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Sultan MH, Zhan Q, Wang Y, Xia Y, Jia X. Precision oncolytic viral therapy in colorectal cancer: Genetic targeting and immune modulation for personalized treatment (Review). Int J Mol Med 2025; 56:104. [PMID: 40342021 DOI: 10.3892/ijmm.2025.5545] [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: 12/13/2024] [Accepted: 04/09/2025] [Indexed: 05/11/2025] Open
Abstract
Colorectal cancer (CRC) is a leading health issue and treatments to eradicate it, such as conventional chemotherapy, are non‑selective and come with a number of complications. The present review focuses on the relatively new area of precision oncolytic viral therapy (OVT), with genetic targeting and immune modifications that offer a new future for CRC treatment. In the present review, an overview of the selection factors that are considered optimal for an oncolytic virus, mechanisms of oncolysis and immunomodulation applied to the OVT, as well as new strategies to improve the efficacy of this method are described. Additionally, cause‑and‑effect relationships are examined for OVT efficacy, mediated by the tumor microenvironment, and directions for genetic manipulation of viral specificity are explored. The possibility of synergy between OVT and immune checkpoint inhibitors and other treatment approaches are demonstrated. Incorporating the details of the present review, biomarker‑guided combination therapies in precision OVT for individualized CRC care, significant issues and future trends in this required area of medicine are highlighted. Increasingly, OVT is leaving the experimental stage and may become routine practice; it provides a new perspective on overcoming CRC and highlights the importance of further research and clinical work.
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Affiliation(s)
- Muhammad Haris Sultan
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci‑Tech University, Hangzhou, Zhejiang 310018, P.R. China
| | - Qi Zhan
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci‑Tech University, Hangzhou, Zhejiang 310018, P.R. China
| | - Yigang Wang
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci‑Tech University, Hangzhou, Zhejiang 310018, P.R. China
| | - Yulong Xia
- Center for Translational Medicine and Precision Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, P.R. China
| | - Xiaoyuan Jia
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci‑Tech University, Hangzhou, Zhejiang 310018, P.R. China
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Yakkala PA, Naaz F, Shafi S, Kamal A. PI3K and tankyrase inhibitors as therapeutic targets in colorectal cancer. Expert Opin Ther Targets 2024; 28:159-177. [PMID: 38497299 DOI: 10.1080/14728222.2024.2331015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 03/12/2024] [Indexed: 03/19/2024]
Abstract
INTRODUCTION The pathways like Wingless-related integration (Wnt/β-catenin) and PI3K play an important role in colorectal cancer (CRC) development; however, their roles are distinct in the process of oncogenesis. Despite their differences, these pathways interact through feedback mechanisms and regulate the common effectors both in the upstream and the downstream processes in normal and pathological conditions. Their ability to reciprocally control each other is a primary resistance mechanism for the selective inhibitors in CRC. AREA COVERED This review highlights the Wnt/β-catenin and PI3K pathways that are interrelated in CRC, recent advances and some key perspectives in developing inhibitors that could target the tankyrase enzyme and PI3K, apart from a brief description of the potential of dual inhibitors of PI3K and Tankyrases (TNKS). EXPERT OPINION Recent research has focused on overcoming the challenges particularly relating to the resistance and efficacy of dual inhibitors targeting PI3K and tankyrase proteins. Despite these challenges, PI3K as well as tankyrases remain promising therapeutic targets for the treatment of solid tumors. The design of potent inhibitors is crucial to effectively block these protein signaling pathways. Moreover, it is essential to explore the potential of dual-target inhibition of other signaling pathways in conjunction with PI3K and tankyrase.
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Affiliation(s)
- Prasanna Anjaneyulu Yakkala
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Fatima Naaz
- Department of Chemistry, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India
| | - Syed Shafi
- Department of Chemistry, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India
| | - Ahmed Kamal
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
- Department of Pharmacy, Birla Institute of Technology and Science (BITS) Pilani, Medchal, India
- Environment, Forests, Science & Technology Department, Telangana State Council of Science & Technlogy, Hyderabad, India
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Sammarco A, Beffagna G, Sacchetto R, Vettori A, Bonsembiante F, Scarin G, Gelain ME, Cavicchioli L, Ferro S, Geroni C, Lombardi P, Zappulli V. Antitumor Effect of Berberine Analogs in a Canine Mammary Tumor Cell Line and in Zebrafish Reporters via Wnt/β-Catenin and Hippo Pathways. Biomedicines 2023; 11:3317. [PMID: 38137538 PMCID: PMC10741123 DOI: 10.3390/biomedicines11123317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/07/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023] Open
Abstract
The heterogeneous nature of human breast cancer (HBC) can still lead to therapy inefficacy and high lethality, and new therapeutics as well as new spontaneous animal models are needed to benefit translational HBC research. Dogs are primarily investigated since they spontaneously develop tumors that share many features with human cancers. In recent years, different natural phytochemicals including berberine, a plant alkaloid, have been reported to have antiproliferative activity in vitro in human cancers and rodent animal models. In this study, we report the antiproliferative activity and mechanism of action of berberine, its active metabolite berberrubine, and eight analogs, on a canine mammary carcinoma cell line and in transgenic zebrafish models. We demonstrate both in vitro and in vivo the significant effects of specific analogs on cell viability via the induction of apoptosis, also identifying their role in inhibiting the Wnt/β-catenin pathway and activating the Hippo signals with a downstream reduction in CTGF expression. In particular, the berberine analogs NAX035 and NAX057 show the highest therapeutic efficacy, deserving further analyses to elucidate their mechanism of action more in detail, and in vivo studies on spontaneous neoplastic diseases are needed, aiming at improving veterinary treatments of cancer as well as translational cancer research.
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Affiliation(s)
- Alessandro Sammarco
- Department of Comparative Biomedicine and Food Science, University of Padua, 35020 Legnaro, Italy; (A.S.); (G.B.); (R.S.); (F.B.); (G.S.); (M.E.G.); (L.C.); (S.F.)
- Department of Urology, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Giorgia Beffagna
- Department of Comparative Biomedicine and Food Science, University of Padua, 35020 Legnaro, Italy; (A.S.); (G.B.); (R.S.); (F.B.); (G.S.); (M.E.G.); (L.C.); (S.F.)
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, 35128 Padua, Italy
| | - Roberta Sacchetto
- Department of Comparative Biomedicine and Food Science, University of Padua, 35020 Legnaro, Italy; (A.S.); (G.B.); (R.S.); (F.B.); (G.S.); (M.E.G.); (L.C.); (S.F.)
| | - Andrea Vettori
- Department of Biotechnology, University of Verona, 37134 Verona, Italy;
| | - Federico Bonsembiante
- Department of Comparative Biomedicine and Food Science, University of Padua, 35020 Legnaro, Italy; (A.S.); (G.B.); (R.S.); (F.B.); (G.S.); (M.E.G.); (L.C.); (S.F.)
- Department of Animal Medicine, Production and Health, University of Padua, 35020 Legnaro, Italy
| | - Giulia Scarin
- Department of Comparative Biomedicine and Food Science, University of Padua, 35020 Legnaro, Italy; (A.S.); (G.B.); (R.S.); (F.B.); (G.S.); (M.E.G.); (L.C.); (S.F.)
| | - Maria Elena Gelain
- Department of Comparative Biomedicine and Food Science, University of Padua, 35020 Legnaro, Italy; (A.S.); (G.B.); (R.S.); (F.B.); (G.S.); (M.E.G.); (L.C.); (S.F.)
| | - Laura Cavicchioli
- Department of Comparative Biomedicine and Food Science, University of Padua, 35020 Legnaro, Italy; (A.S.); (G.B.); (R.S.); (F.B.); (G.S.); (M.E.G.); (L.C.); (S.F.)
| | - Silvia Ferro
- Department of Comparative Biomedicine and Food Science, University of Padua, 35020 Legnaro, Italy; (A.S.); (G.B.); (R.S.); (F.B.); (G.S.); (M.E.G.); (L.C.); (S.F.)
| | - Cristina Geroni
- Naxospharma Srl, 20026 Novate Milanese, Italy; (C.G.); (P.L.)
| | - Paolo Lombardi
- Naxospharma Srl, 20026 Novate Milanese, Italy; (C.G.); (P.L.)
| | - Valentina Zappulli
- Department of Comparative Biomedicine and Food Science, University of Padua, 35020 Legnaro, Italy; (A.S.); (G.B.); (R.S.); (F.B.); (G.S.); (M.E.G.); (L.C.); (S.F.)
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Malyla V, De Rubis G, Paudel KR, Chellappan DK, Hansbro NG, Hansbro PM, Dua K. Berberine nanostructures attenuate ß-catenin, a key component of epithelial mesenchymal transition in lung adenocarcinoma. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:3595-3603. [PMID: 37266589 PMCID: PMC10643271 DOI: 10.1007/s00210-023-02553-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 05/23/2023] [Indexed: 06/03/2023]
Abstract
Lung cancer (LC) is the leading cause of cancer-related deaths globally. It accounts for more than 1.9 million cases each year due to its complex and poorly understood molecular mechanisms that result in unregulated cell proliferation and metastasis. β-Catenin is a developmentally active protein that controls cell proliferation, metastasis, polarity and cell fate during homeostasis and aids in cancer progression via epithelial-mesenchymal transition. Therefore, inhibition of the β-catenin pathway could attenuate the progression of LC. Berberine, an isoquinoline alkaloid which is known for its anti-cancer and anti-inflammatory properties, demonstrates poor solubility and bioavailability. In our study, we have encapsulated berberine into liquid crystalline nanoparticles to improve its physiochemical functions and studied if these nanoparticles target the β-catenin pathway to inhibit the human lung adenocarcinoma cell line (A549) at both gene and protein levels. We observed for the first time that berberine liquid crystalline nanoparticles at 5 µM significantly attenuate the expression of the β-catenin gene and protein. The interaction between berberine and β-catenin was further validated by molecular simulation studies. Targeting β-catenin with berberine nanoparticles represents a promising strategy for the management of lung cancer progression.
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Affiliation(s)
- Vamshikrishna Malyla
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW, 2007, Australia
- Centre for Inflammation, Centenary Institute, Sydney, Sydney, NSW, 2050, Australia
- Australian Research Centre in Complementary and Integrative Medicine, Faculty of Health, University of Technology Sydney, Ultimo, NSW, 2007, Australia
| | - Gabriele De Rubis
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW, 2007, Australia
- Australian Research Centre in Complementary and Integrative Medicine, Faculty of Health, University of Technology Sydney, Ultimo, NSW, 2007, Australia
| | - Keshav Raj Paudel
- Centre for Inflammation, Centenary Institute, Sydney, Sydney, NSW, 2050, Australia
- Faculty of Science, University of Technology Sydney, Sydney, NSW, 2007, Australia
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Nicole G Hansbro
- Centre for Inflammation, Centenary Institute, Sydney, Sydney, NSW, 2050, Australia
- Faculty of Science, University of Technology Sydney, Sydney, NSW, 2007, Australia
| | - Philip M Hansbro
- Centre for Inflammation, Centenary Institute, Sydney, Sydney, NSW, 2050, Australia.
