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Hong Y, Baik H, Lee J, Oh WS, Ryu J, Baek SJ. A novel thrombospondin-1 variant as a potential diagnostic biomarker and therapeutic target in canine mammary tumor and osteosarcoma cells. J Vet Sci 2025; 26:e22. [PMID: 40183909 PMCID: PMC11972944 DOI: 10.4142/jvs.24165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 12/03/2024] [Accepted: 01/05/2025] [Indexed: 04/05/2025] Open
Abstract
IMPORTANCE Thrombospondin-1 (TSP1) is a vital glycoprotein that plays a key role in critical biological functions, including cell migration, invasion, angiogenesis, and proliferation. Understanding the roles of its variants, particularly TSP1 variant (TSP1V), is critical for cancer biology and therapy. OBJECTIVE This study examined the expression of the transcriptional variant TSP1V, focusing on canine TSP1 sequences. METHODS The expression of canine TSP1 sequences was analyzed using a reverse transcription polymerase chain reaction (RT-PCR) to identify the TSP1 wild-type (dTSP1W) and novel canine TSP1V transcripts (dTSP1V). The effects of damnacanthal and genistein, anticancer compounds, on the viability of canine mammary and osteosarcoma cell lines were assessed by modulating the expression ratios of TSP1V to TSP1W at the transcriptional level. RT-PCR analysis compared the relative dTSP1V and dTSP1W concentrations in normal and tumor canine mammary tissues. RESULTS Two dTSP1V were identified. Treatment with damnacanthal and genistein decreased cell proliferation in canine mammary and osteosarcoma cell lines, associated with changes in the TSP1V to TSP1W expression ratio. RT-PCR analysis revealed increased dTSP1V expression in normal tissues, while dTSP1W expression was elevated in tumor tissues. CONCLUSIONS AND RELEVANCE TSP1V may be a potential diagnostic biomarker and therapeutic target for mammary tumors and osteosarcoma in dogs. The differential expression of dTSP1V and dTSP1W in normal versus tumor tissues underscores the importance of TSPIV in cancer biology, expanding the understanding of its role beyond human thyroid cancer and laying the groundwork for future research in other cancers and species.
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Affiliation(s)
- Yukyung Hong
- College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Korea
| | - Heyeon Baik
- College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Korea
| | - Jeongmin Lee
- Korea Animal Medical Center, Cheongju 28651, Korea
| | - Won Seok Oh
- Center for Veterinary Integrative Medicine, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - Junsun Ryu
- Department of Otolaryngology-Head and Neck Surgery, Center for Thyroid Cancer, Research Institute and Hospital, National Cancer Center, Goyang 10408, Korea.
| | - Seung Joon Baek
- College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Korea.
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Hou S, Ma D, Wu S, Hui Q, Hao Z. Morinda citrifolia L.: A Comprehensive Review on Phytochemistry, Pharmacological Effects, and Antioxidant Potential. Antioxidants (Basel) 2025; 14:295. [PMID: 40227265 PMCID: PMC11939675 DOI: 10.3390/antiox14030295] [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: 02/13/2025] [Revised: 02/24/2025] [Accepted: 02/26/2025] [Indexed: 04/15/2025] Open
Abstract
Morinda citrifolia L. (M. citrifolia), commonly referred to as noni, a Polynesian medicinal plant with over 2000 years of traditional use, has garnered global interest for its rich repertoire of antioxidant phytochemicals, including flavonoids (kaempferol, rutin), iridoids (aucubin, asperulosidic acid, deacetylasperulosidic acid, asperuloside), polysaccharides (nonioside A), and coumarins (scopoletin). This comprehensive review synthesizes recent advances (2018-2023) on noni's bioactive constituents, pharmacological properties, and molecular mechanisms, with a focus on its antioxidant potential. Systematic analyses reveal that noni-derived compounds exhibit potent free radical scavenging capacity (e.g., 2,2-Diphenyl-1-picrylhydrazyl/2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonicacid) (DPPH/ABTS) inhibition), upregulate endogenous antioxidant enzymes (Superoxide Dismutase (SOD), Catalase (CAT), Glutathione Peroxidase (GPx)), and modulate key pathways such as Nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) and Nuclear Factor kappa-B (NF-κB). Notably, polysaccharides and iridoids demonstrate dual antioxidant and anti-inflammatory effects via gut microbiota regulation. This highlights the plant's potential for innovation in the medical and pharmaceutical fields. However, it is also recognized that further research is needed to clarify its mechanisms of action and ensure its safety for widespread application. We emphasize the need for mechanistic studies to bridge traditional knowledge with modern applications, particularly in developing antioxidant-rich nutraceuticals and sustainable livestock feed additives. This review underscores noni's role as a multi-target antioxidant agent and provides a roadmap for future research to optimize its health benefits.
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Affiliation(s)
- Silu Hou
- Technology Innovation Center for Food Safety Surveillance and Detection (Hainan), Sanya Institute of China Agricultural University, Sanya 572025, China; (S.H.); (D.M.); (S.W.); (Q.H.)
- National Key Laboratory of Veterinary Public Health Security, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
| | - Danyang Ma
- Technology Innovation Center for Food Safety Surveillance and Detection (Hainan), Sanya Institute of China Agricultural University, Sanya 572025, China; (S.H.); (D.M.); (S.W.); (Q.H.)
- National Key Laboratory of Veterinary Public Health Security, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
| | - Shaofeng Wu
- Technology Innovation Center for Food Safety Surveillance and Detection (Hainan), Sanya Institute of China Agricultural University, Sanya 572025, China; (S.H.); (D.M.); (S.W.); (Q.H.)
- National Key Laboratory of Veterinary Public Health Security, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
| | - Qiaoyue Hui
- Technology Innovation Center for Food Safety Surveillance and Detection (Hainan), Sanya Institute of China Agricultural University, Sanya 572025, China; (S.H.); (D.M.); (S.W.); (Q.H.)
- National Key Laboratory of Veterinary Public Health Security, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
| | - Zhihui Hao
- Technology Innovation Center for Food Safety Surveillance and Detection (Hainan), Sanya Institute of China Agricultural University, Sanya 572025, China; (S.H.); (D.M.); (S.W.); (Q.H.)
- National Key Laboratory of Veterinary Public Health Security, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
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Mohan CD, Shanmugam MK, Gowda SGS, Chinnathambi A, Rangappa KS, Sethi G. c-MET pathway in human malignancies and its targeting by natural compounds for cancer therapy. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 128:155379. [PMID: 38503157 DOI: 10.1016/j.phymed.2024.155379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 01/03/2024] [Accepted: 01/17/2024] [Indexed: 03/21/2024]
Abstract
BACKGROUND c-MET is a receptor tyrosine kinase which is classically activated by HGF to activate its downstream signaling cascades such as MAPK, PI3K/Akt/mTOR, and STAT3. The c-MET modulates cell proliferation, epithelial-mesenchymal transition (EMT), immune response, morphogenesis, apoptosis, and angiogenesis. The c-MET has been shown to serve a prominent role in embryogenesis and early development. The c-MET pathway is deregulated in a broad range of malignancies, due to overexpression of ligands or receptors, genomic amplification, and MET mutations. The link between the deregulation of c-MET signaling and tumor progression has been well-documented. Overexpression or overactivation of c-MET is associated with dismal clinical outcomes and acquired resistance to targeted therapies. Since c-MET activation results in the triggering of oncogenic pathways, abrogating the c-MET pathway is considered to be a pivotal strategy in cancer therapeutics. Herein, an analysis of role of the c-MET pathway in human cancers and its relevance in bone metastasis and therapeutic resistance has been undertaken. Also, an attempt has been made to summarize the inhibitory activity of selected natural compounds towards c-MET signaling in cancers. METHODS The publications related to c-MET pathway in malignancies and its natural compound modulators were obtained from databases such as PubMed, Scopus, and Google Scholar and summarized based on PRISMA guidelines. Some of the keywords used for extracting relevant literature are c-MET, natural compound inhibitors of c-MET, c-MET in liver cancer, c-MET in breast cancer, c-MET in lung cancer, c-MET in pancreatic cancer, c-MET in head and neck cancer, c-MET in bone metastasis, c-MET in therapeutic resistance, and combination of c-MET inhibitors and chemotherapeutic agents. The chemical structure of natural compounds was verified in PubChem database. RESULTS The search yielded 3935 publications, of which 195 reference publications were used for our analysis. Clinical trials were referenced using ClinicalTrials.gov identifier. The c-MET pathway has been recognized as a prominent target to combat the growth, metastasis, and chemotherapeutic resistance in cancers. The key role of the c-MET in bone metastasis as well as therapeutic resistance has been elaborated. Also, suppressive effect of selected natural compounds on the c-MET pathway in clinical/preclinical studies has been discussed.
