDA-MB-231 breast cancer cell lines. APTE showed significant cytotoxic activity in both MCF-7 and MDA-MB-231 cells in a dose and time-dependent manner. The effect of APTE on metastatic parameters e.g., migration, adhesion, and invasion in MCF-7 and MDA-MB-231 cells were studied using wound healing, collagen adhesion, and transwell matrigel invasion assays, respectively. APTE significantly reduced migration in both the cell lines, however, its effect on the inhibition of adhesion and invasion was higher in MDA-MB-231 cells. Annexin V-Cy3 staining suggested that APTE induced apoptosis in these cells which was further validated by attenuation of antiapoptotic Bcl-2 and induction of pro-apoptotic Bax, Caspase-7 expression and cleavage of PARP. High resolution-liquid chromatography mass spectroscopy analysis with bioactive ethyl acetate and butanol fractions of APTE detected several compounds with anticancer activities. Overall, the study described the mechanism of anticancer activity of a common edible tuber A. paeoniifolius and contributes to growing list of naturally occurring chemo-preventive strategies.
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Affiliation(s)
- Munmi Majumder
- Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur, Assam, India
| | - Manoj Sharma
- Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur, Assam, India
| | - Siddhartha Maiti
- Department of Bioscience and Bioengineering, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India
| | - Rupak Mukhopadhyay
- Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur, Assam, India
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Sferrazza G, Corti M, Brusotti G, Pierimarchi P, Temporini C, Serafino A, Calleri E. Nature-derived compounds modulating Wnt/ β -catenin pathway: a preventive and therapeutic opportunity in neoplastic diseases. Acta Pharm Sin B 2020; 10:1814-1834. [PMID: 33163337 PMCID: PMC7606110 DOI: 10.1016/j.apsb.2019.12.019] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 11/08/2019] [Accepted: 11/08/2019] [Indexed: 02/07/2023] Open
Abstract
The Wnt/β-catenin signaling is a conserved pathway that has a crucial role in embryonic and adult life. Dysregulation of the Wnt/β-catenin pathway has been associated with diseases including cancer, and components of the signaling have been proposed as innovative therapeutic targets, mainly for cancer therapy. The attention of the worldwide researchers paid to this issue is increasing, also in view of the therapeutic potential of these agents in diseases, such as Parkinson's disease (PD), for which no cure is existing today. Much evidence indicates that abnormal Wnt/β-catenin signaling is involved in tumor immunology and the targeting of Wnt/β-catenin pathway has been also proposed as an attractive strategy to potentiate cancer immunotherapy. During the last decade, several products, including naturally occurring dietary agents as well as a wide variety of products from plant sources, including curcumin, quercetin, berberin, and ginsenosides, have been identified as potent modulators of the Wnt/β-catenin signaling and have gained interest as promising candidates for the development of chemopreventive or therapeutic drugs for cancer. In this review we make an overview of the nature-derived compounds reported to have antitumor activity by modulating the Wnt/β-catenin signaling, also focusing on extraction methods, chemical features, and bio-activity assays used for the screening of these compounds.
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Affiliation(s)
- Gianluca Sferrazza
- Institute of Translational Pharmacology, National Research Council of Italy, Rome 03018, Italy
| | - Marco Corti
- Department of Drug Sciences, University of Pavia, Pavia 27100, Italy
| | - Gloria Brusotti
- Department of Drug Sciences, University of Pavia, Pavia 27100, Italy
| | - Pasquale Pierimarchi
- Institute of Translational Pharmacology, National Research Council of Italy, Rome 03018, Italy
| | | | - Annalucia Serafino
- Institute of Translational Pharmacology, National Research Council of Italy, Rome 03018, Italy
| | - Enrica Calleri
- Department of Drug Sciences, University of Pavia, Pavia 27100, Italy
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Jain V, Kumar H, Anod HV, Chand P, Gupta NV, Dey S, Kesharwani SS. A review of nanotechnology-based approaches for breast cancer and triple-negative breast cancer. J Control Release 2020; 326:628-647. [PMID: 32653502 DOI: 10.1016/j.jconrel.2020.07.003] [Citation(s) in RCA: 166] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 07/03/2020] [Accepted: 07/04/2020] [Indexed: 12/24/2022]
Abstract
Breast cancer (BC) is one of the most prevalent cancers in women. Triple-negative breast cancer (TNBC) in which the three major receptors i.e. estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), are absent is known to express the most aggressive phenotype and increased metastasis which results in the development of resistance to chemotherapy. It offers various therapeutic advantages in treating BC and TNBC. Nanotechnology offers various unique characteristics such as small size (nanometric), active and passive targeting, and the ability to attach multiple targeting moieties, controlled release, and site-specific targeting. This review focuses on conventional drug therapies, recent treatment strategies, and unique therapeutic approaches available for BC and TNBC. The role of breast cancer stem cells in the recurrence of BC and TNBC has also been highlighted. Several chemotherapeutic agents delivered using nanocarriers such as polymeric nanoparticles/micelles, metallic/inorganic NPs, and lipid-based NPs (Liposome, solid-lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs)), etc. with excellent responses in the treatment of BC/TNBC along with breast cancer stem cells have been discussed in details. Moreover, the application of nanomedicine including CRISPR nanoparticle, exosomes for the treatment of BC/TNBC and other molecular targets available such as poly (ADP-ribose) polymerase (PARP), epidermal growth factor receptor (EGFR), Vascular endothelial growth factor (VEGF), etc. for further exploration have also been discussed.