- Faculty of Science, University of Technology Sydney, Sydney, NSW, 2007, Australia.
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW, 2007, Australia.
- Centre for Inflammation, Centenary Institute, Sydney, Sydney, NSW, 2050, Australia.
- Australian Research Centre in Complementary and Integrative Medicine, Faculty of Health, University of Technology Sydney, Ultimo, NSW, 2007, Australia.
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Alaouna M, Penny C, Hull R, Molefi T, Chauke-Malinga N, Khanyile R, Makgoka M, Bida M, Dlamini Z. Overcoming the Challenges of Phytochemicals in Triple Negative Breast Cancer Therapy: The Path Forward. PLANTS (BASEL, SWITZERLAND) 2023; 12:2350. [PMID: 37375975 DOI: 10.3390/plants12122350] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 06/02/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023]
Abstract
Triple negative breast cancer (TNBC) is a very aggressive subtype of breast cancer that lacks estrogen, progesterone, and HER2 receptor expression. TNBC is thought to be produced by Wnt, Notch, TGF-beta, and VEGF pathway activation, which leads to cell invasion and metastasis. To address this, the use of phytochemicals as a therapeutic option for TNBC has been researched. Plants contain natural compounds known as phytochemicals. Curcumin, resveratrol, and EGCG are phytochemicals that have been found to inhibit the pathways that cause TNBC, but their limited bioavailability and lack of clinical evidence for their use as single therapies pose challenges to the use of these phytochemical therapies. More research is required to better understand the role of phytochemicals in TNBC therapy, or to advance the development of more effective delivery mechanisms for these phytochemicals to the site where they are required. This review will discuss the promise shown by phytochemicals as a treatment option for TNBC.
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Affiliation(s)
- Mohammed Alaouna
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria 0001, South Africa
- Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Parktown 2193, South Africa
| | - Clement Penny
- Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Parktown 2193, South Africa
| | - Rodney Hull
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria 0001, South Africa
| | - Thulo Molefi
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria 0001, South Africa
- Department of Medical Oncology, Steve Biko Academic Hospital and University of Pretoria, Pretoria 0001, South Africa
| | - Nkhensani Chauke-Malinga
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria 0001, South Africa
- Department of Plastic and Reconstructive Surgery, Faculty of Health Sciences, Steve Biko Academic Hospital, University of Pretoria, Pretoria 0001, South Africa
| | - Richard Khanyile
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria 0001, South Africa
- Department of Medical Oncology, Steve Biko Academic Hospital and University of Pretoria, Pretoria 0001, South Africa
| | - Malose Makgoka
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria 0001, South Africa
- Department of Surgery, Faculty of Health Sciences, Steve Biko Academic Hospital, University of Pretoria, Pretoria 0001, South Africa
| | - Meshack Bida
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria 0001, South Africa
- Department of Anatomical Pathology, National Health Laboratory Service (NHLS), University of Pretoria, Pretoria 0001, South Africa
| | - Zodwa Dlamini
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria 0001, South Africa
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Lin X, Chen J, Li X, Chen D, Luo K, Deng Y, Yang D, Huang Z, Tao C. Dimeric oxyberberine CT4-1 targets LINC02331 to induce cytotoxicity and inhibit chemoresistance via suppressing Wnt/β-catenin signaling in hepatocellular carcinoma. Arch Toxicol 2023; 97:1627-1647. [PMID: 37120773 DOI: 10.1007/s00204-023-03501-8] [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: 01/08/2023] [Accepted: 04/20/2023] [Indexed: 05/01/2023]
Abstract
Hepatocellular carcinoma (HCC) is a type of cancer characterized by high recurrence rates. Overcoming chemoresistance can reduce HCC recurrence and improve patients' prognosis. This work aimed to identify HCC chemoresistance-associated long non-coding RNA (lncRNA) and find an effective drug targeting the identified lncRNA for ameliorating the chemoresistance. In this investigation, bioinformatics analysis based on The Cancer Genome Atlas revealed a new chemoresistance index and suggested LINC02331 as an HCC chemoresistance and patients' prognosis-associated lncRNA that served as an independent prognostic indicator. Moreover, LINC02331 promoted DNA damage repair, DNA replication, and epithelial-mesenchymal transition as well as attenuated cell cycle arrest and apoptosis through regulating Wnt/β-catenin signaling, thus stimulating HCC resistance to cisplatin cytotoxicity, proliferation, and metastasis. Interestingly, we developed a novel oxidative coupling approach to synthesize a dimeric oxyberberine CT4-1, which exerted superior anti-HCC activities without obvious side effects measured by in vivo mice model and could downregulate LINC02331 mice model and could downregulate LINC02331 to mitigate LINC02331-induced HCC progression by suppressing Wnt/β-catenin signaling. RNA sequencing analyses verified the involvement of CT4-1-affected differential expression genes in dysregulated pathways and processes, including Wnt, DNA damage repair, cell cycle, DNA replication, apoptosis, and cell adhesion molecules. Furthermore, CT4-1 was demonstrated to be an effective cytotoxic drug in ameliorating HCC patients' prognosis with a prediction model constructed based on RNA-sequencing data from CT4-1-treated cancer cells and public cancer database. In summary, HCC chemoresistance-associated LINC02331 independently predicted poor patients' prognosis and enhanced HCC progression by promoting resistance to cisplatin cytotoxicity, proliferation, and metastasis. Targeting LINC02331 by the dimeric oxyberberine CT4-1 that exhibited synergistic cytotoxicity with cisplatin could alleviate HCC progression and improve patients' prognosis. Our study identified LINC02331 as an alternative target and suggested CT4-1 as an effective cytotoxic drug in HCC treatment.
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Affiliation(s)
- Xian Lin
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, and School of Pharmacy, Guangdong Medical University, Dongguan, 523808, China
| | - Jian Chen
- Shenzhen Key Laboratory of Inflammatory and Immunology Diseases, Shenzhen, 518036, China
- Peking University Shenzhen Hospital, Shenzhen, 518036, China
| | - Xin Li
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, and School of Pharmacy, Guangdong Medical University, Dongguan, 523808, China
| | - Dong Chen
- Peking University Shenzhen Hospital, Shenzhen, 518036, China
| | - Kaixuan Luo
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, and School of Pharmacy, Guangdong Medical University, Dongguan, 523808, China
| | - Yongxing Deng
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, and School of Pharmacy, Guangdong Medical University, Dongguan, 523808, China
| | - Dinghua Yang
- Unit of Hepatobiliary Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Zunnan Huang
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, and School of Pharmacy, Guangdong Medical University, Dongguan, 523808, China.
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Medical University, Dongguan, 523808, China.
| | - Cheng Tao
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, and School of Pharmacy, Guangdong Medical University, Dongguan, 523808, China.
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Devarajan N, Nathan J, Mathangi R, Mahendra J, Ganesan SK. Pharmacotherapeutic values of berberine: A Chinese herbal medicine for the human cancer management. J Biochem Mol Toxicol 2023; 37:e23278. [PMID: 36588295 DOI: 10.1002/jbt.23278] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 08/27/2022] [Accepted: 12/02/2022] [Indexed: 01/03/2023]
Abstract
Berberine (BBR), a traditional Chinese phytomedicine extracted from various parts of Berberis plants, is an isoquinoline alkaloid used for centuries to treat diabetes, hypercholesterolemia, hypertension, and so forth. It has recently received immense attention worldwide to treat cancer due to its potent pro-apoptotic, antiproliferative, and anti-inflammatory properties. BBR efficiently induces tumor apoptosis, replicative quiescence and abrogates cell proliferation, epithelial-mesenchymal transition, tumor neovascularization, and metastasis by modulating diverse molecular and cell signaling pathways. Furthermore, BBR could also reverse drug resistance, make tumor cells sensitive to current cancer treatment and significantly minimize the harmful side effects of cytotoxic therapies. This review comprehensively analyzed the pharmacological effects of BBR against the development, growth, progression, metastasis, and therapy resistance in wide varieties of cancer. Also, it critically discusses the significant limitations behind the development of BBR into pharmaceuticals to treat cancer and the future research directions to overcome these limitations.
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Affiliation(s)
- Nalini Devarajan
- Central Research Laboratory, Meenakshi Academy of Higher Education and Research - MAHER (Deemed to be University), Chennai, Tamilnadu, India
| | - Jhansi Nathan
- Zebrafish Developmental Biology Laboratory, AUKBC Research Centre for Emerging Technologies, Anna University, Chennai, Tamil Nadu, India
| | - Ramalingam Mathangi
- Department of Biochemistry, Sree Balaji Dental College and Hospital, BIHER, Chennai, Tamil Nadu, India
| | - Jaideep Mahendra
- Department of Periodontology, Meenakshi Ammal Dental College and Hospital, Chennai, Tamil Nadu, India
| | - Senthil Kumar Ganesan
- Laboratory of Functional Genomics, Structural Biology & Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, West Bengal, India
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Kaiser A, Eiselt G, Bechler J, Huber O, Schmidt M. WNT3a Signaling Inhibits Aromatase Expression in Breast Adipose Fibroblasts-A Possible Mechanism Supporting the Loss of Estrogen Responsiveness of Triple-Negative Breast Cancers. Int J Mol Sci 2023; 24:ijms24054654. [PMID: 36902090 PMCID: PMC10003471 DOI: 10.3390/ijms24054654] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 02/23/2023] [Accepted: 02/24/2023] [Indexed: 03/04/2023] Open
Abstract
Estrogen-dependent breast cancers rely on a constant supply of estrogens and expression of estrogen receptors. Local biosynthesis, by aromatase in breast adipose fibroblasts (BAFs), is their most important source for estrogens. Triple-negative breast cancers (TNBC) rely on other growth-promoting signals, including those from the Wnt pathway. In this study, we explored the hypothesis that Wnt signaling alters the proliferation of BAFs, and is involved in regulation of aromatase expression in BAFs. Conditioned medium (CM) from TNBC cells and WNT3a consistently increased BAF growth, and reduced aromatase activity up to 90%, by suppression of the aromatase promoter I.3/II region. Database searches identified three putative Wnt-responsive elements (WREs) in the aromatase promoter I.3/II. In luciferase reporter gene assays, promoter I.3/II activity was inhibited by overexpression of full-length T-cell factor (TCF)-4 in 3T3-L1 preadipocytes, which served as a model for BAFs. Full-length lymphoid enhancer-binding factor (LEF)-1 increased the transcriptional activity. However, TCF-4 binding to WRE1 in the aromatase promoter, was lost after WNT3a stimulation in immunoprecipitation-based in vitro DNA-binding assays, and in chromatin immunoprecipitation (ChIP). In vitro DNA-binding assays, ChIP, and Western blotting revealed a WNT3a-dependent switch of nuclear LEF-1 isoforms towards a truncated variant, whereas β-catenin levels remained unchanged. This LEF-1 variant revealed dominant negative properties, and most likely recruited enzymes involved in heterochromatin formation. In addition, WNT3a induced the replacement of TCF-4 by the truncated LEF-1 variant, on WRE1 of the aromatase promoter I.3/II. The mechanism described here may be responsible for the loss of aromatase expression predominantly associated with TNBC. Tumors with (strong) expression of Wnt ligands actively suppress aromatase expression in BAFs. Consequently a reduced estrogen supply could favor the growth of estrogen-independent tumor cells, which consequently would make estrogen receptors dispensable. In summary, canonical Wnt signaling within (cancerous) breast tissue may be a major factor controlling local estrogen synthesis and action.