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Affiliation(s)
- Chakrabhavi Dhananjaya Mohan
- FEST Division, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226 001, India
| | - Muthu K Shanmugam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
| | | | - Arunachalam Chinnathambi
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Kanchugarakoppal S Rangappa
- Institution of Excellence, Vijnana Bhavan, University of Mysore, Manasagangotri, Mysore, Karnataka 570006, India.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.
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Chee CW, Mohd Hashim N, Nor Rashid N. Morindone as a potential therapeutic compound targeting TP53 and KRAS mutations in colorectal cancer cells. Chem Biol Interact 2024; 392:110928. [PMID: 38423379 DOI: 10.1016/j.cbi.2024.110928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/04/2024] [Accepted: 02/22/2024] [Indexed: 03/02/2024]
Abstract
There is an increasing demand for anticancer agent in treating colorectal cancer (CRC) with frequently mutated TP53 and KRAS genes. Phytochemical compounds are suitable as chemoprevention for CRC since dietary factor is a major risk factor. Anthraquinones from Morinda citrifolia L. were previously reported with various pharmacological properties. Various in vitro experiments were conducted to investigate the effects of two anthraquinones: damnacanthal and morindone on the cell proliferation, cell cycle, apoptosis, gene expression and protein expression in two CRC cells: HCT116 and HT29. Real-time monitoring of CRC cells showed that both anthraquinones exerted significant anti-proliferative effects in a dose- and time-dependent manner. Next, cell cycle analysis revealed an increase in the percentage of CRC cells in the G1 phase under anthraquinones treatment. Fluorescence microscopy also showed an increment of apoptotic cells under anthraquinones' treatment. siRNA transfection was conducted to evaluate the mediating effect of gene knockdown on mutated TP53 and KRAS in CRC cells. Before transfection, qRT-PCR analysis showed that only morindone downregulated the gene expression of mutated TP53 and KRAS and then further downregulated them after transfection. Both damnacanthal and morindone treatments further downregulated the expression of these two genes but upregulated at the protein expression level. Furthermore, gene knockdown also sensitised CRC cells to both damnacanthal and morindone treatments, resulting in lowered IC50 values. The accumulation of cells at the G1 phase was reduced after gene knockdown but increased after damnacanthal and morindone treatments. In addition, gene knockdown has increased the number of apoptotic cells in both cell lines and further increment was observed after anthraquinone treatment. In conclusion, morindone could be a competitive therapeutic agent in CRC by exhibiting multiple mechanism of anti-cancer actions.
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Affiliation(s)
- Cheok Wui Chee
- Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Najihah Mohd Hashim
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur, Malaysia; Centre for Natural Products Research and Drug Discovery, Universiti Malaya, Kuala Lumpur, Malaysia; Drug Design and Development Research Group, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Nurshamimi Nor Rashid
- Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia; Centre for Natural Products Research and Drug Discovery, Universiti Malaya, Kuala Lumpur, Malaysia; Drug Design and Development Research Group, Universiti Malaya, Kuala Lumpur, Malaysia.
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Kitic D, Miladinovic B, Randjelovic M, Szopa A, Seidel V, Prasher P, Sharma M, Fatima R, Arslan Ateşşahin D, Calina D, Sharifi-Rad J. Anticancer and chemopreventive potential of Morinda citrifolia L. bioactive compounds: A comprehensive update. Phytother Res 2024; 38:1932-1950. [PMID: 38358681 DOI: 10.1002/ptr.8137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 01/06/2024] [Accepted: 01/14/2024] [Indexed: 02/16/2024]
Abstract
Morinda citrifolia L., commonly known as Noni, has a longstanding history in traditional medicine for treating various diseases. Recently, there has been an increased focus on exploring Noni extracts and phytoconstituents, particularly for their effectiveness against cancers such as lung, esophageal, liver, and breast cancer, and their potential in cancer chemoprevention. This study aims to provide a comprehensive review of in vitro and in vivo studies assessing Noni's impact on cancer, alongside an exploration of its bioactive compounds. A systematic review was conducted, encompassing a wide range of scientific databases to gather pertinent literature. This review focused on in vitro and in vivo studies, as well as clinical trials that explore the effects of Noni fruit and its phytoconstituents-including anthraquinones, flavonoids, sugar derivatives, and neolignans-on cancer. The search was meticulously structured around specific keywords and criteria to ensure a thorough analysis. The compiled studies highlight Noni's multifaceted role in cancer therapy, showcasing its various bioactive components and their modes of action. This includes mechanisms such as apoptosis induction, cell cycle arrest, antiangiogenesis, and immune system modulation, demonstrating significant anticancer and chemopreventive potential. The findings reinforce Noni's potential as a safe and effective option in cancer prevention and treatment. This review underscores the need for further research into Noni's anticancer properties, with the hope of stimulating additional studies and clinical trials to validate and expand upon these promising findings.
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Affiliation(s)
- Dusanka Kitic
- Department of Pharmacy, Faculty of Medicine, University of Niš, Nis, Serbia
| | - Bojana Miladinovic
- Department of Pharmacy, Faculty of Medicine, University of Niš, Nis, Serbia
| | - Milica Randjelovic
- Department of Pharmacy, Faculty of Medicine, University of Niš, Nis, Serbia
| | - Agnieszka Szopa
- Chair and Department of Pharmaceutical Botany, Jagiellonian University, Medical College, Kraków, Poland
| | - Veronique Seidel
- Natural Products Research Laboratory, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | - Parteek Prasher
- Department of Chemistry, University of Petroleum & Energy Studies, Dehradun, India
| | - Mousmee Sharma
- Department of Chemistry, Uttaranchal University, Dehradun, India
| | - Rabab Fatima
- Department of Chemistry, University of Petroleum & Energy Studies, Dehradun, India
| | - Dilek Arslan Ateşşahin
- Baskil Vocational School, Department of Plant and Animal Production, Fırat University, Elazıg, Turkey
| | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, Craiova, Romania
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Basu A, Namporn T, Ruenraroengsak P. Critical Review in Designing Plant-Based Anticancer Nanoparticles against Hepatocellular Carcinoma. Pharmaceutics 2023; 15:1611. [PMID: 37376061 DOI: 10.3390/pharmaceutics15061611] [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: 04/10/2023] [Revised: 05/19/2023] [Accepted: 05/22/2023] [Indexed: 06/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC), accounting for 85% of liver cancer cases, continues to be the third leading cause of cancer-related deaths worldwide. Although various forms of chemotherapy and immunotherapy have been investigated in clinics, patients continue to suffer from high toxicity and undesirable side effects. Medicinal plants contain novel critical bioactives that can target multimodal oncogenic pathways; however, their clinical translation is often challenged due to poor aqueous solubility, low cellular uptake, and poor bioavailability. Nanoparticle-based drug delivery presents great opportunities in HCC therapy by increasing selectivity and transferring sufficient doses of bioactives to tumor areas with minimal damage to adjacent healthy cells. In fact, many phytochemicals encapsulated in FDA-approved nanocarriers have demonstrated the ability to modulate the tumor microenvironment. In this review, information about the mechanisms of promising plant bioactives against HCC is discussed and compared. Their benefits and risks as future nanotherapeutics are underscored. Nanocarriers that have been employed to encapsulate both pure bioactives and crude extracts for application in various HCC models are examined and compared. Finally, the current limitations in nanocarrier design, challenges related to the HCC microenvironment, and future opportunities are also discussed for the clinical translation of plant-based nanomedicines from bench to bedside.
