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Zhao C, Wang J, Guo J, Gao W, Li B, Shang X, Zheng L, Wu B, Fu Y. Dried Apricot Polyphenols Suppress the Growth of A549 Human Lung Adenocarcinoma Cells by Inducing Apoptosis via a Mitochondrial-Dependent Pathway. Foods 2025; 14:108. [PMID: 39796398 PMCID: PMC11719503 DOI: 10.3390/foods14010108] [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: 11/23/2024] [Revised: 12/20/2024] [Accepted: 01/01/2025] [Indexed: 01/13/2025] Open
Abstract
Dried apricots are rich in a variety of polyphenols, which have anti-cancer activity. In this study, 949 phenolic substances were found by means of UPLC-MS/MS, mainly including 2',7-dihydroxy-3',4'-dimethoxyisoflavan, scopoletin, rutin, quercetin-3-O-robinobioside, and elaidolinolenic acid. The results indicated that dried apricot polyphenols (DAPs) could cause cell cycle arrest in the G0/G1 and G2/M phases by decreasing the cyclin D1, CDK4, cyclin B1, CDK1, and CDK6 levels in A549 human lung adenocarcinoma cells. Moreover, the ROS and Bax levels were increased, and the Bcl-2 and mitochondrial membrane potential were decreased in A549 cells treated with DAP, increasing caspase-9, caspase-3, and cleaved-PARP1 activities and leading to apoptosis of the A549 cells. Meanwhile, tumor growth was also inhibited by DAPs in an A549 tumor-bearing mouse model, Bax and caspase-3 were upregulated, and Bcl-2 was downregulated, inducing apoptosis of lung cancer cells. In conclusion, DAPs could inhibit lung cancer cell growth by inducing apoptosis due to cell cycle arrest and mitochondria-dependent pathways.
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Affiliation(s)
- Caiyun Zhao
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China; (C.Z.); (J.W.); (J.G.); (W.G.); (B.L.); (X.S.); (L.Z.)
| | - Jingteng Wang
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China; (C.Z.); (J.W.); (J.G.); (W.G.); (B.L.); (X.S.); (L.Z.)
| | - Jintian Guo
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China; (C.Z.); (J.W.); (J.G.); (W.G.); (B.L.); (X.S.); (L.Z.)
| | - Wenjing Gao
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China; (C.Z.); (J.W.); (J.G.); (W.G.); (B.L.); (X.S.); (L.Z.)
| | - Bin Li
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China; (C.Z.); (J.W.); (J.G.); (W.G.); (B.L.); (X.S.); (L.Z.)
| | - Xin Shang
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China; (C.Z.); (J.W.); (J.G.); (W.G.); (B.L.); (X.S.); (L.Z.)
| | - Li Zheng
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China; (C.Z.); (J.W.); (J.G.); (W.G.); (B.L.); (X.S.); (L.Z.)
| | - Bin Wu
- Institute of Agro-Products Storage and Processing, Xinjiang Academy of Agricultural Sciences, Urumqi 830091, China
| | - Yinghua Fu
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China; (C.Z.); (J.W.); (J.G.); (W.G.); (B.L.); (X.S.); (L.Z.)
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Rehman NU, Rafiq K, Avula SK, Gibbons S, Csuk R, Al-Harrasi A. Triterpenoids from Frankincense and Boswellia: A focus on their pharmacology and 13C-NMR assignments. PHYTOCHEMISTRY 2025; 229:114297. [PMID: 39401649 DOI: 10.1016/j.phytochem.2024.114297] [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: 02/18/2024] [Revised: 08/04/2024] [Accepted: 10/06/2024] [Indexed: 10/18/2024]
Abstract
Here we report for the first time the entire 13C-NMR spectral assignments of 119 (out of 127) triterpenoids from the oleo-gum resins of the medicinally important genus Boswellia, which includes the culturally highly valuable Frankincense species. The complete 13C-NMR resonances of these triterpenoids isolated between 1998 and 2024 and their biological activities are presented. 13C-NMR spectroscopy is a highly powerful tool for the characterization of these bioactive natural products. The compounds are arranged according to their skeletons, i.e., ursane, oleanane, lupane, dammarane, and tirucallane triterpenes. This review will be a future reference for the identification of these compounds, which have key medicinal properties in the areas of cytotoxicity and inflammation.
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Affiliation(s)
- Najeeb Ur Rehman
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, 616, Oman
| | - Kashif Rafiq
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, 616, Oman
| | - Satya K Avula
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, 616, Oman
| | - Simon Gibbons
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, 616, Oman
| | - René Csuk
- Organic Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany
| | - Ahmed Al-Harrasi
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, 616, Oman.
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Keleştemur Ü, Balcioğlu S, Ateş B. Cytotoxic and apoptotic potentials of four native apricot varieties from Malatya, Turkey: A comprehensive evaluation. J Food Sci 2025; 90:e17595. [PMID: 39673362 DOI: 10.1111/1750-3841.17595] [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: 10/07/2024] [Revised: 11/16/2024] [Accepted: 11/20/2024] [Indexed: 12/16/2024]
Abstract
In recent years, the role of functional foods in addressing various health issues, including cancer, has gained significant attention. Among these, the cytotoxic and apoptotic properties of Malatya apricots hold particular interest for their potential therapeutic benefits. This study focused on exploring the effects of methanol and acetone extracts from four popular Malatya apricot varieties-Hacıhaliloğlu, Hasanbey, Kabaaşı, and Soğancı-on cancer cell lines. The extracts were derived from apricots in their raw, ripe, and dried form, which can be consumed in three ways, and were tested for their cytotoxic and apoptotic activities against MCF-7 and Caco-2 cell lines using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide, wound scratch, and acridine orange/ethidium bromide (AO/EB) staining tests. Additionally, we assessed the total phenolic and flavonoid contents of the extracts. Our findings revealed that the acetone extracts of dried and raw Kabaaşı apricots exhibited the lowest IC50 values against the MCF-7 cell line over 24 and 48 h, with values of 3.9 and 0.5 mg/mL, respectively. Similarly, in the Caco-2 cell line, the dried Kabaaşı apricot extracts showed the lowest IC50values of 3.59 and 1.95 mg/mL for the same time frames. In the wound scratch assay, utilizing apricot extracts at their lowest IC50 values revealed significant differences in cell migration inhibition between treated and control groups. For Caco-2 cells, the control group's wound closure was around 70%, whereas apricot extract treatment resulted in 10%-30% opening after 24 h, indicating a strong antiproliferative effect. Similarly, in MCF-7 cells, the control group showed approximately 80% wound closure, in contrast to the 0%-12% opening observed in cells treated with apricot extract, further emphasizing the extracts' potent inhibitory impact on cell proliferation. Additionally, morphological evidence of cell death and apoptosis was observed in the images obtained through the AO/EB staining method, conducted to showcase the cytotoxic and apoptotic effects of the apricot extract. Apricot extracts consistently demonstrated strong cytotoxic and apoptotic effects on both Caco-2 and MCF-7 cell lines, underscoring Malatya apricots' potential as a functional food component with promising therapeutic properties against cancer.