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Affiliation(s)
- Alexander Kaiser
- Institute for Biochemistry II, Jena University Hospital, Friedrich Schiller University, 07743 Jena, Germany
| | - Gabriele Eiselt
- Institute for Biochemistry II, Jena University Hospital, Friedrich Schiller University, 07743 Jena, Germany
| | - Joachim Bechler
- Department of Gynecology and Obstetrics, Robert-Koch-Hospital, 99510 Apolda, Germany
| | - Otmar Huber
- Institute for Biochemistry II, Jena University Hospital, Friedrich Schiller University, 07743 Jena, Germany
| | - Martin Schmidt
- Institute for Biochemistry II, Jena University Hospital, Friedrich Schiller University, 07743 Jena, Germany
- Correspondence: ; Tel.: +49-3641-939-6420
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9
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Alharbi KS, Afzal O, Altamimi ASA, Almalki WH, Kazmi I, Al-Abbasi FA, Alzarea SI, Makeen HA, Albratty M. Potential role of nutraceuticals via targeting a Wnt/β-catenin and NF-κB pathway in treatment of osteoarthritis. J Food Biochem 2022; 46:e14427. [PMID: 36165556 DOI: 10.1111/jfbc.14427] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 08/26/2022] [Accepted: 09/08/2022] [Indexed: 01/13/2023]
Abstract
Osteoarthritis (OA) is a disease due to the aging of the articular cartilage, a post-mitotic tissue that stays functioning until primary homeostatic processes fail. Because of pain and disability, OA significantly influences national healthcare expenses and patient quality of life. It is a whole-joint illness characterized by inflammatory and oxidative signaling pathways and significant epigenetic alterations that cause cartilage extracellular matrix degradation. The canonical Wnt pathway (Wnt/β-catenin pathway) and nuclear factor kappa B (NF-κB) signaling pathways may function in joint tissues by modulating the activity of synovial cells, osteoblasts, and chondrocytes. However, finding innovative ways to treat osteoarthritis and get the joint back to average balance is still a struggle. Nutraceuticals are dietary supplements that promote joint health by balancing anabolic and catabolic signals. New therapeutic methods for OA treatment have been developed based on many research findings that show nutraceuticals have strong anti-inflammation, antioxidant, anti-bone resorption, and anabolic properties. For the treatment of osteoarthritis, we explore the possible involvement of nutraceuticals that target the Wnt/β-catenin and NF-κB pathways. PRACTICAL APPLICATIONS: In keeping with the aging population, osteoarthritis is becoming more widespread. In this extensive research, we studied the role of the Wnt/β-catenin and NF-κB pathway in OA formation and progression. Nutraceuticals that target these OA-related signaling pathways are a viable therapy option. Wnt/β-catenin and NF-κB signaling pathway are inhibited by polyphenols, flavonoids, alkaloids, and vitamins from the nutraceutical category, making them possible therapeutic drugs for OA therapy.
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Affiliation(s)
- Khalid Saad Alharbi
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia
| | - Obaid Afzal
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj, Saudi Arabia
| | | | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Fahad A Al-Abbasi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia
| | - Hafiz A Makeen
- Pharmacy Practice Research Unit, Clinical Pharmacy Department, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Mohammed Albratty
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
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Berberine: An Important Emphasis on Its Anticancer Effects through Modulation of Various Cell Signaling Pathways. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27185889. [PMID: 36144625 PMCID: PMC9505063 DOI: 10.3390/molecules27185889] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 08/31/2022] [Accepted: 09/06/2022] [Indexed: 11/27/2022]
Abstract
Cancer is the most commonly diagnosed type of disease and a major cause of death worldwide. Despite advancement in various treatment modules, there has been little improvement in survival rates and side effects associated with this disease. Medicinal plants or their bioactive compounds have been extensively studied for their anticancer potential. Novel drugs based on natural products are urgently needed to manage cancer through attenuation of different cell signaling pathways. In this regard, berberine is a bioactive alkaloid that is found in variety of plants, and an inverse association has been revealed between its consumption and cancer. Berberine exhibits an anticancer role through scavenging free radicals, induction of apoptosis, cell cycle arrest, inhibition of angiogenesis, inflammation, PI3K/AKT/mammalian target of rapamycin (mTOR), Wnt/β-catenin, and the MAPK/ERK signaling pathway. In addition, synergistic effects of berberine with anticancer drugs or natural compounds have been proven in several cancers. This review outlines the anticancer effects and mechanisms of action of berberine in different cancers through modulation of various cell signaling pathways. Moreover, the recent developments in the drug delivery systems and synergistic effect of berberine are explained.
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Hyperforin and Myrtucommulone Derivatives Act as Natural Modulators of Wnt/β-Catenin Signaling in HCT116 Colon Cancer Cells. Int J Mol Sci 2022; 23:ijms23062984. [PMID: 35328403 PMCID: PMC8954631 DOI: 10.3390/ijms23062984] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/25/2022] [Accepted: 03/08/2022] [Indexed: 12/30/2022] Open
Abstract
The therapeutic activities of natural plant extracts have been well known for centuries. Many of them, in addition to antiviral and antibiotic effects, turned out to have anti-tumor activities by targeting different signaling pathways. The canonical Wnt pathway represents a major tumorigenic pathway deregulated in numerous tumor entities, including colon cancer. Here, we investigated the acylphloroglucinols hyperforin (HF) from St. John's wort (Hypericum perforatum L.) and myrtucommulone A (MC A) from myrtle (Myrtus communis) and semi-synthetic derivatives thereof (HM 177, HM 297, HM298) for their effects on Wnt/β-catenin signaling. None of these substances revealed major cytotoxicity on STF293 embryonic kidney and HCT116 colon carcinoma cells at concentrations up to 10 μM. At this concentration, HF and HM 177 showed the strongest effect on cell proliferation, whereas MC A and HM 177 most prominently inhibited anchorage-independent growth of HCT116 cells. Western blot analyses of active β-catenin and β-catenin/TCF reporter gene assays in STF293 cells revealed inhibitory activities of HF, MC A and HM 177. In line with this, the expression of endogenous Wnt target genes, Axin and Sp5, in HCT116 cells was significantly reduced. Our data suggest that the acylphloroglucinols hyperforin, myrtucommulone A and its derivative HM 177 represent potential new therapeutic agents to inhibit Wnt/β-catenin signaling in colon cancer.
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Molecular Mechanism of Gleditsiae Spina for the Treatment of High-Grade Serous Ovarian Cancer Based on Network Pharmacology and Pharmacological Experiments. BIOMED RESEARCH INTERNATIONAL 2022; 2022:5988310. [PMID: 35299895 PMCID: PMC8923798 DOI: 10.1155/2022/5988310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 02/13/2022] [Accepted: 02/22/2022] [Indexed: 11/17/2022]
Abstract
Background Gleditsiae Spina, widely used in traditional Chinese medicine, has a good curative effect on malignant tumors such as ovarian cancer, but the mechanism is not clear. So, we aimed to analyze the pharmacological mechanism of Gleditsiae Spina in the treatment of high-grade serous ovarian cancer (HGSC) based on network pharmacology and biological experiments. Methods The main active ingredients of Gleditsiae Spina were identified by high performance liquid chromatography (HPLC) and mass spectrometry (MS), and the active ingredients were performed by ADME screening. The component targets of Gleditsiae Spina were screened using the PharmMapper platform, and differentially expressed genes in normal and HGSC tissues were identified through the GEO database. Thereafter, the network of “active ingredient-targets” was constructed by cytoscape 3.7.2 software. The protein-protein interaction network was established by the BioGenet database to mine the potential protein function. Biological processes and pathways were analyzed through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. The binding ability of the core components of the Gleditsiae Spina and the core target of HGSC was verified by molecular docking and molecular dynamics simulation, and the therapeutic effect of Gleditsiae Spina was proved in vitro through cytotoxicity experiments. The effect of Gleditsiae Spina on the core pathway is obtained by western blotting. Results Gleditsiae Spina had cytotoxicity on HGSC based on network pharmacology and biological experiments. Luteolin, genistein, D-(+)-tryptophan, ursolic acid, and berberine are the identified core active ingredients of Gleditsiae Spina for regulating HGSC, with HPSE, PI3KCA, AKT1, and CTNNB1as the ideal targets. The prediction results were verified by molecular docking, molecular dynamic simulation, cell viability, and western blot analysis. Conclusion Gleditsiae Spina mainly downregulates the expression of heparanase and β-catenin to affect the composition of tumor cytoplasmic matrix and can regulate the PI3K-AKT pathway, integrating multiple targets and multiple pathways to play a therapeutic role. It also provides a theoretical basis for the prevention of ovarian cancer and its treatment using traditional Chinese medicine in the future.
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Oliveira LFS, Predes D, Borges HL, Abreu JG. Therapeutic Potential of Naturally Occurring Small Molecules to Target the Wnt/β-Catenin Signaling Pathway in Colorectal Cancer. Cancers (Basel) 2022; 14:cancers14020403. [PMID: 35053565 PMCID: PMC8774030 DOI: 10.3390/cancers14020403] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 12/29/2021] [Accepted: 01/06/2022] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Colorectal cancer (CRC) is an emerging public health problem and the second leading cause of death worldwide, with a significant socioeconomic impact in several countries. The 5-year survival rate is only 12% due to the lack of early diagnosis and resistance to available treatments, and the canonical Wnt signaling pathway is involved in this process. This review underlines the importance of understanding the fundamental roles of this pathway in physiological and pathological contexts and analyzes the use of naturally occurring small molecules that inhibits the Wnt/β-catenin pathway in experimental models of CRC. We also discuss the progress and challenges of moving these small molecules off the laboratory bench into the clinical platform. Abstract Colorectal cancer (CRC) ranks second in the number of cancer deaths worldwide, mainly due to late diagnoses, which restrict treatment in the potentially curable stages and decrease patient survival. The treatment of CRC involves surgery to remove the tumor tissue, in addition to radiotherapy and systemic chemotherapy sessions. However, almost half of patients are resistant to these treatments, especially in metastatic cases, where the 5-year survival rate is only 12%. This factor may be related to the intratumoral heterogeneity, tumor microenvironment (TME), and the presence of cancer stem cells (CSCs), which is impossible to resolve with the standard approaches currently available in clinical practice. CSCs are APC-deficient, and the search for alternative therapeutic agents such as small molecules from natural sources is a promising strategy, as these substances have several antitumor properties. Many of those interfere with the regulation of signaling pathways at the central core of CRC development, such as the Wnt/β-catenin, which plays a crucial role in the cell proliferation and stemness in the tumor. This review will discuss the use of naturally occurring small molecules inhibiting the Wnt/β-catenin pathway in experimental CRC models over the past decade, highlighting the molecular targets in the Wnt/β-catenin pathway and the mechanisms through which these molecules perform their antitumor activities.