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Affiliation(s)
- Aalok Basu
- Department of Pharmacy, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayutthaya Rd., Rajathevi, Bangkok 10400, Thailand
| | - Thanaphon Namporn
- Department of Pharmacy, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayutthaya Rd., Rajathevi, Bangkok 10400, Thailand
| | - Pakatip Ruenraroengsak
- Department of Pharmacy, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayutthaya Rd., Rajathevi, Bangkok 10400, Thailand
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Woradulayapinij W, Pothiluk A, Nualsanit T, Yimsoo T, Yingmema W, Rojanapanthu P, Hong Y, Baek SJ, Treesuppharat W. Acute oral toxicity of damnacanthal and its anticancer activity against colorectal tumorigenesis. Toxicol Rep 2022; 9:1968-1976. [PMID: 36518435 PMCID: PMC9742955 DOI: 10.1016/j.toxrep.2022.10.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 10/25/2022] [Accepted: 10/27/2022] [Indexed: 11/05/2022] Open
Abstract
Damnacanthal is an anthraquinone, extracted, and purified from the root of Morinda citrifolia in Thailand. This study aimed to measure acute oral toxicity and to investigate the anticancer activity of damnacanthal in colorectal tumorigenesis. We found that the growth of human colorectal cancer cells was inhibited by damnacanthal in a dose- and a time-dependent manner. The growth inhibitory effect of damnacanthal was better than that of 5-FU used as a positive control in colorectal cancer cells, along with the downregulation of cell cycle protein cyclin D1. Similarly, an oral treatment of damnacanthal effectively inhibited the growth of colorectal tumor xenografts in nude mice, which was approximately 2-3-fold higher as compared to 5-FU by tumor size as well as expression of bioluminescence. Furthermore, the study of acute oral toxicity in mice exhibited a relatively low toxicity of damnacanthal with a LD50 cut-off value of 2500 mg/kg according to OECD Guideline 423. These results reveal the potential therapeutic activity of a natural damnacanthal compound as an anti-colorectal cancer drug.
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Key Words
- 5-FU, 5-Fluorouracil
- ALT, Alanine aminotransferase
- AST, Aspartate aminotransferase
- Acute oral toxicity
- Anticancer activity
- BSA, Bovine serum albumin
- BUN, Blood urea nitrogen
- Colorectal tumorigenesis
- D20, Damnacanthal at 20 mg/kg
- D40, Damnacanthal at 40 mg/kg
- DMSO, Dimethyl sulfoxide
- DPBS, Dulbecco’s phosphate buffered saline
- Damnacanthal
- F20, 5-Fluorouracil at 20 mg/kg
- FBS, Fetal bovine serum
- FTIR, Fourier transform infrared spectroscopy
- IC50, Half-maximal inhibitory concentration
- LD50, Median lethal dose
- MS, Mass spectrometry
- MTT, 3-(4,5-Dimethythiazol-2-yl)− 2,5-diphenyltetrazolium bromide
- NC, Negative control
- NMR, Nuclear magnetic resonance spectroscopy
- PMSF, Phenylmethanesulfonyl fluoride
- TBST, Tris-buffered saline containing 0.05 % Tween 20
- TLC, Thin layer chromatography
- VLC, Vacuum liquid chromatographic method
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Affiliation(s)
- Warunya Woradulayapinij
- Thammasat University Research Unit in Mechanisms of Drug Action and Molecular Imaging, Drug Discovery and Development Center, Office of Advanced Science and Technology, Thammasat University, Pathum Thani 12120, Thailand
| | - Apipu Pothiluk
- Thammasat University Research Unit in Mechanisms of Drug Action and Molecular Imaging, Drug Discovery and Development Center, Office of Advanced Science and Technology, Thammasat University, Pathum Thani 12120, Thailand
| | - Thararat Nualsanit
- Chulabhorn International College of Medicine, Thammasat University, Pathum Thani 12120, Thailand
| | - Thunyatorn Yimsoo
- Laboratory Animal Center, Office of Advanced Science and Technology, Thammasat University, Pathum Thani 12120, Thailand
| | - Werayut Yingmema
- Laboratory Animal Center, Office of Advanced Science and Technology, Thammasat University, Pathum Thani 12120, Thailand
| | - Pleumchitt Rojanapanthu
- Drug Discovery and Development Center, Office of Advanced Science and Technology, Thammasat University, Pathum Thani 12120, Thailand
| | - Yukyung Hong
- Laboratory of Signal Transduction, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, South Korea
| | - Seung Joon Baek
- Laboratory of Signal Transduction, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, South Korea
| | - Worapapar Treesuppharat
- Thammasat University Research Unit in Mechanisms of Drug Action and Molecular Imaging, Drug Discovery and Development Center, Office of Advanced Science and Technology, Thammasat University, Pathum Thani 12120, Thailand
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Li R, Li H, Lan J, Yang D, Lin X, Xu H, Han B, Yang M, Su B, Liu F, Jiang W. Damnacanthal isolated from morinda species inhibited ovarian cancer cell proliferation and migration through activating autophagy. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 100:154084. [PMID: 35421676 DOI: 10.1016/j.phymed.2022.154084] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 02/28/2022] [Accepted: 03/26/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND Ovarian cancer is a very common gynecological malignant tumor. Natural products are important sources of chemotherapy drugs for ovarian cancer. Damnacanthal is an anthraquinone derivative with anti-cancer pharmacological properties. OBJECTIVE This study aimed to investigate the mechanisms underlying damnacanthal's effects against ovarian cancer. METHODS In vitro experiments, CCK8, colony formation and flow cytometry assays were used to evaluate the anti-ovarian cancer effect of damnacanthal on SKVO3 and A2780 cells. The wound healing tests and the transwell invasion assays were used to detect the migration and infiltration of ovarian cancer cells. Western Blot assays and immunofluorescence staining were used to measure autophagy levels. In vivo experiments, the anti-ovarian cancer effect of damnacanthal was further evaluated in a xenograft nude mouse model of SKVO3 cells. RESULTS Damnacanthal induced significant cell death and apoptosis, as well as significant inhibition in migration and invasion, in SKVO3 and A2780 cells, Furthermore, damnacanthal induced cell cycle arrest by increasing the protein levels of p27Kip1 and decreasing cyclin D1 levels. In addition, damnacanthal induced a significant accumulation of autophagosomes, accompanied with an increase in LC3II protein levels, and a decrease in p62 protein levels. 3-methyladenine, an autophagy formation inhibitor, significantly mitigated the damnacanthal-induced apoptosis and migration hindrance, as well as the decline in cell viability. Furthermore, the inactivation of ERK and its downstream effector mTOR signaling pathways, rather than Akt or P38 pathway, were involved in damnacanthal's activation in autophagy. In addition, TBHQ, an ERK activator, significantly inhibited damnacanthal-boosted LC3 II levels and autophagosome accumulation, and reversed damnacanthal-induced cell death, apoptosis, cell cycle arrest and migration hindrance. Finally, the anti-ovarian cancer effect of damnacanthal was confirmed in the orthotopic xenograft model of SKVO3 cells in nude mice, with tumor growth being significantly inhibited comparably to the efficacy of cisplatin. Damnacanthal was also synergistic with cisplatin and showed inhibition in cisplatin-resistant ovarian cancer cells. CONCLUSION Damnacanthal inhibited the growth of ovarian cancer via the ERK/mTOR/autophagy signaling cascade, indicating that it may be a potential anti-ovarian cancer drug candidate.