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Affiliation(s)
- Ünzile Keleştemur
- Faculty of Health Sciences, Department of Occupational Health and Safety, Muş Alparslan University, Muş, Turkey
| | - Sevgi Balcioğlu
- Department of Medicinal Laboratory, Sakarya University of Applied Sciences, Sakarya, Turkey
| | - Burhan Ateş
- Faculty of Arts and Sciences, Department of Chemistry, İnönü University, Malatya, Turkey
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Zhang M, Wei X, Bai L, Liu H. Preparation of a novel MOF-POPM and its application in online purification and enrichment of oleanolic acid in medicinal plants. ANAL SCI 2024; 40:319-333. [PMID: 38085445 DOI: 10.1007/s44211-023-00465-8] [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: 06/20/2023] [Accepted: 10/30/2023] [Indexed: 02/06/2024]
Abstract
In present work, a method for enrichment, purification, and content determination of oleanolic acid (OA) in medicinal plants was established based on on-line solid phase extraction (SPE). A metal organic frameworks-porous organic polymer monolith (MOF-POPM) was prepared with functionalized UiO-66-(OH)2 as monomer and was used as SPE column for online enrichment and purification of OA. The ratio of adsorbent, enriching and eluting solvent, mobile phase pH, and flow rate had been systematically investigated. Under the optimum conditions, the linear range of OA was 0.59-2500 μg/mL with r = 0.9996. The limit of detection (LOD) was 0.18 μg/mL and the limit of quantification (LOQ) was 0.59 μg/mL. The intra-day relative standard deviations (RSDs) and inter-day RSDs of retention time and peak area were less than 0.3% and 1.3%, respectively. The average recoveries of OA in medicinal plants samples ranged from 87.7 to 104.6%. The results demonstrated that the online system was reliable and accurate for enrichment, purification, and content determination of OA in medicinal plants.
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Affiliation(s)
- Miaomiao Zhang
- College of Pharmaceutical Sciences, Key Laboratory of Public Health Safety of Hebei Province; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, State Key Laboratory of New Pharmaceutical Preparations and Excipients, Hebei University, Baoding, 071002, China
| | - Xuanwen Wei
- College of Pharmaceutical Sciences, Key Laboratory of Public Health Safety of Hebei Province; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, State Key Laboratory of New Pharmaceutical Preparations and Excipients, Hebei University, Baoding, 071002, China
| | - Ligai Bai
- College of Pharmaceutical Sciences, Key Laboratory of Public Health Safety of Hebei Province; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, State Key Laboratory of New Pharmaceutical Preparations and Excipients, Hebei University, Baoding, 071002, China
| | - Haiyan Liu
- College of Pharmaceutical Sciences, Key Laboratory of Public Health Safety of Hebei Province; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, State Key Laboratory of New Pharmaceutical Preparations and Excipients, Hebei University, Baoding, 071002, China.
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Madej M, Gola J, Chrobak E. Synthesis, Pharmacological Properties, and Potential Molecular Mechanisms of Antitumor Activity of Betulin and Its Derivatives in Gastrointestinal Cancers. Pharmaceutics 2023; 15:2768. [PMID: 38140110 PMCID: PMC10748330 DOI: 10.3390/pharmaceutics15122768] [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: 11/08/2023] [Revised: 12/04/2023] [Accepted: 12/08/2023] [Indexed: 12/24/2023] Open
Abstract
Gastrointestinal (GI) cancers are an increasingly common type of malignancy, caused by the unhealthy lifestyles of people worldwide. Limited methods of treatment have prompted the search for new compounds with antitumor activity, in which betulin (BE) is leading the way. BE as a compound is classified as a pentacyclic triterpene of the lupane type, having three highly reactive moieties in its structure. Its mechanism of action is based on the inhibition of key components of signaling pathways associated with proliferation, migration, interleukins, and others. BE also has a number of biological properties, i.e., anti-inflammatory, hepatoprotective, neuroprotective, as well as antitumor. Due to its poor bioavailability, betulin is subjected to chemical modifications, obtaining derivatives with proven enhanced pharmacological and pharmacokinetic properties as a result. The method of synthesis and substituents significantly influence the effect on cells and GI cancers. Moreover, the cytotoxic effect is highly dependent on the derivative as well as the individual cell line. The aim of this study is to review the methods of synthesis of BE and its derivatives, as well as its pharmacological properties and molecular mechanisms of action in colorectal cancer, hepatocellular carcinoma, gastric cancer, and esophageal cancer neoplasms.
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Affiliation(s)
- Marcel Madej
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland;
- Silesia LabMed, Centre for Research and Implementation, Medical University of Silesia, 40-752 Katowice, Poland
| | - Joanna Gola
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland;
| | - Elwira Chrobak
- Department of Organic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland;
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Zhang H, Zhou L, Wang H, Gu W, Li Z, Sun J, Wei X, Zheng Y. Tenascin-C-EGFR activation induces functional human satellite cell proliferation and promotes wound-healing of skeletal muscles via oleanic acid. Dev Biol 2023; 504:86-97. [PMID: 37758009 DOI: 10.1016/j.ydbio.2023.09.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 08/26/2023] [Accepted: 09/24/2023] [Indexed: 09/29/2023]
Abstract
Human satellite cells (HuSCs) have been deemed to be the potential cure to treat muscular atrophy diseases such as Duchenne muscular dystrophy. However, the clinical trials of HuSCs were restricted to the inadequacy of donors because of that freshly isolated HuSCs quickly lost the Pax7 expression and myogenesis capacity in vivo after a few days of culture. Here we found that oleanic acid, a kind of triterpenoid endowed with diverse biological functions with treatment potential, could efficiently promote HuSCs proliferation. The HuSCs cultured in the medium supplement with oleanic acid could maintain a high expression level of Pax7 and retain the ability to differentiate into myotubes as well as facilitate muscle regeneration in injured muscles of recipient mice. We further revealed that Tenascin-C acts as the core mechanism to activate the EGFR signaling pathway followed by HuSCs proliferation. Taken together, our data provide an efficient method to expand functional HuSCs and a novel mechanism that controls HuSCs proliferation, which sheds light on the HuSCs-based therapy to treat muscle diseases.