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Filli MS, Ibrahim AA, Kesse S, Aquib M, Boakye-Yiadom KO, Farooq MA, Raza F, Zhang Y, Wang B. Synthetic berberine derivatives as potential new drugs. BRAZ J PHARM SCI 2022. [DOI: 10.1590/s2175-97902020000318835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
| | | | | | - Md Aquib
- China Pharmaceutical University, China
| | | | | | | | | | - Bo Wang
- China Pharmaceutical University, China
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15
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Targeting the crosstalk between canonical Wnt/β-catenin and inflammatory signaling cascades: A novel strategy for cancer prevention and therapy. Pharmacol Ther 2021; 227:107876. [PMID: 33930452 DOI: 10.1016/j.pharmthera.2021.107876] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 04/05/2021] [Indexed: 02/06/2023]
Abstract
Emerging scientific evidence indicates that inflammation is a critical component of tumor promotion and progression. Most cancers originate from sites of chronic irritation, infections and inflammation, underscoring that the tumor microenvironment is largely orchestrated by inflammatory cells and pro-inflammatory molecules. These inflammatory components are intimately involved in neoplastic processes which foster proliferation, survival, invasion, and migration, making inflammation the primary target for cancer prevention and treatment. The influence of inflammation and the immune system on the progression and development of cancer has recently gained immense interest. The Wnt/β-catenin signaling pathway, an evolutionarily conserved signaling strategy, has a critical role in regulating tissue development. It has been implicated as a major player in cancer development and progression with its regulatory role on inflammatory cascades. Many naturally-occurring and small synthetic molecules endowed with inherent anti-inflammatory properties inhibit this aberrant signaling pathway, making them a promising class of compounds in the fight against inflammatory cancers. This article analyzes available scientific evidence and suggests a crosslink between Wnt/β-catenin signaling and inflammatory pathways in inflammatory cancers, especially breast, gastrointestinal, endometrial, and ovarian cancer. We also highlight emerging experimental findings that numerous anti-inflammatory synthetic and natural compounds target the crosslink between Wnt/β-catenin pathway and inflammatory cascades to achieve cancer prevention and intervention. Current challenges, limitations, and future directions of research are also discussed.
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Patil S, Ashi H, Hosmani J, Almalki AY, Alhazmi YA, Mushtaq S, Parveen S, Baeshen HA, Varadarajan S, Raj AT, Patil VR, Vyas N. Tinospora cordifolia (Thunb.) Miers (Giloy) inhibits oral cancer cells in a dose-dependent manner by inducing apoptosis and attenuating epithelial-mesenchymal transition. Saudi J Biol Sci 2021; 28:4553-4559. [PMID: 34354441 PMCID: PMC8324948 DOI: 10.1016/j.sjbs.2021.04.056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/01/2021] [Accepted: 04/17/2021] [Indexed: 01/23/2023] Open
Abstract
Background Tinospora cordifolia (Thunb.) Miers (Giloy) has been applied successfully as an anti-inflammatory, anti-diabetic, and even as an anti-cancer agent. Yet, to date, the application of Giloy has not been explored concerning oral cancer. Objectives To assess the effect of T cordifolia (Thunb.) Miers (Giloy) extract (TcE) on an oral cancer cell line. Methods AW13516 (oral cancer cell line) cells were treated with the prepared aqueous extract of TcE for 24 h at various concentrations ranging between 5 μg/ml and 100 μg/ml and compared with control (cells without treatment). Thee effect of the extracts on apoptosis was assessed by through Annexin V flow cytometry assay and Luminometry based assessment of Caspase 8, 9 and caspase 3/7 activity. RNA was isolated from treated cells and gene expression of selected metastatic genes (MMP1, MMP10, and CXCL8); epithelial-mesenchymal stem cell genes (TWIST1, SNAIL, ZEB1, Oct4) and stemness related genses (Nanog, Sox2) were analyzed by using a quantitative real-time PCR system. The experiments were performed in triplicates. Results Aqueous extract of TcE was found to induce apoptosis inducer in AW13516 cells in a concentration-dependent manner and was potent even at a low concentration of 5 μg/ml. The apoptosis induction was confirmed with the caspase activity assay. Treatment of the cells with the extract for 24 h exhibited a significant decrease in the expression of EMT genes in a dose-dependent manner without an effect on the metastatic genes. Conclusion Aqueous extract of TcE induces apoptosis-mediated cell death in the oral cancer cell line AW13516 while attenuating its potential for epithelial mesenchymal transition.
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Affiliation(s)
- Shankargouda Patil
- Department of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry Jazan University, Jazan, Saudi Arabia
| | - Heba Ashi
- Department of Dental Public Health, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Jagadish Hosmani
- Oral Pathology Section, Department of Diagnostic Dental Sciences, College of Dentistry, King Khalid University, Abha, Saudi Arabia
| | | | - Yaser Ali Alhazmi
- Department of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry Jazan University, Jazan, Saudi Arabia
| | - Shazia Mushtaq
- College of Applied Medical Sciences, Dental Health Department, King Saud University, Riyadh, Saudi Arabia
| | - Sameena Parveen
- Department of Maxillofacial Surgery and Diagnostic Sciences, College of Dentistry, Jazan University, Jazan, Saudi Arabia
| | - Hosam Ali Baeshen
- Department of Orthodontics, College of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Saranya Varadarajan
- Department of Oral Pathology and Microbiology, Sri Venkateswara Dental College and Hospital, Chennai, India
| | - A Thirumal Raj
- Department of Oral Pathology and Microbiology, Sri Venkateswara Dental College and Hospital, Chennai, India
| | | | - Nishant Vyas
- Logical Life Science Private Limited, Pune, India
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Vishnoi K, Ke R, Saini KS, Viswakarma N, Nair RS, Das S, Chen Z, Rana A, Rana B. Berberine Represses β-Catenin Translation Involving 4E-BPs in Hepatocellular Carcinoma Cells. Mol Pharmacol 2021; 99:1-16. [PMID: 33130557 PMCID: PMC7725064 DOI: 10.1124/molpharm.120.000029] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 10/02/2020] [Indexed: 12/17/2022] Open
Abstract
Aberrant activation of Wnt/β-catenin axis occurs in several gastrointestinal malignancies due to inactivating mutations of adenomatous polyposis coli (in colorectal cancer) or activating mutations of β-catenin itself [in hepatocellular carcinoma (HCC)]. These lead to β-catenin stabilization, increase in β-catenin/T-cell factor (TCF)-mediated transcriptional activation, and target gene expression, many of which are involved in tumor progression. While studying pharmaceutical agents that can target β-catenin in cancer cells, we observed that the plant compound berberine (BBR), a potent activator of AMP-activated protein kinase (AMPK), can reduce β-catenin expression and downstream signaling in HCC cells in a dose-dependent manner. More in-depth analyses to understand the mechanism revealed that BBR-induced reduction of β-catenin occurs independently of AMPK activation and does not involve transcriptional or post-translational mechanisms. Pretreatment with protein synthesis inhibitor cycloheximide antagonized BBR-induced β-catenin reduction, suggesting that BBR affects β-catenin translation. BBR treatment also antagonized mammalian target of rapamycin (mTOR) activity and was associated with increased recruitment of eukaryotic translation initiation factor 4E-binding protein (4E-BP) 1 in the translational complex, which was revealed by 7-methyl-cap-binding assays, suggesting inhibition of cap-dependent translation. Interestingly, knocking down 4E-BP1 and 4E-BP2 significantly attenuated BBR-induced reduction of β-catenin levels and expression of its downstream target genes. Moreover, cells with 4E-BP knockdown were resistant to BBR-induced cell death and were resensitized to BBR after pharmacological inhibition of β-catenin. Our findings indicate that BBR antagonizes β-catenin pathway by inhibiting β-catenin translation and mTOR activity and thereby reduces HCC cell survival. These also suggest that BBR could be used for targeting HCCs that express mutated/activated β-catenin variants that are currently undruggable. SIGNIFICANCE STATEMENT: β-catenin signaling is aberrantly activated in different gastrointestinal cancers, including hepatocellular carcinoma, which is currently undruggable. In this study we describe a novel mechanism of targeting β-catenin translation via utilizing a plant compound, berberine. Our findings provide a new avenue of targeting β-catenin axis in cancer, which can be utilized toward the designing of effective therapeutic strategies to combat β-catenin-dependent cancers.
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Affiliation(s)
- Kanchan Vishnoi
- Department of Surgery, Division of Surgical Oncology (K.V., R.K., K.S.S., N.V., R.S.N., S.D., A.R., B.R.), University of Illinois Hospital and Health Sciences System Cancer Center (S.D., A.R., B.R.), and Division of Epidemiology and Biostatistics, School of Public Health (Z.C.), University of Illinois at Chicago, Chicago, Illinois; Biostatistics Shared Resource Core, University of Illinois Cancer Institute, Chicago, Illinois (Z.C.); and Jesse Brown VA Medical Center, Chicago, Illinois (A.R., B.R.)
| | - Rong Ke
- Department of Surgery, Division of Surgical Oncology (K.V., R.K., K.S.S., N.V., R.S.N., S.D., A.R., B.R.), University of Illinois Hospital and Health Sciences System Cancer Center (S.D., A.R., B.R.), and Division of Epidemiology and Biostatistics, School of Public Health (Z.C.), University of Illinois at Chicago, Chicago, Illinois; Biostatistics Shared Resource Core, University of Illinois Cancer Institute, Chicago, Illinois (Z.C.); and Jesse Brown VA Medical Center, Chicago, Illinois (A.R., B.R.)
| | - Karan S Saini
- Department of Surgery, Division of Surgical Oncology (K.V., R.K., K.S.S., N.V., R.S.N., S.D., A.R., B.R.), University of Illinois Hospital and Health Sciences System Cancer Center (S.D., A.R., B.R.), and Division of Epidemiology and Biostatistics, School of Public Health (Z.C.), University of Illinois at Chicago, Chicago, Illinois; Biostatistics Shared Resource Core, University of Illinois Cancer Institute, Chicago, Illinois (Z.C.); and Jesse Brown VA Medical Center, Chicago, Illinois (A.R., B.R.)
| | - Navin Viswakarma
- Department of Surgery, Division of Surgical Oncology (K.V., R.K., K.S.S., N.V., R.S.N., S.D., A.R., B.R.), University of Illinois Hospital and Health Sciences System Cancer Center (S.D., A.R., B.R.), and Division of Epidemiology and Biostatistics, School of Public Health (Z.C.), University of Illinois at Chicago, Chicago, Illinois; Biostatistics Shared Resource Core, University of Illinois Cancer Institute, Chicago, Illinois (Z.C.); and Jesse Brown VA Medical Center, Chicago, Illinois (A.R., B.R.)
| | - Rakesh Sathish Nair
- Department of Surgery, Division of Surgical Oncology (K.V., R.K., K.S.S., N.V., R.S.N., S.D., A.R., B.R.), University of Illinois Hospital and Health Sciences System Cancer Center (S.D., A.R., B.R.), and Division of Epidemiology and Biostatistics, School of Public Health (Z.C.), University of Illinois at Chicago, Chicago, Illinois; Biostatistics Shared Resource Core, University of Illinois Cancer Institute, Chicago, Illinois (Z.C.); and Jesse Brown VA Medical Center, Chicago, Illinois (A.R., B.R.)