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Affiliation(s)
- Ruli Li
- Molecular Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, North Sichuan Medical College, Nanchong, Sichuan, 637000, China
| | - He Li
- Molecular Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Jie Lan
- Molecular Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Dongmei Yang
- Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, North Sichuan Medical College, Nanchong, Sichuan, 637000, China
| | - Xinjing Lin
- Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, North Sichuan Medical College, Nanchong, Sichuan, 637000, China
| | - Hongling Xu
- Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, North Sichuan Medical College, Nanchong, Sichuan, 637000, China
| | - Bin Han
- Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, North Sichuan Medical College, Nanchong, Sichuan, 637000, China
| | - Ming Yang
- Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, North Sichuan Medical College, Nanchong, Sichuan, 637000, China
| | - Bo Su
- Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, North Sichuan Medical College, Nanchong, Sichuan, 637000, China
| | - Fu Liu
- Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, North Sichuan Medical College, Nanchong, Sichuan, 637000, China
| | - Wei Jiang
- Molecular Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
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9
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OZKOK F, BOĞA M, TUNEG M, ENİSOĞLU ATALAY V, ONUL N, ASGAROVA K, TIĞLI R, ARSLAN S, AKAGÜNDÜZ D, CEBECİOĞLU R, ÇATAL T. Evaluation of Acetyl- and Butyrylcholinesterase Enzyme Inhibitory Activities and Cytotoxic Activities of Anthraquinone Derivatives. JOURNAL OF THE TURKISH CHEMICAL SOCIETY, SECTION A: CHEMISTRY 2022. [DOI: 10.18596/jotcsa.963290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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10
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Chanthira Kumar H, Lim XY, Mohkiar FH, Suhaimi SN, Mohammad Shafie N, Chin Tan TY. Efficacy and Safety of Morinda citrifolia L. (Noni) as a Potential Anticancer Agent. Integr Cancer Ther 2022; 21:15347354221132848. [PMID: 36448674 PMCID: PMC9716600 DOI: 10.1177/15347354221132848] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 08/25/2022] [Accepted: 09/28/2022] [Indexed: 12/03/2022] Open
Abstract
Cancer is a major cause of morbidity and mortality worldwide and therefore there has been interest in discovering the phytoconstituents of medicinal plants exhibiting anticancer activities. Morinda citrifolia L., commonly known as Noni, has shown anticancer properties in in vitro, in vivo, and in clinical studies. A systematic review was conducted to collate scientific evidence on the anticancer properties of M. citrifolia using pre-determined keywords on 5 electronic databases: MEDLINE, CENTRAL, LILACS, Web of Science, and EBSCOHost. A total of 51 clinical and preclinical studies comprising 41 efficacy and 10 safety studies were included in this review. Our findings showed that M. citrifolia demonstrated various anticancer properties in different cancer models, via multiple mechanisms including antitumor, antiproliferative, pro-apoptotic, antiangiogenesis, antimigratory, anti-inflammatory, and immunomodulatory activities. M. citrifolia is deemed to be a potentially valuable medicinal plant in the treatment of cancer through its many intrinsic pathways. More well-designed and reported preclinical efficacy and safety studies are needed to allow for better translation into future clinical studies which could further substantiate the role of M. citriflolia in cancer treatment.
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Affiliation(s)
- Hemahwathy Chanthira Kumar
- Herbal Medicine Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Shah Alam, Selangor, Malaysia
| | - Xin Yi Lim
- Herbal Medicine Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Shah Alam, Selangor, Malaysia
| | - Farah Huda Mohkiar
- Nutrition, Metabolic, and Cardiovascular Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Shah Alam, Selangor, Malaysia
| | - Shazlan Noor Suhaimi
- Herbal Medicine Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Shah Alam, Selangor, Malaysia
| | | | - Terence Yew Chin Tan
- Herbal Medicine Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Shah Alam, Selangor, Malaysia
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11
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Song YM, Lee HJ, Min SK, Park YH, Oh JK, Kim JY, Park JB. Effects of noni on cellular viability and osteogenic differentiation of gingiva-derived stem cells demonstrated by RNA sequencing and quantitative PCR. Exp Ther Med 2021; 23:32. [PMID: 34824640 PMCID: PMC8611496 DOI: 10.3892/etm.2021.10954] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 10/13/2021] [Indexed: 12/28/2022] Open
Abstract
Noni fruit (Morinda citrifolia) has been widely used in traditional medicine across tropical and subtropical regions, and is now being paid more attention in Western medicine. The present study aimed to investigate the effects of noni extract on the change in the cellular morphology, maintenance of cellular viability and enhancement of osteogenic differentiation of stem cells. Stem cells obtained from gingiva were cultured where noni extracts existed at concentrations ranging from 10-200 ng/ml. Evaluations of cell morphology and cellular viability were performed. Alkaline phosphatase activity assays were performed to assess the osteogenic differentiation. Alizarin Red S staining was performed to evaluate the calcium deposits in the culture, with the addition of noni extract. Global gene expression was analyzed via next-generation mRNA sequencing. Gene ontology and pathway analyses were performed to determine the associated mechanisms. Validation procedures were performed via quantitative (q)PCR analysis. The addition of noni at concentrations ranging from 10-200 ng/ml did not produce significant morphological changes. There were significantly higher values of cellular viability, with the highest value at 100 ng/ml compared with the control (P<0.05). Furthermore, significantly higher values of alkaline phosphatase activity was noted in the 10 and 100 ng/ml groups compared with the 0 ng/ml group on day 7 (P<0.05). Alizarin Red S staining revealed calcium deposits in each group. In addition, the highest value for Alizarin Red S staining was observed at 100 ng/ml compared with the unloaded control (P<0.05). qPCR analysis demonstrated that the mRNA expression levels of RUNX2, BSP, OCN and COL1A1 increased following treatment with noni. Taken together, the results of the present study suggest that noni extract has enhancing effects on gingiva-derived mesenchymal stem cells, by enhancing cellular viability and osteogenic differentiation.