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Affiliation(s)
- Hao Zhang
- Department of Orthopedics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shi's Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Institute of Traumatology and Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 200025, China
| | - Lin Zhou
- Department of Orthopedics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shi's Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Institute of Traumatology and Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 200025, China
| | - Huihao Wang
- Shi's Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Institute of Traumatology and Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 200025, China
| | - Wei Gu
- Department of Orthopedics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shi's Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Institute of Traumatology and Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 200025, China
| | - Zhiqiang Li
- Department of Orthopedics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shi's Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Institute of Traumatology and Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 200025, China
| | - Jun Sun
- Department of Orthopedics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shi's Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Institute of Traumatology and Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 200025, China
| | - Xiaoen Wei
- Department of Orthopedics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shi's Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Institute of Traumatology and Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 200025, China.
| | - Yuxin Zheng
- Department of Orthopedics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shi's Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Institute of Traumatology and Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 200025, China.
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Lahmadi G, Horchani M, Dbeibia A, Mahdhi A, Romdhane A, Lawson AM, Daïch A, Harrath AH, Ben Jannet H, Othman M. Novel Oleanolic Acid-Phtalimidines Tethered 1,2,3 Triazole Hybrids as Promising Antibacterial Agents: Design, Synthesis, In Vitro Experiments and In Silico Docking Studies. Molecules 2023; 28:4655. [PMID: 37375209 DOI: 10.3390/molecules28124655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 06/04/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
As part of the valorization of agricultural waste into bioactive compounds, a series of structurally novel oleanolic acid ((3β-hydroxyolean-12-en-28-oic acid, OA-1)-phtalimidines (isoindolinones) conjugates 18a-u bearing 1,2,3-triazole moieties were designed and synthesized by treating an azide 4 previously prepared from OA-1 isolated from olive pomace (Olea europaea L.) with a wide range of propargylated phtalimidines using the Cu(I)-catalyzed click chemistry approach. OA-1 and its newly prepared analogues, 18a-u, were screened in vitro for their antibacterial activity against two Gram-positive bacteria, Staphylococcus aureus and Listeria monocytogenes, and two Gram-negative bacteria, Salmonella thyphimurium and Pseudomonas aeruginosa. Attractive results were obtained, notably against L. monocytogenes. Compounds 18d, 18g, and 18h exhibited the highest antibacterial activity when compared with OA-1 and other compounds in the series against tested pathogenic bacterial strains. A molecular docking study was performed to explore the binding mode of the most active derivatives into the active site of the ABC substrate-binding protein Lmo0181 from L. monocytogenes. Results showed the importance of both hydrogen bonding and hydrophobic interactions with the target protein and are in favor of the experimental data.
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Affiliation(s)
- Ghofrane Lahmadi
- Normandie University, URCOM, UNILEHAVRE, FR3021, UR 3221, 25 Rue Philippe Lebon, BP 540, F-76058 Le Havre, France
- Laboratory of Heterocyclic Chemistry, LR11ES39, Faculty of Science of Monastir, University of Monastir, Avenue of Environment, Monastir 5019, Tunisia
| | - Mabrouk Horchani
- Laboratory of Heterocyclic Chemistry, LR11ES39, Faculty of Science of Monastir, University of Monastir, Avenue of Environment, Monastir 5019, Tunisia
| | - Amal Dbeibia
- Laboratory of Analysis, Treatment and Valorization of Pollutants of the Environment and Products, Faculty of Pharmacy, University of Monastir, Monastir 5000, Tunisia
| | - Abdelkarim Mahdhi
- Laboratory of Analysis, Treatment and Valorization of Pollutants of the Environment and Products, Faculty of Pharmacy, University of Monastir, Monastir 5000, Tunisia
| | - Anis Romdhane
- Laboratory of Heterocyclic Chemistry, LR11ES39, Faculty of Science of Monastir, University of Monastir, Avenue of Environment, Monastir 5019, Tunisia
| | - Ata Martin Lawson
- Normandie University, URCOM, UNILEHAVRE, FR3021, UR 3221, 25 Rue Philippe Lebon, BP 540, F-76058 Le Havre, France
| | - Adam Daïch
- Normandie University, URCOM, UNILEHAVRE, FR3021, UR 3221, 25 Rue Philippe Lebon, BP 540, F-76058 Le Havre, France
| | - Abdel Halim Harrath
- Department of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Hichem Ben Jannet
- Laboratory of Heterocyclic Chemistry, LR11ES39, Faculty of Science of Monastir, University of Monastir, Avenue of Environment, Monastir 5019, Tunisia
| | - Mohamed Othman
- Normandie University, URCOM, UNILEHAVRE, FR3021, UR 3221, 25 Rue Philippe Lebon, BP 540, F-76058 Le Havre, France
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Piet M, Paduch R. Ursolic and oleanolic acids in combination therapy inhibit migration of colon cancer cells through down-regulation of the uPA/uPAR-dependent MMPs pathway. Chem Biol Interact 2022; 368:110202. [PMID: 36191607 DOI: 10.1016/j.cbi.2022.110202] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 09/12/2022] [Accepted: 09/21/2022] [Indexed: 11/15/2022]
Abstract
BACKGROUND Colorectal cancer is one the most lethal cancers worldwide. Since chemotherapy is burdened with harmful effects, agents capable of enhancing the chemotherapeutic effect are being sought. Ursolic acid (UA) and oleanolic acid (OA) were analyzed for such properties. The aim of the study was to evaluate the ability of UA and OA administered individually and in combination with each other and/or a cytostatic drug camptothecin-11 (CPT-11) to limit the viability and migration of colorectal cancer cells. MATERIALS AND METHODS The cytotoxic effect of UA, OA and CPT-11 and impact on normal and cancer cell migration rate were assessed. Furthermore, the effect on factors crucial in cancer metastasis: MMP-2 and -9, uPA/uPAR, and E-cadherin were assessed with ELISA, Western Blotting and immunofluorescence assays. Statistical analysis was performed with One-Way Anova with Dunnett's test. RESULTS The studied compounds exhibited the most favorable properties, i.e. they reduced the viability and migration of cancer cells. Furthermore, the secretion, activity, and cellular level of cancer MMP-2 and -9 were decreased, as a result of uPA/uPAR down-regulation. The agents also increased the level of cellular E-cadherin. The effect of the studied agents on normal cells was milder. CONCLUSIONS The compounds exhibited stronger activity when administered in combination and, combined with CPT-11, enhanced anti-tumorigenic activity of the drug. The migration-limiting activity was based on down-regulation of the uPA/uPAR-dependent MMP pathway. Moreover, UA and OA exhibited a protective effect towards normal cells.