| | - Subhasis Das
- Department of Surgery, Division of Surgical Oncology (K.V., R.K., K.S.S., N.V., R.S.N., S.D., A.R., B.R.), University of Illinois Hospital and Health Sciences System Cancer Center (S.D., A.R., B.R.), and Division of Epidemiology and Biostatistics, School of Public Health (Z.C.), University of Illinois at Chicago, Chicago, Illinois; Biostatistics Shared Resource Core, University of Illinois Cancer Institute, Chicago, Illinois (Z.C.); and Jesse Brown VA Medical Center, Chicago, Illinois (A.R., B.R.)
| | - Zhengjia Chen
- Department of Surgery, Division of Surgical Oncology (K.V., R.K., K.S.S., N.V., R.S.N., S.D., A.R., B.R.), University of Illinois Hospital and Health Sciences System Cancer Center (S.D., A.R., B.R.), and Division of Epidemiology and Biostatistics, School of Public Health (Z.C.), University of Illinois at Chicago, Chicago, Illinois; Biostatistics Shared Resource Core, University of Illinois Cancer Institute, Chicago, Illinois (Z.C.); and Jesse Brown VA Medical Center, Chicago, Illinois (A.R., B.R.)
| | - Ajay Rana
- Department of Surgery, Division of Surgical Oncology (K.V., R.K., K.S.S., N.V., R.S.N., S.D., A.R., B.R.), University of Illinois Hospital and Health Sciences System Cancer Center (S.D., A.R., B.R.), and Division of Epidemiology and Biostatistics, School of Public Health (Z.C.), University of Illinois at Chicago, Chicago, Illinois; Biostatistics Shared Resource Core, University of Illinois Cancer Institute, Chicago, Illinois (Z.C.); and Jesse Brown VA Medical Center, Chicago, Illinois (A.R., B.R.)
| | - Basabi Rana
- Department of Surgery, Division of Surgical Oncology (K.V., R.K., K.S.S., N.V., R.S.N., S.D., A.R., B.R.), University of Illinois Hospital and Health Sciences System Cancer Center (S.D., A.R., B.R.), and Division of Epidemiology and Biostatistics, School of Public Health (Z.C.), University of Illinois at Chicago, Chicago, Illinois; Biostatistics Shared Resource Core, University of Illinois Cancer Institute, Chicago, Illinois (Z.C.); and Jesse Brown VA Medical Center, Chicago, Illinois (A.R., B.R.)
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Kasprzak A. Angiogenesis-Related Functions of Wnt Signaling in Colorectal Carcinogenesis. Cancers (Basel) 2020; 12:cancers12123601. [PMID: 33276489 PMCID: PMC7761462 DOI: 10.3390/cancers12123601] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/29/2020] [Accepted: 12/01/2020] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Angiogenesis belongs to the most clinical characteristics of colorectal cancer (CRC) and is strongly linked to the activation of Wnt/β-catenin signaling. The most prominent factors stimulating constitutive activation of this pathway, and in consequence angiogenesis, are genetic alterations (mainly mutations) concerning APC and the β-catenin encoding gene (CTNNB1), detected in a large majority of CRC patients. Wnt/β-catenin signaling is involved in the basic types of vascularization (sprouting and nonsprouting angiogenesis), vasculogenic mimicry as well as the formation of mosaic vessels. The number of known Wnt/β-catenin signaling components and other pathways interacting with Wnt signaling, regulating angiogenesis, and enabling CRC progression continuously increases. This review summarizes the current knowledge about the role of the Wnt/Fzd/β-catenin signaling pathway in the process of CRC angiogenesis, aiming to improve the understanding of the mechanisms of metastasis as well as improvements in the management of this cancer. Abstract Aberrant activation of the Wnt/Fzd/β-catenin signaling pathway is one of the major molecular mechanisms of colorectal cancer (CRC) development and progression. On the other hand, one of the most common clinical CRC characteristics include high levels of angiogenesis, which is a key event in cancer cell dissemination and distant metastasis. The canonical Wnt/β-catenin downstream signaling regulates the most important pro-angiogenic molecules including vascular endothelial growth factor (VEGF) family members, matrix metalloproteinases (MMPs), and chemokines. Furthermore, mutations of the β-catenin gene associated with nuclear localization of the protein have been mainly detected in microsatellite unstable CRC. Elevated nuclear β-catenin increases the expression of many genes involved in tumor angiogenesis. Factors regulating angiogenesis with the participation of Wnt/β-catenin signaling include different groups of biologically active molecules including Wnt pathway components (e.g., Wnt2, DKK, BCL9 proteins), and non-Wnt pathway factors (e.g., chemoattractant cytokines, enzymatic proteins, and bioactive compounds of plants). Several lines of evidence argue for the use of angiogenesis inhibition in the treatment of CRC. In the context of this paper, components of the Wnt pathway are among the most promising targets for CRC therapy. This review summarizes the current knowledge about the role of the Wnt/Fzd/β-catenin signaling pathway in the process of CRC angiogenesis, aiming to improve the understanding of the mechanisms of metastasis as well as improvements in the management of this cancer.
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Affiliation(s)
- Aldona Kasprzak
- Department of Histology and Embryology, Poznan University of Medical Sciences, Swiecicki Street 6, 60-781 Poznań, Poland
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Damjanović A, Kolundžija B, Matić IZ, Krivokuća A, Zdunić G, Šavikin K, Janković R, Stanković JA, Stanojković TP. Mahonia aquifolium Extracts Promote Doxorubicin Effects against Lung Adenocarcinoma Cells In Vitro. Molecules 2020; 25:E5233. [PMID: 33182665 PMCID: PMC7697947 DOI: 10.3390/molecules25225233] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 10/26/2020] [Accepted: 10/26/2020] [Indexed: 11/16/2022] Open
Abstract
Mahonia aquifolium and its secondary metabolites have been shown to have anticancer potential. We performed MTT, scratch, and colony formation assays; analyzed cell cycle phase distribution and doxorubicin uptake and retention with flow cytometry; and detected alterations in the expression of genes involved in the formation of cell-cell interactions and migration using quantitative real-time PCR following treatment of lung adenocarcinoma cells with doxorubicin, M. aquifolium extracts, or their combination. MTT assay results suggested strong synergistic effects of the combined treatments, and their application led to an increase in cell numbers in the subG1 phase of the cell cycle. Both extracts were shown to prolong doxorubicin retention time in cancer cells, while the application of doxorubicin/extract combination led to a decrease in MMP9 expression. Furthermore, cells treated with doxorubicin/extract combinations were shown to have lower migratory and colony formation potentials than untreated cells or cells treated with doxorubicin alone. The obtained results suggest that nontoxic M. aquifolium extracts can enhance the activity of doxorubicin, thus potentially allowing the application of lower doxorubicin doses in vivo, which may decrease its toxic effects in normal tissues.
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Affiliation(s)
- Ana Damjanović
- Department for Experimental Oncology, Institute of Oncology and Radiology of Serbia, 11 000 Belgrade, Serbia; (A.D.); (B.K.); (I.Z.M.); (A.K.); (R.J.); (T.P.S.)
| | - Branka Kolundžija
- Department for Experimental Oncology, Institute of Oncology and Radiology of Serbia, 11 000 Belgrade, Serbia; (A.D.); (B.K.); (I.Z.M.); (A.K.); (R.J.); (T.P.S.)
| | - Ivana Z. Matić
- Department for Experimental Oncology, Institute of Oncology and Radiology of Serbia, 11 000 Belgrade, Serbia; (A.D.); (B.K.); (I.Z.M.); (A.K.); (R.J.); (T.P.S.)
| | - Ana Krivokuća
- Department for Experimental Oncology, Institute of Oncology and Radiology of Serbia, 11 000 Belgrade, Serbia; (A.D.); (B.K.); (I.Z.M.); (A.K.); (R.J.); (T.P.S.)
| | - Gordana Zdunić
- Department for Pharmaceutical Investigations and Development, Institute for Medicinal Plant Research, Dr. Josif Pančić, 11 070 Belgrade, Serbia; (G.Z.); (K.Š.)
| | - Katarina Šavikin
- Department for Pharmaceutical Investigations and Development, Institute for Medicinal Plant Research, Dr. Josif Pančić, 11 070 Belgrade, Serbia; (G.Z.); (K.Š.)
| | - Radmila Janković
- Department for Experimental Oncology, Institute of Oncology and Radiology of Serbia, 11 000 Belgrade, Serbia; (A.D.); (B.K.); (I.Z.M.); (A.K.); (R.J.); (T.P.S.)
| | - Jelena Antić Stanković
- Department for Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, 11 221 Belgrade, Serbia
| | - Tatjana P. Stanojković
- Department for Experimental Oncology, Institute of Oncology and Radiology of Serbia, 11 000 Belgrade, Serbia; (A.D.); (B.K.); (I.Z.M.); (A.K.); (R.J.); (T.P.S.)
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Habtemariam S. Recent Advances in Berberine Inspired Anticancer Approaches: From Drug Combination to Novel Formulation Technology and Derivatization. Molecules 2020; 25:molecules25061426. [PMID: 32245062 PMCID: PMC7144379 DOI: 10.3390/molecules25061426] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 03/01/2020] [Accepted: 03/19/2020] [Indexed: 12/13/2022] Open
Abstract
Berberine is multifunctional natural product with potential to treat diverse pathological conditions. Its broad-spectrum anticancer effect through direct effect on cancer cell growth and metastasis have been established both in vitro and in vivo. The cellular targets that account to the anticancer effect of berberine are incredibly large and range from kinases (protein kinase B (Akt), mitogen activated protein kinases (MAPKs), cell cycle checkpoint kinases, etc.) and transcription factors to genes and protein regulators of cell survival, motility and death. The direct effect of berberine in cancer cells is however relatively weak and occur at moderate concentration range (10–100 µM) in most cancer cells. The poor pharmacokinetics profile resulting from poor absorption, efflux by permeability-glycoprotein (P-gc) and extensive metabolism in intestinal and hepatic cells are other dimensions of berberine’s limitation as anticancer agent. This communication addresses the research efforts during the last two decades that were devoted to enhancing the anticancer potential of berberine. Strategies highlighted include using berberine in combination with other chemotherapeutic agents either to reduce toxic side effects or enhance their anticancer effects; the various novel formulation approaches which by order of magnitude improved the pharmacokinetics of berberine; and semisynthetic approaches that enhanced potency by up to 100-fold.