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Affiliation(s)
- Young-Min Song
- Department of Periodontics, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Hyun-Jin Lee
- Department of Periodontics, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Sae-Kyung Min
- Department of Periodontics, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | | | - Jae-Kwen Oh
- Merden Dental Hospital, Bucheon-si, Gyeonggi 14544, Republic of Korea
| | - Ji-Youn Kim
- Division of Oral and Maxillofacial Surgery, Department of Dentistry, College of Medicine, St. Vincent's Hospital, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Jun-Beom Park
- Department of Periodontics, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
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12
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Development and Validation of an Analytical Method for Deacetylasperulosidic Acid, Asperulosidic Acid, Scopolin, Asperuloside and Scopoletin in Fermented Morinda citrifolia L. (Noni). SEPARATIONS 2021. [DOI: 10.3390/separations8060080] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Fermentation is a technology that enhances biologically active ingredients, improves the absorption rate and induces the generation of new functional ingredients by the catalytic action of enzyme systems possessed by microorganisms. In this study, changes in the content of five kinds of bioactive compounds (deacetylasperulosidic acid, asperulosidic acid, scopolin, asperuloside and scopoletin) of Morinda citrifolia L. were confirmed by fermentation, and a high-performance liquid chromatography-photodiode array (HPLC-PDA) analysis method for measuring analytes was developed and validated. HPLC method for the determination of five bioactive compounds in Morinda citrifolia L. extracts (MCE) was validated in terms of sensitivity, linearity, selectivity, limit of detection (LOD) and quantification (LOQ), precision and accuracy. The coefficient of determination of the calibration curve for bioactive compounds (1.56–100 μg/mL) showed linearity (R2 ≥ 0.9999). LOD and LOQ were in the range 0.04–0.97 and 0.13–2.95 μg/mL, respectively. The range of intra- and intraday accuracies values (recovery) were 97.5–121.9% and 98.8–118.1%, respectively, and precision value (RSDs) of the bioactive compounds were <4%. In addition, changes in the content of five bioactive compounds in MCE by fermentation were confirmed. These results indicate that the developed fermentation and analysis method could be applied in the development of potential functional food ingredients.
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Haque A, Brazeau D, Amin AR. Perspectives on natural compounds in chemoprevention and treatment of cancer: an update with new promising compounds. Eur J Cancer 2021; 149:165-183. [PMID: 33865202 PMCID: PMC8113151 DOI: 10.1016/j.ejca.2021.03.009] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/04/2021] [Accepted: 03/13/2021] [Indexed: 12/21/2022]
Abstract
Cancer is the second deadliest disease worldwide. Although recent advances applying precision treatments with targeted (molecular and immune) agents are promising, the histological and molecular heterogeneity of cancer cells and huge mutational burdens (intrinsic or acquired after therapy) leading to drug resistance and treatment failure are posing continuous challenges. These recent advances do not negate the need for alternative approaches such as chemoprevention, the pharmacological approach to reverse, suppress or prevent the initial phases of carcinogenesis or the progression of premalignant cells to invasive disease by using non-toxic agents. Although data are limited, the success of several clinical trials in preventing cancer in high-risk populations suggests that chemoprevention is a rational, appealing and viable strategy to prevent carcinogenesis. Particularly among higher-risk groups, the use of safe, non-toxic agents is the utmost consideration because these individuals have not yet developed invasive disease. Natural dietary compounds present in fruits, vegetables and spices are especially attractive for chemoprevention and treatment because of their easy availability, high margin of safety, relatively low cost and widespread human consumption. Hundreds of such compounds have been widely investigated for chemoprevention and treatment in the last few decades. Previously, we reviewed the most widely studied natural compounds and their molecular mechanisms, which were highly exploited by the cancer research community. In the time since our initial review, many promising new compounds have been identified. In this review, we critically review these promising new natural compounds, their molecular targets and mechanisms of anticancer activity that may create novel opportunities for further design and conduct of preclinical and clinical studies.
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Affiliation(s)
- Abedul Haque
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Daniel Brazeau
- Department of Pharmacy Practice, Administration and Research, School of Pharmacy, Marshall University, Huntington, WV, 25701, USA
| | - Arm R Amin
- Department of Pharmaceutical Sciences and Research, School of Pharmacy, Marshall University, Huntington, WV, 25701, USA.
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14
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Latifah SY, Gopalsamy B, Abdul Rahim R, Manaf Ali A, Haji Lajis N. Anticancer Potential of Damnacanthal and Nordamnacanthal from Morinda elliptica Roots on T-lymphoblastic Leukemia Cells. Molecules 2021; 26:molecules26061554. [PMID: 33808969 PMCID: PMC7998966 DOI: 10.3390/molecules26061554] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/01/2021] [Accepted: 02/02/2021] [Indexed: 12/24/2022] Open
Abstract
Background: This study reports on the cytotoxic properties of nordamnacanthal and damnacanthal, isolated from roots of Morinda elliptica on T-lymphoblastic leukaemia (CEM-SS) cell lines. Methods: MTT assay, DNA fragmentation, ELISA and cell cycle analysis were carried out. Results: Nordamnacanthal and damnacanthal at IC50 values of 1.7 μg/mL and10 μg/mL, respectively. At the molecular level, these compounds caused internucleosomal DNA cleavage producing multiple 180–200 bp fragments that are visible as a “ladder” on the agarose gel. This was due to the activation of the Mg2+/Ca2+-dependent endonuclease. The induction of apoptosis by nordamnacanthal was different from the one induced by damnacanthal, in a way that it occurs independently of ongoing transcription process. Nevertheless, in both cases, the process of dephosphorylation of protein phosphates 1 and 2A, the ongoing protein synthesis and the elevations of the cytosolic Ca2+ concentration were not needed for apoptosis to take place. Nordamnacanthal was found to have a cytotoxic effect by inducing apoptosis, while damnacanthal caused arrest at the G0/G1 phase of the cell cycle. Conclusion: Damnacanthal and nordamnacanthal have anticancer properties, and could act as potential treatment for T-lymphoblastic leukemia.
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Affiliation(s)
- Saiful Yazan Latifah
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400 UPM, Selangor, Malaysia;
- Correspondence: ; Tel.: +603-89472308
| | - Banulata Gopalsamy
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400 UPM, Selangor, Malaysia;
| | - Raha Abdul Rahim
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400 UPM, Selangor, Malaysia;
| | - Abdul Manaf Ali
- Faculty of Bioresources and Food Industry, Universiti Sultan Zainal Abidin (UniSZA), Kuala 20300, Terengganu, Malaysia;
| | - Nordin Haji Lajis
- Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400 UPM, Selangor, Malaysia;
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15
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Akhtar MS, Yang W, Kim SH, Lee YR. Organic‐Inorganic Dual Catalytic System for the Regioselective Construction of Diverse Quinone Derivatives
via
Benzannulation. ASIAN J ORG CHEM 2021. [DOI: 10.1002/ajoc.202000725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Muhammad Saeed Akhtar
- School of Chemical Engineering Yeungnam University Gyeongsan 38541 Republic of Korea
| | - Won‐Guen Yang
- Analysis Research Division, Daegu Center Korea Basic Science Institute Daegu 41566 Republic of Korea
| | - Sung Hong Kim
- Analysis Research Division, Daegu Center Korea Basic Science Institute Daegu 41566 Republic of Korea
| | - Yong Rok Lee
- School of Chemical Engineering Yeungnam University Gyeongsan 38541 Republic of Korea
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16
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Rey-Blanes C, Pérez-Portero Y, Morris-Quevedo HJ, Casas V, Abdala R, Quesada AR, Martínez-Poveda B, Medina MÁ. In vitro evaluation of the antitumoral and antiangiogenic effects of extracts from Spondias mombin L. leaves. Biomed Pharmacother 2020; 131:110716. [PMID: 32920516 DOI: 10.1016/j.biopha.2020.110716] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 08/24/2020] [Accepted: 08/30/2020] [Indexed: 01/05/2023] Open
Abstract
The traditional ethnobotanic and pharmacologic use of Spondias mombin L. samples includes a wide range of applications. In the present study, new antiangiogenic and antitumor effects of two types of extracts from Spondias mombin L. leaves have been demonstrated by using a number of in vitro assays in both endothelial and human cancer and non cancer cells.