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Affiliation(s)
- Mateusz Piet
- Department of Virology and Immunology, Institute of Biological Sciences, Faculty of Biology and Biotechnology, Maria Curie-Sklodowska University, Akademicka 19, 20-033, Lublin, Poland.
| | - Roman Paduch
- Department of Virology and Immunology, Institute of Biological Sciences, Faculty of Biology and Biotechnology, Maria Curie-Sklodowska University, Akademicka 19, 20-033, Lublin, Poland; Department of General Ophthalmology, Faculty of Medicine, Medical University of Lublin, ul Chmielna 1, 20-079, Lublin, Poland.
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de Sousa BCM, de Castro SP, Lourido KA, Kasper AAM, Paulino GDS, Delarmelina C, Duarte MCT, Sartoratto A, Vieira TA, Lustosa DC, Barata LES. Identification of Coumarins and Antimicrobial Potential of Ethanolic Extracts of Dipteryx odorata and Dipteryx punctata. Molecules 2022; 27:5837. [PMID: 36144574 PMCID: PMC9505109 DOI: 10.3390/molecules27185837] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 09/02/2022] [Accepted: 09/04/2022] [Indexed: 11/25/2022] Open
Abstract
Dipteryx odorata and Dipteryx punctata are species native to the Amazonian, traded by extractivists to obtain coumarin. We aimed to analyze the presence of coumarin in the ethanolic extracts of leaves, branches and fruits of D. odorata and D. punctata and to evaluate the antimicrobial activity of these extracts against phytopathogenic fungi and bacteria of clinical interest. Chemical analyses were performed by thin layer chromatography (TLC) and by gas chromatography coupled to mass spectrometry (GC-MS). For the antifungal assays, the fungi used were Cercospora longissima, Colletotrichum gloeosporioides, two isolates of Fusarium spp. and Sclerotium rolfsii, and the antibacterial assay was performed using the minimum inhibitory concentration (MIC) test with Burkholderia cepacia, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus bacteria. In D. odorata seed extracts and in D. punctata husks, endocarps, and seeds, we identified 1,2-benzopyrone. D. odorata endocarp extracts and D. punctata seeds provided the greatest decrease in mycelial growth of the evaluated phytopathogens, showing promise as an alternative control. The husk and endocarp extracts of both species had a weak effect on E. coli. This research is the first to compare the different parts of species of the genus Dipteryx and to evaluate the use of husks and endocarps of D. punctata fruits to obtain coumarin. Chemical analyses used to quantify the compounds existing in the extracts, and tests with phytopathogens in vitro and in vivo are currently being carried out.
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Affiliation(s)
- Bruna Cristine Martins de Sousa
- Instituto de Biodiversidade e Florestas (IBEF), Universidade Federal do Oeste do Pará (UFOPA), Santarem 68040-255, Brazil
- Programa de Pós-Graduação em Sociedade, Natureza e Desenvolvimento (PPGSND), Universidade Federal do Oeste do Pará (UFOPA), Santarem 68040-255, Brazil
| | - Santana Pinto de Castro
- Rede Integrada de Desenvolvimento Humano (RIDH), Universidade Federal do Oeste do Pará (UFOPA), Santarem 68040-255, Brazil
| | - Katiane Araújo Lourido
- Instituto de Biodiversidade e Florestas (IBEF), Universidade Federal do Oeste do Pará (UFOPA), Santarem 68040-255, Brazil
| | - Aline Aparecida München Kasper
- Programa de Pós-Graduação em Sociedade, Natureza e Desenvolvimento (PPGSND), Universidade Federal do Oeste do Pará (UFOPA), Santarem 68040-255, Brazil
| | - Geomarcos da Silva Paulino
- Programa de Pós-Graduação em Sociedade, Natureza e Desenvolvimento (PPGSND), Universidade Federal do Oeste do Pará (UFOPA), Santarem 68040-255, Brazil
| | - Camila Delarmelina
- Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas, Universidade Estadual de Campinas, Campinas 13148-218, Brazil
| | - Marta Cristina Teixeira Duarte
- Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas, Universidade Estadual de Campinas, Campinas 13148-218, Brazil
| | - Adilson Sartoratto
- Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas, Universidade Estadual de Campinas, Campinas 13148-218, Brazil
| | - Thiago Almeida Vieira
- Instituto de Biodiversidade e Florestas (IBEF), Universidade Federal do Oeste do Pará (UFOPA), Santarem 68040-255, Brazil
- Programa de Pós-Graduação em Sociedade, Natureza e Desenvolvimento (PPGSND), Universidade Federal do Oeste do Pará (UFOPA), Santarem 68040-255, Brazil
| | - Denise Castro Lustosa
- Instituto de Biodiversidade e Florestas (IBEF), Universidade Federal do Oeste do Pará (UFOPA), Santarem 68040-255, Brazil
| | - Lauro Euclides Soares Barata
- Programa de Pós-Graduação em Sociedade, Natureza e Desenvolvimento (PPGSND), Universidade Federal do Oeste do Pará (UFOPA), Santarem 68040-255, Brazil
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10
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Móricz ÁM, Ott PG. Separation and detection of apricot leaf triterpenes by high-performance thin-layer chromatography combined with direct bioautography and mass spectrometry. J Chromatogr A 2022; 1675:463167. [DOI: 10.1016/j.chroma.2022.463167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/19/2022] [Accepted: 05/19/2022] [Indexed: 10/18/2022]
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11
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Hiraishi K, Jimma F, Soma H, Kagawa T, Yamaoka I. Investigating a novel hepatoprotective substance from ume extract (heated Japanese apricot juice concentrate). Part 1: Finding an active substance using a liver injury rat model. NFS JOURNAL 2022. [DOI: 10.1016/j.nfs.2021.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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12
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Investigating a novel hepatoprotective substance from ume extract (heated Japanese apricot juice concentrate). Part 2: Elucidation of chemical structure. NFS JOURNAL 2022. [DOI: 10.1016/j.nfs.2021.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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13
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Oleanolic Acid: Extraction, Characterization and Biological Activity. Nutrients 2022; 14:nu14030623. [PMID: 35276982 PMCID: PMC8838233 DOI: 10.3390/nu14030623] [Citation(s) in RCA: 123] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/18/2022] [Accepted: 01/25/2022] [Indexed: 11/28/2022] Open
Abstract
Oleanolic acid, a pentacyclic triterpenoid ubiquitously present in the plant kingdom, is receiving outstanding attention from the scientific community due to its biological activity against multiple diseases. Oleanolic acid is endowed with a wide range of biological activities with therapeutic potential by means of complex and multifactorial mechanisms. There is evidence suggesting that oleanolic acid might be effective against dyslipidemia, diabetes and metabolic syndrome, through enhancing insulin response, preserving the functionality and survival of β-cells and protecting against diabetes complications. In addition, several other functions have been proposed, including antiviral, anti-HIV, antibacterial, antifungal, anticarcinogenic, anti-inflammatory, hepatoprotective, gastroprotective, hypolipidemic and anti-atherosclerotic activities, as well as interfering in several stages of the development of different types of cancer; however, due to its hydrophobic nature, oleanolic acid is almost insoluble in water, which has led to a number of approaches to enhance its biopharmaceutical properties. In this scenario, the present review aimed to summarize the current knowledge and the research progress made in the last years on the extraction and characterization of oleanolic acid and its biological activities and the underlying mechanisms of action.