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Affiliation(s)
- Solomon Habtemariam
- Pharmacognosy Research Laboratories & Herbal Analysis Services UK, University of Greenwich, Chatham-Maritime, ME4 4TB Kent, UK
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21
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Palmieri A, Scapoli L, Iapichino A, Mercolini L, Mandrone M, Poli F, Giannì AB, Baserga C, Martinelli M. Berberine and Tinospora cordifolia exert a potential anticancer effect on colon cancer cells by acting on specific pathways. Int J Immunopathol Pharmacol 2020; 33:2058738419855567. [PMID: 31663444 PMCID: PMC6822188 DOI: 10.1177/2058738419855567] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Berberine (BBR) is a natural active principle with potential antitumor activity. The compound targets multiple cell signaling pathways, including proliferation, differentiation, and epithelial–mesenchymal transition. The aim of this study was to elucidate the mechanisms behind the anticancer activity of BBR by comparing the effects of purified BBR with those of the extract of Tinospora cordifolia, a medicinal plant that produces this metabolite. The expression levels of a panel of 44 selected genes in human colon adenocarcinoma (HCA-7) cell line were quantified by real-time polymerase chain reaction (PCR). BBR treatment resulted in a time- and dose-dependent down regulation of 33 genes differently involved in cell cycle, differentiation, and epithelial–mesenchymal transition. The trend was confirmed across the two types of treatment, the two time points, and the different absolute dosage of BBR. These findings suggest that the presence of BBR in T. cordifolia extract significantly contributes to its antiproliferative activity.
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Affiliation(s)
- Annalisa Palmieri
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Luca Scapoli
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Anastasia Iapichino
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Laura Mercolini
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Manuela Mandrone
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Ferruccio Poli
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Aldo Bruno Giannì
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.,Maxillofacial and Dental Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Camilla Baserga
- Maxillofacial and Dental Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Marcella Martinelli
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
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22
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Blagodatski A, Klimenko A, Jia L, Katanaev VL. Small Molecule Wnt Pathway Modulators from Natural Sources: History, State of the Art and Perspectives. Cells 2020; 9:cells9030589. [PMID: 32131438 PMCID: PMC7140537 DOI: 10.3390/cells9030589] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 02/25/2020] [Accepted: 02/28/2020] [Indexed: 02/07/2023] Open
Abstract
The Wnt signaling is one of the major pathways known to regulate embryonic development, tissue renewal and regeneration in multicellular organisms. Dysregulations of the pathway are a common cause of several types of cancer and other diseases, such as osteoporosis and rheumatoid arthritis. This makes Wnt signaling an important therapeutic target. Small molecule activators and inhibitors of signaling pathways are important biomedical tools which allow one to harness signaling processes in the organism for therapeutic purposes in affordable and specific ways. Natural products are a well known source of biologically active small molecules with therapeutic potential. In this article, we provide an up-to-date overview of existing small molecule modulators of the Wnt pathway derived from natural products. In the first part of the review, we focus on Wnt pathway activators, which can be used for regenerative therapy in various tissues such as skin, bone, cartilage and the nervous system. The second part describes inhibitors of the pathway, which are desired agents for targeted therapies against different cancers. In each part, we pay specific attention to the mechanisms of action of the natural products, to the models on which they were investigated, and to the potential of different taxa to yield bioactive molecules capable of regulating the Wnt signaling.
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Affiliation(s)
- Artem Blagodatski
- School of Biomedicine, Far Eastern Federal University, Vladivostok 690090, Russia;
- Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia
- Correspondence: (A.B.); (V.L.K.)
| | - Antonina Klimenko
- School of Biomedicine, Far Eastern Federal University, Vladivostok 690090, Russia;
| | - Lee Jia
- Institute of Oceanography, Minjiang University, Fuzhou 350108, China;
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou 350108, China
| | - Vladimir L. Katanaev
- School of Biomedicine, Far Eastern Federal University, Vladivostok 690090, Russia;
- Institute of Oceanography, Minjiang University, Fuzhou 350108, China;
- Translational Research Center in Oncohaematology, Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Correspondence: (A.B.); (V.L.K.)
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23
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Papi F, Bazzicalupi C, Ferraroni M, Ciolli G, Lombardi P, Khan AY, Kumar GS, Gratteri P. Pyridine Derivative of the Natural Alkaloid Berberine as Human Telomeric G 4-DNA Binder: A Solution and Solid-State Study. ACS Med Chem Lett 2020; 11:645-650. [PMID: 32435365 DOI: 10.1021/acsmedchemlett.9b00516] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 02/07/2020] [Indexed: 12/18/2022] Open
Abstract
Telomerase is an enzyme deputed to the maintenance of eukaryotic chromosomes; however, its overexpression is a recognized hallmark of many cancer forms. A viable route for the inhibition of telomerase in malignant cells is the stabilization of G-quadruplex structures (G4) at the 3' overhang of telomeres. Berberine has shown in this regard valuable G4 binding properties together with a significant anticancer activity and telomerase inhibition effects. Here, we focused on a berberine derivative featuring a pyridine containing side group at the 13th position. Such modification actually improves the binding toward telomeric G-quadruplexes and establishes a degree of selectivity in the interaction with different sequences. Moreover, the X-ray crystal structure obtained for the complex formed by the ligand and a bimolecular human telomeric quadruplex affords a better understanding of the 13-berberine derivatives behavior with telomeric G4 and allows to draw useful insights for the future design of derivatives with remarkable anticancer properties.
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Affiliation(s)
- Francesco Papi
- Department of Chemistry ’Ugo Schiff’, University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino (FI), Italy
| | - Carla Bazzicalupi
- Department of Chemistry ’Ugo Schiff’, University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino (FI), Italy
| | - Marta Ferraroni
- Department of Chemistry ’Ugo Schiff’, University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino (FI), Italy
| | - Giulia Ciolli
- Department of Chemistry ’Ugo Schiff’, University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino (FI), Italy
| | - Paolo Lombardi
- Naxospharma srl, Via G. Di Vittorio 70, 20026 Novate Milanese (MI), Italy
| | - Asma Yasmeen Khan
- Biophysical Chemistry Laboratory, CSIR-Indian Institute of Chemical Biology, Kolkata 700 032, India
| | - Gopinatha Suresh Kumar
- Biophysical Chemistry Laboratory, CSIR-Indian Institute of Chemical Biology, Kolkata 700 032, India
| | - Paola Gratteri
- Department NEUROFARBA − Pharmaceutical and Nutraceutical Section and Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy
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Wang L, Yang X, Li X, Stoika R, Wang X, Lin H, Ma Y, Wang R, Liu K. Synthesis of hydrophobically modified berberine derivatives with high anticancer activity through modulation of the MAPK pathway. NEW J CHEM 2020. [DOI: 10.1039/d0nj01645d] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Linoleic acid-modified berberine derivative induces apoptosis of A549 cells and affects the expression of proteins associated with the MAPK pathway.
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Affiliation(s)
- Lizhen Wang
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences)
- Jinan 250353
- China
- Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province
- Qilu University of Technology (Shandong Academy of Sciences)
| | - Xueliang Yang
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences)
- Jinan 250353
- China
- Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province
- Qilu University of Technology (Shandong Academy of Sciences)
| | - Xiaobin Li
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences)
- Jinan 250353
- China
- Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province
- Qilu University of Technology (Shandong Academy of Sciences)
| | - Rostyslav Stoika
- Department of Regulation of Cell Proliferation and Apoptosis
- Institute of Cell Biology
- National Academy of Sciences of Ukraine
- Lviv
- Ukraine
| | - Xue Wang
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences)
- Jinan 250353
- China
- Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province
- Qilu University of Technology (Shandong Academy of Sciences)
| | - Houwen Lin
- Research Center for Marine Drugs
- State Key Laboratory of Oncogenes and Related Genes
- Shanghai Jiao Tong University
- Shanghai
- China
| | - Yukui Ma
- Shandong Provincial Key Laboratory of Chemical Drugs
- Shandong Academy of Pharmaceutical Sciences
- 250101 Jinan
- China
| | - Rongchun Wang
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences)
- Jinan 250353
- China
- Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province
- Qilu University of Technology (Shandong Academy of Sciences)
| | - Kechun Liu
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences)
- Jinan 250353
- China
- Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province
- Qilu University of Technology (Shandong Academy of Sciences)
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25
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Grebinyk A, Prylutska S, Buchelnikov A, Tverdokhleb N, Grebinyk S, Evstigneev M, Matyshevska O, Cherepanov V, Prylutskyy Y, Yashchuk V, Naumovets A, Ritter U, Dandekar T, Frohme M. C 60 Fullerene as an Effective Nanoplatform of Alkaloid Berberine Delivery into Leukemic Cells. Pharmaceutics 2019; 11:pharmaceutics11110586. [PMID: 31717305 PMCID: PMC6920783 DOI: 10.3390/pharmaceutics11110586] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 11/04/2019] [Accepted: 11/05/2019] [Indexed: 12/20/2022] Open
Abstract
A herbal alkaloid Berberine (Ber), used for centuries in Ayurvedic, Chinese, Middle-Eastern, and native American folk medicines, is nowadays proved to function as a safe anticancer agent. Yet, its poor water solubility, stability, and bioavailability hinder clinical application. In this study, we have explored a nanosized carbon nanoparticle-C60 fullerene (C60)-for optimized Ber delivery into leukemic cells. Water dispersions of noncovalent C60-Ber nanocomplexes in the 1:2, 1:1, and 2:1 molar ratios were prepared. UV-Vis spectroscopy, dynamic light scattering (DLS), and atomic force microscopy (AFM) evidenced a complexation of the Ber cation with the negatively charged C60 molecule. The computer simulation showed that π-stacking dominates in Ber and C60 binding in an aqueous solution. Complexation with C60 was found to promote Ber intracellular uptake. By increasing C60 concentration, the C60-Ber nanocomplexes exhibited higher antiproliferative potential towards CCRF-CEM cells, in accordance with the following order: free Ber < 1:2 < 1:1 < 2:1 (the most toxic). The activation of caspase 3/7 and accumulation in the sub-G1 phase of CCRF-CEM cells treated with C60-Ber nanocomplexes evidenced apoptosis induction. Thus, this study indicates that the fast and easy noncovalent complexation of alkaloid Ber with C60 improved its in vitro efficiency against cancer cells.
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Affiliation(s)
- Anna Grebinyk
- Division Molecular Biotechnology and Functional Genomics, Technical University of Applied Sciences Wildau, Hochschulring 1, 15745 Wildau, Germany; (A.G.); s (S.G.)
- Department of Bioinformatics, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany;
| | - Svitlana Prylutska
- Taras Shevchenko National University of Kyiv, Volodymyrska 64, 01601 Kyiv, Ukraine; (S.P.); (Y.P.); (V.Y.)
| | - Anatoliy Buchelnikov
- Laboratory of Molecular and Cell Biophysics, Sevastopol State University, 299053 Sevastopol, Crimea; (A.B.); (N.T.); (M.E.)
| | - Nina Tverdokhleb
- Laboratory of Molecular and Cell Biophysics, Sevastopol State University, 299053 Sevastopol, Crimea; (A.B.); (N.T.); (M.E.)
| | - Sergii Grebinyk
- Division Molecular Biotechnology and Functional Genomics, Technical University of Applied Sciences Wildau, Hochschulring 1, 15745 Wildau, Germany; (A.G.); s (S.G.)
| | - Maxim Evstigneev
- Laboratory of Molecular and Cell Biophysics, Sevastopol State University, 299053 Sevastopol, Crimea; (A.B.); (N.T.); (M.E.)