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Affiliation(s)
- Cristina Rey-Blanes
- Universidad de Málaga, Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, E-29071, Málaga, Spain
| | - Yalina Pérez-Portero
- Facultad de Ciencias Naturales y Exactas, Departamento de Biología, Universidad de Oriente, Santiago de Cuba, Cuba
| | - Humberto J Morris-Quevedo
- Centro de Estudios de Biotecnología Industrial (CEBI), Universidad de Oriente, Santiago de Cuba, Cuba
| | - Virginia Casas
- Universidad de Málaga, Andalucía Tech, Departamento de Ecología y Geología, Facultad de Ciencias, E-29071, Málaga, Spain
| | - Roberto Abdala
- Universidad de Málaga, Andalucía Tech, Departamento de Ecología y Geología, Facultad de Ciencias, E-29071, Málaga, Spain; IBYDA (Institute of Blue Biotechnology and Development), Málaga, Spain
| | - Ana R Quesada
- Universidad de Málaga, Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, E-29071, Málaga, Spain; IBIMA (Biomedical Research Institute of Málaga), E-29071, Málaga, Spain; CIBER de Enfermedades Raras (CIBERER), E-29071, Málaga, Spain
| | - Beatriz Martínez-Poveda
- Universidad de Málaga, Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, E-29071, Málaga, Spain; IBIMA (Biomedical Research Institute of Málaga), E-29071, Málaga, Spain; CIBER de Enfermedades Vasculares (CIBERCV), Madrid, Spain
| | - Miguel Ángel Medina
- Universidad de Málaga, Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, E-29071, Málaga, Spain; IBIMA (Biomedical Research Institute of Málaga), E-29071, Málaga, Spain; CIBER de Enfermedades Raras (CIBERER), E-29071, Málaga, Spain.
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17
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Wen Y, Cai X, Chen S, Fu W, Chai D, Zhang H, Zhang Y. 7-Methoxy-1-Tetralone Induces Apoptosis, Suppresses Cell Proliferation and Migration in Hepatocellular Carcinoma via Regulating c-Met, p-AKT, NF-κB, MMP2, and MMP9 Expression. Front Oncol 2020; 10:58. [PMID: 32117722 PMCID: PMC7020565 DOI: 10.3389/fonc.2020.00058] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Accepted: 01/13/2020] [Indexed: 12/25/2022] Open
Abstract
This study aimed to determine the anti-proliferative and anti-migratory effects of 7-methoxy-1-tetralone (MT) in hepatocellular carcinoma (HCC) cells. MTT assay assessed HCC cell viability; cell apoptosis of HCC cells was determined by flow cytometry; wound healing assay evaluated HCC cell migratory ability; protein expression levels were assessed using western blot assay; the in vivo antitumor effects of MT were tested in BALB/c nude mice and the pathological changes within the tumor tissues were evaluated by immunohistochemistry. MT treatment significantly suppressed the cell proliferative and migratory potentials of HepG2 cells, and induced HepG2 cell apoptosis. The western blot assay showed that MT treatment caused a suppression on c-Met, phosphorylated AKT (p-AKT), NF-κB, matrix metallopeptidase 2 (MMP2)/MMP9 protein levels in HepG2 cells. Further in vivo animal studies deciphered that MT treatment suppressed tumor growth of HepG2 cells in the nude mice, but had no effect on the body weight and the organ index of liver and spleen. Further immunohistochemistry analysis of the dissected tumor tissues showed that MT treatment significantly suppressed the protein expression levels of NF-κB, MMP9, MMP2, and p-AKT. In summary, the present study demonstrated the anti-tumor effects of MT on the HCC, and MT suppressed HCC progression possibly via regulating proliferation- and migration-related mediators including c-Met, p-AKT, NF-κB, MMP2, and MMP9 in HepG2 cells.
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Affiliation(s)
- Ying Wen
- Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou, China
- Department of Cell Biology and Medical Genetics, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xiaoyan Cai
- Department of Cell Biology and Medical Genetics, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Shaolian Chen
- Department of Clinical Laboratory, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, China
| | - Wei Fu
- Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou, China
- Department of Cell Biology and Medical Genetics, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Dong Chai
- Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou, China
- Department of Cell Biology and Medical Genetics, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Huainian Zhang
- Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou, China
- Department of Cell Biology and Medical Genetics, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yongli Zhang
- Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou, China
- Department of Cell Biology and Medical Genetics, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
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18
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Shebl RI. Anti-cancer Potential of Captopril and Botulinum Toxin Type-A and Associated p53 Gene Apototic Stimulating Activity. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2019; 18:1967-1977. [PMID: 32184862 PMCID: PMC7059072 DOI: 10.22037/ijpr.2019.1100800] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Mutational inactivation of p53 is a key player in the development of human cancer. Thus, retrieving the tumor suppressor activity of p53 gene is considered a novel strategy in cancer therapy. Current study aimed to investigate the anti-cancer potentials of botulinum toxin type-A (BTX-A) and captopril as a trial to shed light on effective anti-cancer therapy with lower side effects. Cytotoxic effect of captopril and BTX-A was determined using MTT assay against colon (HCT116) and prostate cancer (DU145) cells compared to their effect on normal vero cells. Anti-proliferation assay and anti-metastatic effect were carried out using trypan blue exclusion method and wound scratch migration test, respectively. The ability of test drugs to induce apoptosis in cancer cells was examined using real time PCR. Recorded data revealed that captopril exhibited a statistically significant cytotoxicity (P < 0.05) to cancer cells (IC50 values of 1.5 and 1.2 mg/mL) with much lower toxicity to normal cells. At the same time, IC50 values post BTX-A treatment were 7.2 and 6.4 U/mL for HCT116 and DU145 cells, respectively without any toxicity to vero cells. Both drugs showed inhibitory potentials on cellular proliferation and the ability of cancer cells to migrate in scratched monolayers was obviously inhibited along with increasing their concentrations. P53 expression levels in captopril and BTX-A treated DU145 cells were elevated by 4 and 2.5 folds, respectively, while lower level of apoptosis induction in HCT116 cells was observed. Accordingly, BTX-A and captopril could present potential anti-cancer candidates through triggering cancer cells towards self-destruction.
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Affiliation(s)
- Rania Ibrahim Shebl
- Department of Microbiology and Immunology, Faculty of Pharmacy, Ahram Canadian University (ACU), Cairo, Egypt
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19
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Chaichanasak N, Rojanapanthu P, Yoon Y, Gritsanapan W, Chirachanchai S, Sathirakul K, Nualsanit T, Seong JK, Baek SJ. Chitosan-based nanoparticles with damnacanthal suppress CRM1 expression. Oncol Lett 2018; 16:7029-7034. [PMID: 30546436 PMCID: PMC6256335 DOI: 10.3892/ol.2018.9507] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 08/08/2018] [Indexed: 12/13/2022] Open
Abstract
Cancer is one of the leading causes of mortality worldwide. Phytochemicals may be promising anticancer agents given their various chemical structures and diverse biological activities. Damnacanthal (DAM) is a major bioactive component of Noni, which has been investigated previously as a cancer-preventive or chemotherapeutic agent. DAM has also been reported to exhibit anti-proliferative activity in several cancer types. In the present study, it was identified that DAM downregulates chromosome maintenance protein 1 (CRM1) expression in human cancer cells. The application of chitosan-based nanoparticles (NPs) with DAM also induced CRM1 downregulation, which suggests that chitosan-based NPs may be effective vehicles for delivery of phytochemicals such as DAM. It was also identified that DAM increased the levels of the tumor suppressor non-steroidal anti-inflammatory drugs-activated gene 1 in the nucleus, thereby leading to enhanced anticancer effects. The results of the present study indicate that DAM and its nanoformulation may be a candidate anticancer drug.