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Tuli HS, Sak K, Gupta DS, Kaur G, Aggarwal D, Chaturvedi Parashar N, Choudhary R, Yerer MB, Kaur J, Kumar M, Garg VK, Sethi G. Anti-Inflammatory and Anticancer Properties of Birch Bark-Derived Betulin: Recent Developments. PLANTS (BASEL, SWITZERLAND) 2021; 10:2663. [PMID: 34961132 PMCID: PMC8705846 DOI: 10.3390/plants10122663] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 11/26/2021] [Accepted: 11/29/2021] [Indexed: 05/03/2023]
Abstract
Birch tree bark-derived betulin has attracted scientific interest already for several centuries, being one of the first natural products identified from plants. However, the cellular events regulated by betulin and precise molecular mechanisms under these processes have been begun to be understood only recently. Today, we know that betulin can exert important anticancer activities through modulation of diverse cellular pathways. In this review article, betulin-regulated molecular signaling is unraveled and presented with a special focus on its participation in anti-inflammatory processes, especially by modulating nuclear factor-κB (NF-κB), prostaglandin/COX, and nuclear factor erythroid2-related factor 2 (Nrf2)-mediated cascades. By regulating these diverse pathways, betulin can not only affect the development and progression of different cancers, but also enhance the antitumor action of traditional therapeutic modalities. It is expected that by overcoming the low bioavailability of betulin by encapsulating it into nanocarriers, this promising natural compound may provide novel possibilities for targeting inflammation-related cancers.
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Affiliation(s)
- Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala 133207, Haryana, India; (D.A.); (N.C.P.); (R.C.)
| | | | - Dhruv Sanjay Gupta
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM’s NMIMS, Mumbai 40056, Maharashtra, India; (D.S.G.); (G.K.)
| | - Ginpreet Kaur
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM’s NMIMS, Mumbai 40056, Maharashtra, India; (D.S.G.); (G.K.)
| | - Diwakar Aggarwal
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala 133207, Haryana, India; (D.A.); (N.C.P.); (R.C.)
| | - Nidarshana Chaturvedi Parashar
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala 133207, Haryana, India; (D.A.); (N.C.P.); (R.C.)
| | - Renuka Choudhary
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala 133207, Haryana, India; (D.A.); (N.C.P.); (R.C.)
| | - Mukerrem Betul Yerer
- Department of Pharmacology, Faculty of Pharmacy, Erciyes University, Kayseri 38039, Turkey;
| | - Jagjit Kaur
- ARC Centre of Excellence in Nanoscale Biophotonics (CNBP), Graduate School of Biomedical Engineering, Faculty of Engineering, The University of New South Wales, Sydney 2052, Australia;
| | - Manoj Kumar
- Department of Chemistry, Maharishi Markandeshwar University, Sadopur 134007, Haryana, India;
| | - Vivek Kumar Garg
- Department of Medical Laboratory Technology, University Institute of Applied Health Sciences, Chandigarh University, Gharuan, Mohali 140413, Punjab, India;
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
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Unravelling the bioprospects of mycoendophytes residing in Withania somnifera for productive pharmaceutical applications. BIOCATALYSIS AND AGRICULTURAL BIOTECHNOLOGY 2021. [DOI: 10.1016/j.bcab.2021.102172] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Gong XP, Tang Y, Song YY, Du G, Li J. Comprehensive Review of Phytochemical Constituents, Pharmacological Properties, and Clinical Applications of Prunus mume. Front Pharmacol 2021; 12:679378. [PMID: 34122104 PMCID: PMC8195681 DOI: 10.3389/fphar.2021.679378] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 05/04/2021] [Indexed: 12/18/2022] Open
Abstract
Prunus mume is one of the most ancient medicinal herbs and health foods commonly used in Asian countries. It is widely used as a constituent of many medicinal preparations and as a food ingredient for its beneficial health effects. In this review, we retrieved reports from PubMed, embase, Scopus, and SciFinder databases, to collect extensive scientific evidence on the phytochemical constituents, pharmacological properties, and clinical applications of Prunus mume. The literature review revealed that approximately 192 compounds have been isolated from different parts of the plant, and their molecular structures have been identified. The pharmacological properties of the plant, including anti-diabetic, liver-protective, antitumor, antimicrobial, antioxidant, and anti-inflammatory activities, as well as their underlying mechanisms, have been clarified by in vitro and in vivo studies. Clinical studies, although very limited, have been highlighted in this review to provide a reference for further exploration on therapeutic applications of the plant.
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Affiliation(s)
- Xue-Peng Gong
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ying Tang
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan-Yuan Song
- Department of Pharmacy, General Hospital of Central Theater Command, Wuhan, China
| | - Guang Du
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Juan Li
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Rajamani K, Thirugnanasambandan SS, Natesan C, Subramaniam S, Thangavel B, Aravindan N. Squalene deters drivers of RCC disease progression beyond VHL status. Cell Biol Toxicol 2020; 37:611-631. [PMID: 33219891 DOI: 10.1007/s10565-020-09566-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 10/26/2020] [Indexed: 12/12/2022]
Abstract
Identifying drug candidates to target cellular events/signaling that evades von Hippel-Lindau tumor suppressor (VHL) gene interaction is critical for the cure of renal cell carcinoma (RCC). Recently, we characterized a triterpene-squalene derived from marine brown alga. Herein, we investigated the potential of squalene in targeting HIF-signaling and other drivers of RCC progression. Squalene inhibited cell proliferation, induced cell dealth and reverted the cells' metastatic state (migration, clonal expansion) independent of their VHL status. Near-identical inhibition of HIF-1α and HIF-2α and the regulation of downstream targets in VHL wild type and mutant cell lines demonstrated squalene efficacy beyond VHL-HIF interaction. In a rat model of chemically induced RCC, squalene displayed chemopreventive capabilities by substantial reversal of lipid peroxidation, mitochondrial redox regulation, maintaining ∆ψm, inflammation [Akt, nuclear factor κB (NF-κB)], angiogenesis (VEGFα), metastasis [matrix metalloproteinase 2 (MMP-2)], and survival (Bax/Bcl2, cytochrome-c, Casp3). Squalene restored glutathione, glutathione reductase, glutathione-s-transferase, catalase, and superoxide dismutase and stabilized alkaline phosphatase, alkaline transaminase, and aspartate transaminase. The correlation of thiobarbituric acid reactive substance with VEGF/NF-κB and negative association of GSH with Casp3 show that squalene employs reduction in ROS regulation. Cytokinesis-block micronuclei (CBMN) assay in VHLwt/mut cells revealed both direct and bystander effects of squalene with increased micronucleus (MN) frequency. Clastogenicity analysis of rat bone marrow cells demonstrated an anti-clastogenic effect of squalene, with increased polychromatic erythrocytes (PCEs), decreased MNPCE,s and MN normochromatic erythrocytes. Squalene could effectively target HIF signaling that orchestrate RCC evolution. The efficacy of squalene is similar in VHLwt and VHLmut RCC cells, and hence, squalene could serve as a promising drug candidate for an RCC cure beyond VHL status and VHL-HIF interaction dependency. Summary: Squalene derived from marine brown algae displays strong anti-cancer (RCC) activity, functionally targeting HIF-signaling pathway, and affects various cellular process. The significance of squalene effect for RCC is highlighted by its efficiency beyond VHL status, designating itself a promising drug candidate. Graphical abstract.