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Affiliation(s)
- Vikas Jain
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, 570015, India.
| | - Hitesh Kumar
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, 570015, India
| | - Haritha V Anod
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, 570015, India
| | - Pallavi Chand
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, 570015, India
| | - N Vishal Gupta
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, 570015, India
| | - Surajit Dey
- College of Pharmacy, Roseman University of Health Sciences, Henderson, NV, USA
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Flavonoids and Mitochondria: Activation of Cytoprotective Pathways? Molecules 2020; 25:molecules25133060. [PMID: 32635481 PMCID: PMC7412508 DOI: 10.3390/molecules25133060] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 07/01/2020] [Accepted: 07/02/2020] [Indexed: 02/07/2023] Open
Abstract
A large number of diverse mechanisms that lead to cytoprotection have been described to date. Perhaps, not surprisingly, the role of mitochondria in these phenomena is notable. In addition to being metabolic centers, due to their role in cell catabolism, ATP synthesis, and biosynthesis these organelles are triggers and/or end-effectors of a large number of signaling pathways. Their role in the regulation of the intrinsic apoptotic pathway, calcium homeostasis, and reactive oxygen species signaling is well documented. In this review, we aim to characterize the prospects of influencing cytoprotective mitochondrial signaling routes by natural substances of plant origin, namely, flavonoids (e.g., flavanones, flavones, flavonols, flavan-3-ols, anthocyanidins, and isoflavones). Flavonoids are a family of widely distributed plant secondary metabolites known for their beneficial effects on human health and are widely applied in traditional medicine. Their pharmacological characteristics include antioxidative, anticarcinogenic, anti-inflammatory, antibacterial, and antidiabetic properties. Here, we focus on presenting mitochondria-mediated cytoprotection against various insults. Thus, the role of flavonoids as antioxidants and modulators of antioxidant cellular response, apoptosis, mitochondrial biogenesis, autophagy, and fission and fusion is reported. Finally, an emerging field of flavonoid-mediated changes in the activity of mitochondrial ion channels and their role in cytoprotection is outlined.
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Yu WK, Xu ZY, Yuan L, Mo S, Xu B, Cheng XD, Qin JJ. Targeting β-Catenin Signaling by Natural Products for Cancer Prevention and Therapy. Front Pharmacol 2020; 11:984. [PMID: 32695004 PMCID: PMC7338604 DOI: 10.3389/fphar.2020.00984] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 06/18/2020] [Indexed: 12/15/2022] Open
Abstract
The mutations and deregulation of Wnt signaling pathway occur commonly in human cancer and cause the aberrant activation of β-catenin and β-catenin-dependent transcription, thus contributing to cancer development and progression. Therefore, β-catenin has been demonstrated as a promising target for cancer prevention and therapy. Many natural products have been characterized as inhibitors of the β-catenin signaling through down-regulating β-catenin expression, modulating its phosphorylation, promoting its ubiquitination and proteasomal degradation, inhibiting its nuclear translocation, or other molecular mechanisms. These natural product inhibitors have shown preventive and therapeutic efficacy in various cancer models in vitro and in vivo. In the present review, we comprehensively discuss the natural product β-catenin inhibitors, their in vitro and in vivo anticancer activities, and underlying molecular mechanisms. We also discuss the current β-catenin-targeting strategies and other potential strategies that may be examined for identifying new β-catenin inhibitors as cancer preventive and therapeutic drugs.
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Affiliation(s)
- Wen-Kai Yu
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhi-Yuan Xu
- Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Li Yuan
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Shaowei Mo
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Beihua Xu
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiang-Dong Cheng
- Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Jiang-Jiang Qin
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.,Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
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Wang L, Chen N, Cheng H. Fisetin inhibits vascular endothelial growth factor-induced angiogenesis in retinoblastoma cells. Oncol Lett 2020; 20:1239-1244. [PMID: 32724364 PMCID: PMC7377090 DOI: 10.3892/ol.2020.11679] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 05/01/2019] [Indexed: 12/24/2022] Open
Abstract
Fisetin is a small phytochemical molecule with antitumor activity. Angiogenesis is a basic process that occurs during tumor growth and metastasis. The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway is a key regulator of angiogenesis. The aim of the present study was to evaluate whether fisetin affects angiogenesis through the VEGFR pathway. In the present study, Y79 cells were treated with 100 ng/ml VEGF in the presence of fisetin at concentrations of 0, 25, 50 and 100 µM. A Cell Counting Kit-8 assay was used to detect proliferation and the Transwell and Matrigel assays were used to assess cell migration and invasion, respectively. Reverse transcription-quantitative polymerase chain reaction analysis was applied to measure the expression level of VEGFR mRNA and western blot analysis was used to measure the protein expression of VEGFR. An immunofluorescence assay was used to detect the expression of VEGFR. Angiogenesis in vitro was assessed by a tube formation assay. The results demonstrated that fisetin significantly inhibited the proliferation of Y79 cells in a time- and dose-dependent manner. Fisetin also inhibited the migration and invasion of Y79 cells in a dose-dependent manner. Furthermore, fisetin inhibited the expression of VEGFR in Y79 cells in a dose-dependent manner and tumor angiogenesis in vitro. Thus, fisetin was found to inhibit angiogenesis via inhibition of the VEGF/VEGFR signaling pathway, and could be used as a candidate drug to inhibit angiogenesis in retinoblastoma.
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Affiliation(s)
- Liangjun Wang
- Department of Ophthalmology, Yantai Mountain Hospital, Yantai, Shandong 264001, P.R. China
| | - Ning Chen
- Department of Ophthalmology, Yuhuangding Hospital, Yantai, Shandong 264000, P.R. China
| | - Hongxia Cheng
- Department of Ophthalmology, Yuhuangding Hospital, Yantai, Shandong 264000, P.R. China
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