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Affiliation(s)
- Nadda Chaichanasak
- Department of Veterinary Medicine, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Republic of Korea.,Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand
| | - Pleumchitt Rojanapanthu
- Drug Discovery and Development Center, Thammasat University, Rangsit, Pathumthani 12121, Thailand
| | - Yongdae Yoon
- Department of Veterinary Medicine, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Republic of Korea
| | | | - Suwabun Chirachanchai
- The Petroleum and Petrochemical College, Chulalongkorn University, Bangkok 10330, Thailand
| | - Korbtham Sathirakul
- Drug Discovery and Development Center, Thammasat University, Rangsit, Pathumthani 12121, Thailand
| | - Thararat Nualsanit
- Chulabhorn International College of Medicine, Thammasat University, Rangsit, Pathumthani 12121, Thailand
| | - Je Kyung Seong
- Department of Veterinary Medicine, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Republic of Korea
| | - Seung Joon Baek
- Department of Veterinary Medicine, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Republic of Korea
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20
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García-Vilas JA, Medina MÁ. Updates on the hepatocyte growth factor/c-Met axis in hepatocellular carcinoma and its therapeutic implications. World J Gastroenterol 2018; 24:3695-3708. [PMID: 30197476 PMCID: PMC6127652 DOI: 10.3748/wjg.v24.i33.3695] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 06/28/2018] [Accepted: 07/16/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer and is the second leading cause of cancer death. Since the diagnosis of HCC is difficult, in many cases patients with HCC are diagnosed advanced stage of development. Hepatocyte growth factor (HGF)/c-mesenchymal-epithelial transition receptor (c-Met) axis is a key signaling pathway in HCC, either via canonical or non-canonical pathways. Available treatments against HCC based upon HGF/c-Met inhibition can increase patient lifespan, but do not reach the expected therapeutic benefits. In HCC, c-Met monomers can bind other receptor monomers, activating several noncanonical signaling pathways, leading to increased cell proliferation, invasion, motility, and drug resistance. All of these processes are enhanced by the tumor microenvironment, with stromal cells contributing to boost tumor progression through oxidative stress, angiogenesis, lymphangiogenesis, inflammation, and fibrosis. Novel treatments against HCC are being explored to modulate other targets such as microRNAs, methyltransferases, and acetyltransferases, which are all involved in the regulation of gene expression in cancer. This review compiles basic knowledge regarding signaling pathways in HCC, and compounds already used or showing potential to be used in clinical trials.
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Affiliation(s)
| | - Miguel Ángel Medina
- Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Andalucía Tech, Universidad de Málaga, Málaga 29071, Spain
- Unidad 741 de CIBER “de Enfermedades Raras” (CIBERER), Málaga 29071, Spain
- Institute of Biomedical Research in Málaga, Málaga 29071, Spain
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21
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Tan J, Li L, Shi W, Sun D, Xu C, Miao Y, Fan H, Liu J, Cheng H, Wu M, Shen W. Protective Effect of 2-Hydroxymethyl Anthraquinone from Hedyotis diffusa Willd in Lipopolysaccharide-Induced Acute Lung Injury Mediated by TLR4-NF-κB Pathway. Inflammation 2018; 41:2136-2148. [DOI: 10.1007/s10753-018-0857-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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22
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Manetti F. Recent advances in the rational design and development of LIM kinase inhibitors are not enough to enter clinical trials. Eur J Med Chem 2018; 155:445-458. [PMID: 29908439 DOI: 10.1016/j.ejmech.2018.06.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 06/05/2018] [Accepted: 06/06/2018] [Indexed: 12/19/2022]
Abstract
LIM kinases are involved in various pathophysiological processes that depend on actin organization. Alteration of microtubule dynamics by LIMK dysregulation is in fact related to tumor progression and metastasis, viral infection, and ocular diseases, such as glaucoma. As a consequence, many efforts have been done in recent years to rationally design small molecules able to inhibit LIMK activity selectively, without affecting other kinases. As a result, compounds optimized in terms of binding affinity and pharmacokinetic parameters have been discovered, that however failed to access clinical trials. In this review, a comprehensive survey of recent LIMK inhibitors is reported, together with SAR considerations and optimization processes.
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Affiliation(s)
- Fabrizio Manetti
- Dipartimento di Biotecnologie, Chimica e Farmacia (Dipartimento di Eccellenza 2018-2022), via A. Moro 2, I-53100 Siena, Italy.
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Sukamporn P, Baek SJ, Gritsanapan W, Chirachanchai S, Nualsanit T, Rojanapanthu P. Self-assembled nanomicelles of damnacanthal-loaded amphiphilic modified chitosan: Preparation, characterization and cytotoxicity study. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2017; 77:1068-1077. [DOI: 10.1016/j.msec.2017.03.263] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Revised: 03/23/2017] [Accepted: 03/26/2017] [Indexed: 01/22/2023]
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Mbaveng AT, Kuete V, Efferth T. Potential of Central, Eastern and Western Africa Medicinal Plants for Cancer Therapy: Spotlight on Resistant Cells and Molecular Targets. Front Pharmacol 2017; 8:343. [PMID: 28626426 PMCID: PMC5454075 DOI: 10.3389/fphar.2017.00343] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2017] [Accepted: 05/19/2017] [Indexed: 12/26/2022] Open
Abstract
Cancer remains a major health hurdle worldwide and has moved from the third leading cause of death in the year 1990 to second place after cardiovascular disease since 2013. Chemotherapy is one of the most widely used treatment modes; however, its efficiency is limited due to the resistance of cancer cells to cytotoxic agents. The present overview deals with the potential of the flora of Central, Eastern and Western African (CEWA) regions as resource for anticancer drug discovery. It also reviews the molecular targets of phytochemicals of these plants such as ABC transporters, namely P-glycoprotein (P-gp), multi drug-resistance-related proteins (MRPs), breast cancer resistance protein (BCRP, ABCG2) as well as the epidermal growth factor receptor (EGFR/ErbB-1/HER1), human tumor suppressor protein p53, caspases, mitochondria, angiogenesis, and components of MAP kinase signaling pathways. Plants with the ability to preferentially kills resistant cancer cells were also reported. Data compiled in the present document were retrieved from scientific websites such as PubMed, Scopus, Sciencedirect, Web-of-Science, and Scholar Google. In summary, plant extracts from CEWA and isolated compounds thereof exert cytotoxic effects by several modes of action including caspases activation, alteration of mitochondrial membrane potential (MMP), induction of reactive oxygen species (ROS) in cancer cells and inhibition of angiogenesis. Ten strongest cytotoxic plants from CEWA recorded following in vitro screening assays are: Beilschmiedia acuta Kosterm, Echinops giganteus var. lelyi (C. D. Adams) A. Rich., Erythrina sigmoidea Hua (Fabaceae), Imperata cylindrical Beauv. var. koenigii Durand et Schinz, Nauclea pobeguinii (Pobég. ex Pellegr.) Merr. ex E.M.A., Piper capense L.f., Polyscias fulva (Hiern) Harms., Uapaca togoensis Pax., Vepris soyauxii Engl. and Xylopia aethiopica (Dunal) A. Rich. Prominent antiproliferative compounds include: isoquinoline alkaloid isotetrandrine (51), two benzophenones: guttiferone E (26) and isoxanthochymol (30), the isoflavonoid 6α-hydroxyphaseollidin (9), the naphthyl butenone guieranone A (25), two naphthoquinones: 2-acetylfuro-1,4-naphthoquinone (4) and plumbagin (37) and xanthone V1 (46). However, only few research activities in the African continent focus on cytotoxic drug discovery from botanicals. The present review is expected to stimulate further scientific efforts to better valorize the African flora.