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Affiliation(s)
- Karthikeyan Rajamani
- Centre of Advanced Study in Marine Biology, Annamalai University, Parangipettai, 608502, TN, India.
- Rajah Muthiah Medical College, Annamalai University, Annamalai Nagar, Chidambaram, 608002, TN, India.
- WHO Collaborating Center for Occupational and Environmental Health, ICMR Center for Air Quality, Climate and Health, Department of Environmental Health Engineering, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, TN, 600116, India.
| | | | - Chidambaram Natesan
- Rajah Muthiah Medical College, Annamalai University, Annamalai Nagar, Chidambaram, 608002, TN, India
| | - Sethupathy Subramaniam
- Rajah Muthiah Medical College, Annamalai University, Annamalai Nagar, Chidambaram, 608002, TN, India
| | | | - Natarajan Aravindan
- Department of Radiation Oncology, University of Oklahoma Health Sciences Center, BMSB 737, 947 Stanton L. Young Boulevard, Oklahoma City, OK, 73104, USA.
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Castellano JM, Espinosa JM, Perona JS. Modulation of Lipid Transport and Adipose Tissue Deposition by Small Lipophilic Compounds. Front Cell Dev Biol 2020; 8:555359. [PMID: 33163484 PMCID: PMC7591460 DOI: 10.3389/fcell.2020.555359] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 09/01/2020] [Indexed: 12/14/2022] Open
Abstract
Small lipophilic molecules present in foods of plant origin have relevant biological activities at rather low concentrations. Evidence suggests that phytosterols, carotenoids, terpenoids, and tocopherols can interact with different metabolic pathways, exerting beneficial effects against a number of metabolic diseases. These small molecules can modulate triacylglycerol absorption in the intestine and the biosynthesis of chylomicrons, the lipid carriers in the blood. Once in the bloodstream, they can impact lipoprotein clearance from blood, thereby affecting fatty acid release, incorporation into adipocytes and triglyceride reassembling and deposit. Consequently, some of these molecules can regulate pathophysiological processes associated to obesity and its related conditions, such as insulin resistance, metabolic syndrome and type-2 diabetes. The protective capacity of some lipophilic small molecules on oxidative and chemotoxic stress, can modify the expression of key genes in the adaptive cellular response, such as transcription factors, contributing to prevent the inflammatory status of adipose tissue. These small lipophilic compounds can be incorporated into diet as natural parts of food but they can also be employed to supplement other dietary and pharmacologic products as nutraceuticals, exerting protective effects against the development of metabolic diseases in which inflammation is involved. The aim of this review is to summarize the current knowledge of the influence of dietary lipophilic small biomolecules (phytosterols, carotenoids, tocopherols, and triterpenes) on lipid transport, as well as on the effects they may have on pathophysiological metabolic states, related to obesity, insulin resistance and inflammation, providing an evidence-based summary of their main beneficial effects on human health.
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Affiliation(s)
- José M Castellano
- Group of Bioactive Compounds, Nutrition and Health, Department of Food and Health, Instituto de la Grasa-Consejo Superior de Investigaciones Científicas, Seville, Spain
| | - Juan M Espinosa
- Group of Bioactive Compounds, Nutrition and Health, Department of Food and Health, Instituto de la Grasa-Consejo Superior de Investigaciones Científicas, Seville, Spain
| | - Javier S Perona
- Group of Bioactive Compounds, Nutrition and Health, Department of Food and Health, Instituto de la Grasa-Consejo Superior de Investigaciones Científicas, Seville, Spain
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19
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Rosa HH, Carvalho P, Ortmann CF, Schneider NFZ, Reginatto FH, Simões CMO, Silva IT. Cytotoxic effects of a triterpene‐enriched fraction of Cecropia pachystachya on the human hormone-refractory prostate cancer PC3 cell line. Biomed Pharmacother 2020; 130:110551. [DOI: 10.1016/j.biopha.2020.110551] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/13/2020] [Accepted: 07/20/2020] [Indexed: 01/10/2023] Open
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20
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Bailly C. Anticancer properties of Prunus mume extracts (Chinese plum, Japanese apricot). JOURNAL OF ETHNOPHARMACOLOGY 2020; 246:112215. [PMID: 31491438 DOI: 10.1016/j.jep.2019.112215] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 08/30/2019] [Accepted: 09/02/2019] [Indexed: 05/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Extracts of the fruit of Prunus mume (Rosaceae) have been used for a long time in Eastern Asia, in many culinary and medicinal preparations. The plant originates from the south of mainland China (named méi) and was introduced later in Japan (ume), Korea (maesil) and Vietnam (mai or mo). Extracts of the fruits (Chinese plum or Japanese apricot, 'Nanko' mume cultivar of Prunus mume Sieb. et Zucc.) are used in traditional Chinese and Japanese medicine, and various Korean medical preparations, for more than 2000 years. The medicinal use of the flesh of the fruits is cited in ancient Japanese monographies (such as Shokokukodenhiho published in 1817). AIM OF THE STUDY To analyze the anticancer activities of P. mume extracts and their potential use to prevent or treat cancers. The use of P. mume extracts to alleviate the side effects of chemotherapy, notably drug-induced gastro-intestinal toxicities, is also reviewed. METHODS Extensive database retrieval, such as SciFinder and PubMed, was performed by using keywords such as "Prunus mume", "Chinese plum", "Japanese apricot", and "cancer". In addition, relevant textbooks, patents, reviews, and digital documents (in English) were consulted to collate all available scientific literature and to provide a complete science-based survey of the topic. RESULTS P. mume extracts display hepatoprotective, anti-inflammatory, antioxidative and antibacterial effects, as well as anticancer properties. A survey of the antitumor activities of MK615 and other P. mume extracts is provided here, with information about the natural products found in the extracts (such as ursolic acid and oleanic acid) and the mechanisms of action of these extracts. MK615 inhibits proliferation and induces apoptotic death of different types of cancer cells from both solid and hematological tumors. CONCLUSION The pool of in vitro data and signs of anticancer activities in mice models and in Human, although very limited, support the use of this extract to treat cancer, notably gastro-intestinal tumors. However, more robust evidence of anticancer activity in Human are awaited. Beyond cancer treatment, the use of P. mume extracts to prevent or to treat mucositis and other gastro-intestinal damages induced by anticancer drugs is underlined. The woody plant Prunus mume, a member of the Rosaceae family, has a long plantation history in China, and has widely been planted in Asia due to its high ornamental value (colorful corollas, pleasant fragrance, weeping trait) and the culinary, nutritional and medicinal potential of the fruits from the specie Prunus mume Sieb. et Zucc (Mei). Over the past 20 years the therapeutic potential of the extract of Japanese apricot "Ume" has been regularly reported. Anti-bacterial, anti-oxidative, anti-inflammatory and anti-cancer properties have been described. A complete analysis of the published scientific literature on Ume and cancer is presented here.