- Laboratory of Organic Synthesis and NMR Spectroscopy, Belgorod State University, 308015 Belgorod, Russia
| | - Olga Matyshevska
- Palladin Institute of Biochemistry, NAS of Ukraine, Leontovicha Str. 9, 01030 Kyiv, Ukraine;
| | - Vsevolod Cherepanov
- Institute of Physics, NAS of Ukraine, 46 av. Nauki, 03028 Kyiv, Ukraine; (V.C.); (A.N.)
| | - Yuriy Prylutskyy
- Taras Shevchenko National University of Kyiv, Volodymyrska 64, 01601 Kyiv, Ukraine; (S.P.); (Y.P.); (V.Y.)
| | - Valeriy Yashchuk
- Taras Shevchenko National University of Kyiv, Volodymyrska 64, 01601 Kyiv, Ukraine; (S.P.); (Y.P.); (V.Y.)
| | - Anton Naumovets
- Institute of Physics, NAS of Ukraine, 46 av. Nauki, 03028 Kyiv, Ukraine; (V.C.); (A.N.)
| | - Uwe Ritter
- Institute of Chemistry and Biotechnology, University of Technology Ilmenau, Weimarer Straße 25 (Curiebau), 98693 Ilmenau, Germany;
| | - Thomas Dandekar
- Department of Bioinformatics, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany;
| | - Marcus Frohme
- Division Molecular Biotechnology and Functional Genomics, Technical University of Applied Sciences Wildau, Hochschulring 1, 15745 Wildau, Germany; (A.G.); s (S.G.)
- Correspondence: ; Tel.: +49-(0)-3375-508-249
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26
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Kirsanov KI, Vlasova OA, Fetisov TI, Zenkov RG, Lesovaya EA, Belitsky GA, Gurova K, Yakubovskaya MG. Influence of DNA-binding compounds with cancer preventive activity on the mechanisms of gene expression regulation. ADVANCES IN MOLECULAR ONCOLOGY 2019. [DOI: 10.17650/2313-805x-2018-5-4-41-63] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- K. I. Kirsanov
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia; Peoples’ Friendship University of Russia
| | - O. A. Vlasova
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - T. I. Fetisov
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - R. G. Zenkov
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - E. A. Lesovaya
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia; I.P. Pavlov Ryazan State Medical University
| | - G. A. Belitsky
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | | | - M. G. Yakubovskaya
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
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27
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Tiwari A, Saraf S, Verma A, Panda PK, Jain SK. Novel targeting approaches and signaling pathways of colorectal cancer: An insight. World J Gastroenterol 2018; 24:4428-4435. [PMID: 30357011 PMCID: PMC6196338 DOI: 10.3748/wjg.v24.i39.4428] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 08/24/2018] [Accepted: 10/05/2018] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer of mortality in the world. Chemotherapy based treatment leads to innumerable side effects as it delivers the anticancer drug to both normal cells besides cancer cells. Sonic Hedgehog (SHH), Wnt wingless-type mouse mammary tumor virus/β-catenin, transforming growth factor-β/SMAD, epidermal growth factor receptor and Notch are the main signaling pathways involved in the progression of CRC. Targeted therapies necessitate information regarding the particular aberrant pathways. Advancements in gene therapies have resulted in the recognition of novel therapeutic targets related with these signal-transduction cascades. CRC is a step-wise process where mutations occur over the time and activation of oncogenes and deactivation of tissue suppressor genes takes place. Genetic changes which are responsible for the induction of carcinogenesis include loss of heterozygosity in tumor suppressor genes such as adenomatous polyposis coli, mutation or deletion of genes like p53 and K-ras. Therefore, many gene-therapy approaches like gene correction, virus-directed enzyme-prodrug therapy, immunogenetic manipulation and virotherapy are currently being explored. Development of novel strategies for the safe and effective delivery of drugs to the cancerous site is the need of the hour. This editorial accentuates different novel strategies with emphasis on gene therapy and immunotherapy for the management of CRC.
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Affiliation(s)
- Ankita Tiwari
- Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar 470003, India
| | - Shivani Saraf
- Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar 470003, India
| | - Amit Verma
- Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar 470003, India
| | - Pritish Kumar Panda
- Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar 470003, India
| | - Sanjay K Jain
- Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar 470003, India
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Cavuturu BM, Bhandare VV, Ramaswamy A, Arumugam N. Molecular dynamics of interaction of Sesamin and related compounds with the cancer marker β-catenin: an in silico study. J Biomol Struct Dyn 2018; 37:877-891. [DOI: 10.1080/07391102.2018.1442250] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Bindu Madhuri Cavuturu
- Department of Biotechnology, School of Life Sciences, Pondicherry University, Pondicherry 605014, India
| | | | - Amutha Ramaswamy
- Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Pondicherry 605014, India
| | - Neelakantan Arumugam
- Department of Biotechnology, School of Life Sciences, Pondicherry University, Pondicherry 605014, India
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29
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Grebinyk A, Yashchuk V, Bashmakova N, Gryn D, Hagemann T, Naumenko A, Kutsevol N, Dandekar T, Frohme M. A new triple system DNA-Nanosilver-Berberine for cancer therapy. APPLIED NANOSCIENCE 2018. [DOI: 10.1007/s13204-018-0688-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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30
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Qiu S, Wu X, Liao H, Zeng X, Zhang S, Lu X, He X, Zhang X, Ye W, Wu H, Zhu X. Pteisolic acid G, a novel ent-kaurane diterpenoid, inhibits viability and induces apoptosis in human colorectal carcinoma cells. Oncol Lett 2017; 14:5540-5548. [PMID: 29113182 DOI: 10.3892/ol.2017.6889] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 06/27/2016] [Indexed: 12/27/2022] Open
Abstract
Human colorectal cancer (CRC) is a major cause of cancer morbidity and mortality, and its incidence rates are increasing in economical transitioning areas globally. To develop efficient chemotherapy drugs for CRC, the present study isolated and identified a novel ent-kaurane diterpenoid from Pteris semipinnata, termed pterisolic acid G (PAG). This ent-kaurane diterpenoid was demonstrated to significantly inhibit the growth of human CRC HCT116 cells in a time- and dose-dependent manner, determined using the Cell Counting Kit-8 assay. Additionally, western blot analysis, Hoechst 33342 staining and cytometry analysis revealed that PAG not only inhibited the viability of HCT116 cells by suppressing the dishevelled segment polarity protein 2/glycogen synthase kinase 3 β/β-catenin pathway, but also induced the apoptosis of HCT116 cells by downregulating nuclear factor-κB p65 activity, stimulating p53 expression and promoting the generation of intracellular reactive oxygen species. These results suggest that PAG, a novel inhibitor of the Wnt/β-catenin pathway and inducer of apoptosis, should be investigated in more detail using in vivo experiments and comprehensive mechanistic studies in order to examine the potential use of PAG as a novel therapeutic agent for the treatment of CRC.
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Affiliation(s)
- Shuangli Qiu
- Cancer Center, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Xin Wu
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, Guangdong 524023, P.R. China.,Key Laboratory for New Drug Research of TCM and Shenzhen Branch, State R&D Centre for Vitro-Biotech, Research Institute of Tsinghua University in Shenzhen, Shenzhen, Guangdong 518057, P.R. China
| | - Hongbo Liao
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, Guangdong 524023, P.R. China
| | - Xiaobin Zeng
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, Guangdong 524023, P.R. China.,Key Laboratory for New Drug Research of TCM and Shenzhen Branch, State R&D Centre for Vitro-Biotech, Research Institute of Tsinghua University in Shenzhen, Shenzhen, Guangdong 518057, P.R. China
| | - Senwang Zhang
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, Guangdong 524023, P.R. China
| | - Xiaofen Lu
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, Guangdong 524023, P.R. China
| | - Xiaohong He
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, Guangdong 524023, P.R. China
| | - Xiaoqi Zhang
- Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Wencai Ye
- Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Hua Wu
- Cancer Center, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Xiaohui Zhu
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, Guangdong 524023, P.R. China
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31
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Berberine binds RXRα to suppress β-catenin signaling in colon cancer cells. Oncogene 2017; 36:6906-6918. [PMID: 28846104 PMCID: PMC5735301 DOI: 10.1038/onc.2017.296] [Citation(s) in RCA: 105] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 06/22/2017] [Accepted: 07/17/2017] [Indexed: 02/07/2023]
Abstract
Berberine, an isoquinoline alkaloid, is a traditional oriental medicine used to treat diarrhea and gastroenteritis. Recently, we reported that it could inhibit the growth of intestinal polyp in animals and in patients with the familial adenomatous polyposis by downregulating β-catenin signaling. However, the intracellular target mediating the effects of berberine remains elusive. Here, we provide evidence that berberine inhibits β-catenin function via directly binding to a unique region comprising residues Gln275, Arg316 and Arg371 in nuclear receptor retinoid X receptor alpha (RXRα), where berberine concomitantly binding to and synergistically activating RXRα with 9-cis-retinoic acid (9-cis-RA), a natural ligand binding to the classical ligand-binding pocket of RXRα. Berberine binding promotes RXRα interaction with nuclear β-catenin, leading to c-Cbl mediated degradation of β-catenin, and consequently inhibits the proliferation of colon cancer cells. Furthermore, berberine suppresses the growth of human colon carcinoma xenograft in nude mice in an RXRα-dependent manner. Together, our study not only identifies RXRα as a direct protein target for berberine but also dissects their binding mode and validates that berberine indeed suppresses β-catenin signaling and cell growth in colon cancer via binding RXRα, which provide new strategies for the design of new RXRα-based antitumor agents and drug combinations.
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Tao K, Xiao D, Weng J, Xiong A, Kang B, Zeng H. Berberine promotes bone marrow-derived mesenchymal stem cells osteogenic differentiation via canonical Wnt/β-catenin signaling pathway. Toxicol Lett 2016; 240:68-80. [DOI: 10.1016/j.toxlet.2015.10.007] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 10/03/2015] [Accepted: 10/10/2015] [Indexed: 12/11/2022]
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Roos J, Grösch S, Werz O, Schröder P, Ziegler S, Fulda S, Paulus P, Urbschat A, Kühn B, Maucher I, Fettel J, Vorup-Jensen T, Piesche M, Matrone C, Steinhilber D, Parnham MJ, Maier TJ. Regulation of tumorigenic Wnt signaling by cyclooxygenase-2, 5-lipoxygenase and their pharmacological inhibitors: A basis for novel drugs targeting cancer cells? Pharmacol Ther 2016; 157:43-64. [PMID: 26549540 DOI: 10.1016/j.pharmthera.2015.11.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Wang N, Tan HY, Li L, Yuen MF, Feng Y. Berberine and Coptidis Rhizoma as potential anticancer agents: Recent updates and future perspectives. JOURNAL OF ETHNOPHARMACOLOGY 2015; 176:35-48. [PMID: 26494507 DOI: 10.1016/j.jep.2015.10.028] [Citation(s) in RCA: 106] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/02/2015] [Revised: 10/17/2015] [Accepted: 10/17/2015] [Indexed: 06/05/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The antineoplastic property of Coptidis Rhizoma and berberine was correlated with its traditional use of clearing internal fire, removing damp-heat and counteracting toxic pathogens. AIM OF THE STUDY The anti-tumor effect of Coptidis Rhizoma and berberine was extensively studied since our last comprehensive review in 2009. This study aims to summarize the recent updates and give rise to perspectives of Coptidis Rhizoma and berberine as potential novel antineoplastic agents. METHODS Quality studies in recent 5 years were retrieved from PubMed, Medline and CNKI with keywords including Coptis, Coptidis Rhizoma, huanglian, berberine, tumor and cancer. Studies were focused on the pharmacological actions of Coptidis Rhizoma and berberine in cancer progression. RESULTS It was shown that Coptidis Rhizoma extract and berberine may repress tumor progression by regressing abnormal cell proliferation, arresting cell cycle and inducing cell death. Studies also highlighted the actions of Coptidis Rhizoma extract and berberine in inhibiting tumor cell invasion and angiogenesis, which in turn abolish cancer metastasis. Some studies have also been conducted to reveal the potential effect of Coptidis Rhizoma extract and berberine in regulating tumor stromal microenvironment, as well as in preventing carcinogenesis. Most of the results have been demonstrated with in vivo models, but results of high-quality clinical trials are not yet available. Unspecified cancer type and staging, fluctuated dose information and variants of targets across studies of berberine/ Coptidis Rhizoma impede their clinical use for cancer treatment. CONCLUSION Recent advances highlighted by this review may shed light on future direction of studies featuring Coptidis Rhizoma and berberine as novel antineoplastic agents, which should be repeatedly proven in future animal and clinical studies. Although more evidences on its specificity and clinical efficacy are necessary to support its clinical use, Coptidis Rhizoma and berberine are highly expected to be effective, safe and affordable treatments for cancer patients.