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Affiliation(s)
- Armelle T. Mbaveng
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of MainzMainz, Germany
- Department of Biochemistry, Faculty of Science, University of DschangDschang, Cameroon
| | - Victor Kuete
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of MainzMainz, Germany
- Department of Biochemistry, Faculty of Science, University of DschangDschang, Cameroon
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of MainzMainz, Germany
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25
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Cybulski M, Sidoryk K, Formela A, Michalak O, Rosa A, Mróz K, Maruszak W. A New Method for the Preparation of Intermediates for 2,6-Substituted Anthrapyridazones. J Heterocycl Chem 2017. [DOI: 10.1002/jhet.2738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Marcin Cybulski
- Pharmaceutical Research Institute; 8 Rydygiera Street 01-793 Warsaw Poland
| | - Katarzyna Sidoryk
- Pharmaceutical Research Institute; 8 Rydygiera Street 01-793 Warsaw Poland
| | - Adam Formela
- Pharmaceutical Research Institute; 8 Rydygiera Street 01-793 Warsaw Poland
| | - Olga Michalak
- Pharmaceutical Research Institute; 8 Rydygiera Street 01-793 Warsaw Poland
| | - Anna Rosa
- Pharmaceutical Research Institute; 8 Rydygiera Street 01-793 Warsaw Poland
| | - Katarzyna Mróz
- Pharmaceutical Research Institute; 8 Rydygiera Street 01-793 Warsaw Poland
| | - Wioleta Maruszak
- Pharmaceutical Research Institute; 8 Rydygiera Street 01-793 Warsaw Poland
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García-Vilas JA, Pino-Ángeles A, Martínez-Poveda B, Quesada AR, Medina MÁ. The noni anthraquinone damnacanthal is a multi-kinase inhibitor with potent anti-angiogenic effects. Cancer Lett 2016; 385:1-11. [PMID: 27816491 DOI: 10.1016/j.canlet.2016.10.037] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 10/22/2016] [Accepted: 10/25/2016] [Indexed: 12/29/2022]
Abstract
The natural bioactive compound damnacanthal inhibits several tyrosine kinases. Herein, we show that -in fact- damancanthal is a multi kinase inhibitor. A docking and molecular dynamics simulation approach allows getting further insight on the inhibitory effect of damnacanthal on three different kinases: vascular endothelial growth factor receptor-2, c-Met and focal adhesion kinase. Several of the kinases targeted and inhibited by damnacanthal are involved in angiogenesis. Ex vivo and in vivo experiments clearly demonstrate that, indeed, damnacanthal is a very potent inhibitor of angiogenesis. A number of in vitro assays contribute to determine the specific effects of damnacanthal on each of the steps of the angiogenic process, including inhibition of tubulogenesis, endothelial cell proliferation, survival, migration and production of extracellular matrix remodeling enzyme. Taken altogether, these results suggest that damancanthal could have potential interest for the treatment of cancer and other angiogenesis-dependent diseases.
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Affiliation(s)
- Javier A García-Vilas
- Universidad de Málaga, Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, E-29071 Málaga, Spain; IBIMA (Biomedical Research Institute of Málaga), E-29071 Málaga, Spain
| | | | - Beatriz Martínez-Poveda
- Universidad de Málaga, Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, E-29071 Málaga, Spain; IBIMA (Biomedical Research Institute of Málaga), E-29071 Málaga, Spain
| | - Ana R Quesada
- Universidad de Málaga, Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, E-29071 Málaga, Spain; IBIMA (Biomedical Research Institute of Málaga), E-29071 Málaga, Spain; CIBER de Enfermedades Raras (CIBERER), E-29071 Málaga, Spain
| | - Miguel Ángel Medina
- Universidad de Málaga, Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, E-29071 Málaga, Spain; IBIMA (Biomedical Research Institute of Málaga), E-29071 Málaga, Spain; CIBER de Enfermedades Raras (CIBERER), E-29071 Málaga, Spain.
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Damnacanthal and its nanoformulation exhibit anti-cancer activity via cyclin D1 down-regulation. Life Sci 2016; 152:60-6. [PMID: 27018445 DOI: 10.1016/j.lfs.2016.03.038] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 03/11/2016] [Accepted: 03/20/2016] [Indexed: 12/22/2022]
Abstract
AIMS Damnacanthal is an anthraquinone isolated from the root of Morinda citrifolia L. (noni), and it exhibits many pharmacological properties, including anti-cancer activity. Damnacanthal targets several signal transduction proteins related to cell growth inhibition or apoptosis. However, the molecular mechanisms by which damnacanthal affects cell cycle regulation have not been elucidated in detail. MAIN METHODS Cyclin D1 is an important regulatory protein in cell cycle progression and is overexpressed in many cancer cells. In this study, we investigated the molecular mechanism of damnacanthal on cyclin D1 expression. KEY FINDINGS We found that damnacanthal inhibited growth of several cancer cell lines (HCT-116, HT-29, MCF-7 and PC-3) in a dose- and time-dependent manner with a decrease in cyclin D1 protein expression. Damnacanthal did not change mRNA of cyclin D1; rather it suppressed cyclin D1 expression at the post-translational level. Subsequent experiments with several mutant cyclin D1 constructs suggest that the lysine sites of cyclin D1 play a pivotal role in damnacanthal-mediated cyclin D1 degradation. Furthermore, damnacanthal was encapsulated in self-assembled chitosan nanoparticles to improve both physicochemical and biological activities. SIGNIFICANCE Our results suggest that encapsulated damnacanthal exhibits better activity in cell growth inhibition, compared to non-encapsulated damnacanthal. Thus, damnacanthal has potential to be a candidate for the development of chemoprevention or therapeutic agents for cancers.
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Nerurkar PV, Hwang PW, Saksa E. Anti-Diabetic Potential of Noni: The Yin and the Yang. Molecules 2015; 20:17684-719. [PMID: 26404212 PMCID: PMC6331903 DOI: 10.3390/molecules201017684] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Revised: 09/03/2015] [Accepted: 09/16/2015] [Indexed: 12/26/2022] Open
Abstract
Escalating trends of chronic diseases such as type-2 diabetes (T2D) have sparked a renewed interest in complementary and alternative medicine, including herbal products. Morinda citrifolia (noni) has been used for centuries by Pacific Islanders to treat various ailments. Commercial noni fruit juice has been marketed as a dietary supplement since 1996. In 2003, the European Commission approved Tahitian noni juice as a novel food by the Health and Consumer Protection Directorate General. Among noni's several health benefits, others and we have demonstrated the anti-diabetic effects of fermented noni fruit juice in animal models. Unfortunately, noni's exciting journey from Polynesian medicine to the research bench does not reach its final destination of successful clinical outcomes when translated into commercial products. Noni products are perceived to be safe due to their "natural" origin. However, inadequate evidence regarding bioactive compounds, molecular targets, mechanism of action, pharmacokinetics, long-term safety, effective dosages, and/or unanticipated side effects are major roadblocks to successful translation "from bench side to bedside". In this review we summarize the anti-diabetic potential of noni, differences between traditional and modern use of noni, along with beneficial clinical studies of noni products and challenges in clinical translation of noni's health benefits.
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Affiliation(s)
- Pratibha V Nerurkar
- Laboratory of Metabolic Disorders and Alternative Medicine, Department of Molecular Biosciences and Bioengineering, College of Tropical Agriculture and Human Resources, University of Hawaii at Manoa, Honolulu, HI 96822, USA.
| | - Phoebe W Hwang
- Laboratory of Metabolic Disorders and Alternative Medicine, Department of Molecular Biosciences and Bioengineering, College of Tropical Agriculture and Human Resources, University of Hawaii at Manoa, Honolulu, HI 96822, USA.
| | - Erik Saksa
- Laboratory of Metabolic Disorders and Alternative Medicine, Department of Molecular Biosciences and Bioengineering, College of Tropical Agriculture and Human Resources, University of Hawaii at Manoa, Honolulu, HI 96822, USA.
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