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21
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Sadgrove NJ, Jones GL. From Petri Dish to Patient: Bioavailability Estimation and Mechanism of Action for Antimicrobial and Immunomodulatory Natural Products. Front Microbiol 2019; 10:2470. [PMID: 31736910 PMCID: PMC6834656 DOI: 10.3389/fmicb.2019.02470] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 10/15/2019] [Indexed: 01/02/2023] Open
Abstract
The new era of multidrug resistance of pathogens against frontline antibiotics has compromised the immense therapeutic gains of the 'golden age,' stimulating a resurgence in antimicrobial research focused on antimicrobial and immunomodulatory components of botanical, fungal or microbial origin. While much valuable information has been amassed on the potency of crude extracts and, indeed, purified compounds there are too many reports that uncritically extrapolate observed in vitro activity to presumed ingestive and/or topical therapeutic value, particularly in the discipline of ethnopharmacology. Thus, natural product researchers would benefit from a basic pharmacokinetic and pharmacodynamic understanding. Furthermore, therapeutic success of complex mixtures or single components derived therefrom is not always proportionate to their MIC values, since immunomodulation can be the dominant mechanism of action. Researchers often fail to acknowledge this, particularly when 'null' activity is observed. In this review we introduce the most up to date theories of oral and topical bioavailability including the metabolic processes affecting xenobiotic biotransformation before and after drugs reach the site of their action in the body. We briefly examine the common methodologies employed in antimicrobial, immunomodulatory and pharmacokinetic research. Importantly, we emphasize the contribution of synergies and/or antagonisms in complex mixtures as they affect absorptive processes in the body and sometimes potentiate activity. Strictly in the context of natural product research, it is important to acknowledge the potential for chemotypic variation within important medicinal plants. Furthermore, polar head space and rotatable bonds give a priori indications of the likelihood of bioavailability of active metabolites. Considering this and other relatively simple chemical insights, we hope to provide the basis for a more rigorous scientific assessment, enabling researchers to predict the likelihood that observed in vitro anti-infective activity will translate to in vivo outcomes in a therapeutic context. We give worked examples of tentative pharmacokinetic assessment of some well-known medicinal plants.
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Affiliation(s)
- Nicholas John Sadgrove
- Pharmaceuticals and Nutraceuticals (PAN) Group, School of Science and Technology, University of New England, Armidale, NSW, Australia
- Jodrell Science Laboratory, Royal Botanic Gardens, Kew, Richmond, United Kingdom
| | - Graham Lloyd Jones
- Pharmaceuticals and Nutraceuticals (PAN) Group, School of Science and Technology, University of New England, Armidale, NSW, Australia
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Evaluation of the Betulinic Acid-Cisplatin conjugate APC and its precursor DE9B for the treatment of human malignant glioma. Chem Biol Interact 2019; 314:108841. [PMID: 31586452 DOI: 10.1016/j.cbi.2019.108841] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 08/19/2019] [Accepted: 09/29/2019] [Indexed: 01/28/2023]
Abstract
Despite the existence of multimodal therapy concepts, glioblastoma remains a tumor type with one of the worst prognoses. In particular, the poor prognosis is due to the lack of therapeutic efficacy of chemical agents and irradiation in hypoxic tumor areas. New therapeutic strategies could improve the treatment of glioblastoma. In this study, we investigated the therapeutic efficacy of a conjugate of cisplatin (DDP), a widely used chemotherapeutic agent, and betulinic acid (BA), a natural product from plane tree bark, in glioblastoma cells under different oxygen conditions. We investigated the effects of the BA-DDP conjugate κN',N''-{3-acetyloxy-BA-28-[2-(2-aminoethyl)aminoethyl]amide} dichlorido platinum(II) (APC) and its precursor 3-acetyloxy-BA-28-[2-(2-aminoethyl)aminoethyl]amide (DE9B) on cytotoxicity, cell growth, apoptosis, migration and radiosensitivity compared to BA or DDP alone under different oxygen conditions. Based on the EC50 values, the precursor DE9B exhibited the strongest cytotoxic effects of the analyzed chemotherapeutic agents. The BA-DDP conjugate APC achieved a moderate cytotoxic effect in glioma cells. Both of the newly developed agents induced cell growth delay, apoptosis and inhibition of migration. Furthermore, additive effects could be achieved in combination with irradiation. In contrast to those of BA and DDP, the cell biological effects of APC and DE9B were not influenced by the oxygen concentration. In this study, the linking of BA and DDP did not produce a compound with additive therapeutic effects on glioblastoma cell lines in vitro. Nevertheless, the results of this study suggest that the precursor DE9B is an effective BA derivative for the treatment of glioblastoma in vitro.