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Affiliation(s)
- Ning Wang
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Hor-Yue Tan
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Lei Li
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Man-Fung Yuen
- Division of Gastroenterology and Hepatology, Queen Mary Hospital, and Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yibin Feng
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China.
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Small-molecule inhibitors of Wnt signaling pathway: towards novel anticancer therapeutics. Future Med Chem 2015; 7:2485-505. [PMID: 26670195 DOI: 10.4155/fmc.15.159] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The Wnt signaling pathway involves secreted glycoproteins that bind to the Frizzled family receptors to activate intracellular signal transduction events that regulate cell proliferation, apoptosis, cell migration and many critical aspects of developmental biology. DISCUSSION Aberrant Wnt signaling underlies a wide range of pathologies in humans including tumor initiation, tumor growth, cell senescence, cell death, differentiation and metastasis. The inhibition of Wnt signaling offers a novel approach for anticancer therapeutics. CONCLUSION Focusing on recent developments, we reviewed the small-molecule inhibitors targeting various components of Wnt signaling pathways and the progress from the discovery of lead compounds to highly potent inhibitors with significant therapeutic potential.
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Knutti N, Kuepper M, Friedrich K. Soluble extracellular matrix metalloproteinase inducer (EMMPRIN, EMN) regulates cancer-related cellular functions by homotypic interactions with surface CD147. FEBS J 2015; 282:4187-200. [PMID: 26277583 DOI: 10.1111/febs.13414] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Revised: 07/12/2015] [Accepted: 08/12/2015] [Indexed: 12/27/2022]
Abstract
EMMPRIN (extracellular matrix metalloproteinase inducer) is a widely expressed glycoprotein and a member of the immunoglobulin superfamily which exists in both a membrane-spanning and a soluble form. Homotypic interactions of EMMPRIN underlie its multiple roles in normal development and pathological situations such as viral infections, Alzheimer's disease and cancer. This study employed a recombinant soluble, fully glycosylated EMMPRIN domain (rhsEMN) as a tool to characterize the structural basis of EMMPRIN-EMMPRIN receptor (EMNR) contacts and their functional effects on MCF-7 breast carcinoma cells. rhsEMN did not form dimers in solution but bound to surface EMMPRIN (EMN) on MCF-7 cells with high affinity and was readily internalized. The interaction interface for the homotypic contact was localized to the N-terminal Ig domain. rhsEMN exerted a stimulatory effect on proliferation of MCF-7 cells whereas it reduced cell migration in a dose-dependent manner. These effects were accompanied by an upregulation of endogenous EMMPRIN as well as of matrix metalloproteinase-14 (MMP-14), a membrane-bound protease involved in the extracellular release of soluble EMMPRIN, indicating a regulatory feedback mechanism. The proliferation-promoting activity of rhsEMN was mimicked by a novel functional antibody directed to EMMPRIN, underscoring that crosslinking of cell surface EMMPRIN (EMNR) is crucial for eliciting intracellular signalling. Addressing malignancy-related signal transduction in HEK-293 cells, we could show that rhsEMN triggers the oncogenic Wnt pathway.
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Affiliation(s)
- Nadine Knutti
- Institute of Biochemistry II, Jena University Hospital, Germany
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Henry C, Quadir A, Hawkins NJ, Jary E, Llamosas E, Kumar D, Daniels B, Ward RL, Ford CE. Expression of the novel Wnt receptor ROR2 is increased in breast cancer and may regulate both β-catenin dependent and independent Wnt signalling. J Cancer Res Clin Oncol 2015; 141:243-54. [PMID: 25209439 DOI: 10.1007/s00432-014-1824-y] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 09/01/2014] [Indexed: 10/24/2022]
Abstract
PURPOSE Wnt signalling has been implicated in breast cancer, and in particular aberrant β-catenin-independent Wnt signalling has been associated with breast cancer metastasis and Tamoxifen resistance. Despite Wnt pathway involvement in many human cancers, attempts to target the pathway therapeutically have been disappointing. The recent discovery that the receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a novel Wnt receptor provides a potential new therapeutic and diagnostic target. METHODS To clarify the role of ROR2 in breast cancer, we investigated its expression via ROR2 immunohistochemistry in a clinical cohort of breast cancer patients, and via in vitro studies incorporating both overexpression and knock-down of ROR2. RESULTS ROR2 was expressed in the majority of breast cancer patients (87%), including those classed as triple negative. Breast cancer patients expressing ROR2 had a significantly shorter overall survival than those lacking ROR2 expression (P < 0.05). Overexpression of ROR2 in the mammary epithelial cell line, MCF10A, increased both β-catenin-dependent and β-catenin-independent targets and decreased cell adhesion. Knock-down of ROR2 in the breast cancer cell lines, MDA-MB-453 and HCC1143, decreased both β-catenin-dependent and β-catenin-independent targets and increased cell adhesion. Treatment of ROR2-expressing breast cancer cells with the novel berberine derivative, NAX53, significantly inhibited cell proliferation and migration. CONCLUSIONS This is the first study to report the expression of ROR2 in breast cancer. Breast cancer patients expressing ROR2 had a significantly worse prognosis than those lacking ROR2. ROR2 may regulate both β-catenin-dependent and β-catenin-independent Wnt signalling pathways, and represents a potential diagnostic and therapeutic target.
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Affiliation(s)
- C Henry
- Adult Cancer Program, Level 2, Metastasis Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, UNSW, NSW, 2052, Australia,
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Ortiz LMG, Lombardi P, Tillhon M, Scovassi AI. Berberine, an epiphany against cancer. Molecules 2014; 19:12349-67. [PMID: 25153862 PMCID: PMC6271598 DOI: 10.3390/molecules190812349] [Citation(s) in RCA: 183] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Revised: 08/06/2014] [Accepted: 08/11/2014] [Indexed: 12/21/2022] Open
Abstract
Alkaloids are used in traditional medicine for the treatment of many diseases. These compounds are synthesized in plants as secondary metabolites and have multiple effects on cellular metabolism. Among plant derivatives with biological properties, the isoquinoline quaternary alkaloid berberine possesses a broad range of therapeutic uses against several diseases. In recent years, berberine has been reported to inhibit cell proliferation and to be cytotoxic towards cancer cells. Based on this evidence, many derivatives have been synthesized to improve berberine efficiency and selectivity; the results so far obtained on human cancer cell lines support the idea that they could be promising agents for cancer treatment. The main properties of berberine and derivatives will be illustrated.
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Affiliation(s)
| | - Paolo Lombardi
- Naxospharma, Via Giuseppe di Vittorio 70, Novate Milanese 20026, Italy.
| | - Micol Tillhon
- Istituto di Genetica Molecolare CNR, Via Abbiategrasso 207, Pavia 27100, Italy.
| | - Anna Ivana Scovassi
- Istituto di Genetica Molecolare CNR, Via Abbiategrasso 207, Pavia 27100, Italy.
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Jabbarzadeh Kaboli P, Rahmat A, Ismail P, Ling KH. Targets and mechanisms of berberine, a natural drug with potential to treat cancer with special focus on breast cancer. Eur J Pharmacol 2014; 740:584-95. [PMID: 24973693 DOI: 10.1016/j.ejphar.2014.06.025] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Revised: 06/10/2014] [Accepted: 06/17/2014] [Indexed: 01/02/2023]
Abstract
Breast cancer is the most common cancer among women worldwide and novel therapeutic agents are needed to treat this disease. The plant-based alkaloid berberine has potential therapeutic applications for breast cancer, although a better understanding of the genes and cellular pathways regulated by this compound is needed to define the mechanism of its action in cancer treatment. In this review, the molecular targets of berberine in various cancers, particularly breast cancer, are discussed. Berberine was shown to be effective in inhibiting cell proliferation and promoting apoptosis in various cancerous cells. Some signaling pathways affected by berberine, including the MAP (mitogen-activated protein) kinase and Wnt/β-catenin pathways, are critical for reducing cellular migration and sensitivity to various growth factors. This review will discuss recent studies and consider the application of new prospective approaches based on microRNAs and other crucial regulators for use in future studies to define the action of berberine in cancer. The effects of berberine on cancer cell survival and proliferation are also outlined.
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Affiliation(s)
- Parham Jabbarzadeh Kaboli
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, UPM Serdang 43400, Selangor, Malaysia; Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, UPM Serdang 43400, Selangor, Malaysia.
| | - Asmah Rahmat
- Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, UPM Serdang 43400, Selangor, Malaysia.
| | - Patimah Ismail
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, UPM Serdang 43400, Selangor, Malaysia.
| | - King-Hwa Ling
- Department of Obstetrics and Gynecology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, UPM Serdang 43400, Selangor, Malaysia; Genetics and Regenerative Medicine Research Centre, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, UPM Serdang 43400, Selangor, Malaysia.
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Multiple effects of berberine derivatives on colon cancer cells. BIOMED RESEARCH INTERNATIONAL 2014; 2014:924585. [PMID: 25045712 PMCID: PMC4086420 DOI: 10.1155/2014/924585] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 04/24/2014] [Accepted: 04/24/2014] [Indexed: 01/21/2023]
Abstract
The pharmacological use of the plant alkaloid berberine is based on its antibacterial and anti-inflammatory properties; recently, anticancer activity has been attributed to this compound. To exploit this interesting feature, we synthesized three berberine derivatives, namely, NAX012, NAX014, and NAX018, and we tested their effects on two human colon carcinoma cell lines, that is, HCT116 and SW613-B3, which are characterized by wt and mutated p53, respectively. We observed that cell proliferation is more affected by cell treatment with the derivatives than with the lead compound; moreover, the derivatives proved to induce cell cycle arrest and cell death through apoptosis, thus suggesting that they could be promising anticancer drugs. Finally, we detected typical signs of autophagy in cells treated with berberine derivatives.
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