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Abbasi BA, Iqbal J, Ahmad R, Bibi S, Mahmood T, Kanwal S, Bashir S, Gul F, Hameed S. Potential phytochemicals in the prevention and treatment of esophagus cancer: A green therapeutic approach. Pharmacol Rep 2019; 71:644-652. [DOI: 10.1016/j.pharep.2019.03.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 02/07/2019] [Accepted: 03/09/2019] [Indexed: 02/07/2023]
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Silva AM, Alvarado HL, Abrego G, Martins-Gomes C, Garduño-Ramirez ML, García ML, Calpena AC, Souto EB. In Vitro Cytotoxicity of Oleanolic/Ursolic Acids-Loaded in PLGA Nanoparticles in Different Cell Lines. Pharmaceutics 2019; 11:pharmaceutics11080362. [PMID: 31344882 PMCID: PMC6723971 DOI: 10.3390/pharmaceutics11080362] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 07/19/2019] [Accepted: 07/22/2019] [Indexed: 12/20/2022] Open
Abstract
Oleanolic (OA) and ursolic (UA) acids are recognized triterpenoids with anti-cancer properties, showing cell-specific activity that can be enhanced when loaded into polymeric nanoparticles. The cytotoxic activity of OA and UA was assessed by Alamar Blue assay in three different cell lines, i.e., HepG2 (Human hepatoma cell line), Caco-2 (Human epithelial colorectal adenocarcinoma cell line) and Y-79 (Human retinoblastoma cell line). The natural and synthetic mixtures of these compounds were tested as free and loaded in polymeric nanoparticles in a concentration range from 2 to 32 µmol/L. The highest tested concentrations of the free triterpene mixtures produced statistically significant cell viability reduction in HepG2 and Caco-2 cells, compared to the control (untreated cells). When loaded in the developed PLGA nanoparticles, no differences were recorded for the tested concentrations in the same cell lines. However, in the Y-79 cell line, a decrease on cell viability was observed when testing the lowest concentration of both free triterpene mixtures, and after their loading into PLGA nanoparticles.
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Affiliation(s)
- Amélia M Silva
- Centre for Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os Montes e Alto Douro (UTAD), Quinta de Prados, 5001-801 Vila Real, Portugal.
- Department of Biology and Environment, UTAD, Quinta de Prados, 5001-801 Vila Real, Portugal.
| | - Helen L Alvarado
- Department of Biology and Environment, UTAD, Quinta de Prados, 5001-801 Vila Real, Portugal
- Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy, University of Barcelona, Ave. Joan XXIII s/n, 08028 Barcelona, Spain
| | - Guadalupe Abrego
- Department of Biology and Environment, UTAD, Quinta de Prados, 5001-801 Vila Real, Portugal
- Department of Chemical and Instrumental Analysis, Faculty of Chemistry and Pharmacy, University of El Salvador, Final 25 Ave. Norte, 3026 San Salvador, El Salvador
| | - Carlos Martins-Gomes
- Centre for Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os Montes e Alto Douro (UTAD), Quinta de Prados, 5001-801 Vila Real, Portugal
- Department of Biology and Environment, UTAD, Quinta de Prados, 5001-801 Vila Real, Portugal
| | - Maria L Garduño-Ramirez
- Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Av. Universidad No. 1001, Col Chamilpa, 62209 Cuernavaca, Mexico
| | - María L García
- Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy, University of Barcelona, Ave. Joan XXIII s/n, 08028 Barcelona, Spain
| | - Ana C Calpena
- Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy, University of Barcelona, Ave. Joan XXIII s/n, 08028 Barcelona, Spain
| | - Eliana B Souto
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), Pólo das Ciências da Saúde, 3000-548 Coimbra, Portugal.
- CEB-Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
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Mantzorou M, Zarros A, Vasios G, Theocharis S, Pavlidou E, Giaginis C. Cranberry: A Promising Natural Source of Potential Nutraceuticals with Anticancer Activity. Anticancer Agents Med Chem 2019; 19:1672-1686. [PMID: 31272361 DOI: 10.2174/1871520619666190704163301] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 05/23/2019] [Accepted: 05/27/2019] [Indexed: 12/12/2022]
Abstract
Studies have shown that cranberry and its components may exert anticancer properties. The present study aims to critically summarise the existing experimental studies evaluating the potential effects of cranberry on cancer prevention and treatment. PubMed database was searched to identify relevant studies. Current in vitro studies have indicated that cranberry and/or its components may act as chemopreventive agents, diminishing the risk for cancer by inhibiting cells oxidation and inflammatory-related processes, while they may also exert chemotherapeutic effects by inhibiting cell proliferation and angiogenesis, inducing cell apoptosis and attenuating the ability of tumour cells to invade and metastasis. Limited in vivo studies have further documented potential anticancer activity. Cranberry could be considered as a conglomeration of potential effective anticancer druglike compounds.
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Affiliation(s)
- Maria Mantzorou
- Department of Food Science and Nutrition, University of the Aegean, Lemnos, Greece
| | - Apostolos Zarros
- Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom
| | - Georgios Vasios
- Department of Food Science and Nutrition, University of the Aegean, Lemnos, Greece
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, University of Athens, Athens, Greece
| | - Eleni Pavlidou
- Department of Food Science and Nutrition, University of the Aegean, Lemnos, Greece
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Reichenbach ZW, Murray MG, Saxena R, Farkas D, Karassik EG, Klochkova A, Patel K, Tice C, Hall TM, Gang J, Parkman HP, Ward SJ, Tétreault MP, Whelan KA. Clinical and translational advances in esophageal squamous cell carcinoma. Adv Cancer Res 2019; 144:95-135. [PMID: 31349905 DOI: 10.1016/bs.acr.2019.05.004] [Citation(s) in RCA: 142] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) is among the most deadly forms of human malignancy characterized by late stage diagnosis, metastasis, therapy resistance and frequent recurrence. Clinical management of ESCC remains challenging and the disease presently lacks approved targeted therapeutics. However, emerging data from recent clinical and translational investigations hold great promise for future progress toward improving patient outcomes in this deadly disease. Here, we review current clinical perspectives in ESCC epidemiology, pathophysiology, and clinical care, highlighting recent advances with potential to impact ESCC prevention, diagnosis and management. We further provide an overview of recent translational investigations contributing to our understanding of the molecular mechanisms underlying ESCC development, progression and therapy response, including insights gained from genetic studies and various murine model systems. Finally, we discuss future perspectives in the clinical and translational realms, along with remaining hurdles that must be overcome to eradicate ESCC.
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Affiliation(s)
- Zachary Wilmer Reichenbach
- Department of Medicine, Gastroenterology Section, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States; Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Mary Grace Murray
- Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Reshu Saxena
- Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Daniel Farkas
- Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Erika G Karassik
- Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Alena Klochkova
- Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Kishan Patel
- Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Caitlin Tice
- Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Timothy M Hall
- Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Julie Gang
- Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Henry P Parkman
- Department of Medicine, Gastroenterology Section, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Sarah J Ward
- Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States; Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Marie-Pier Tétreault
- Department of Medicine, Gastroenterology and Hepatology Division, Northwestern University Feinberg School of Medicine, Chicago, IL, United States.
| | - Kelly A Whelan
- Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States; Department of Pathology & Laboratory Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States.
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Martín-García B, Verardo V, León L, De la Rosa R, Arráez-Román D, Segura-Carretero A, Gómez-Caravaca AM. GC-QTOF-MS as valuable tool to evaluate the influence of cultivar and sample time on olive leaves triterpenic components. Food Res Int 2018; 115:219-226. [PMID: 30599934 DOI: 10.1016/j.foodres.2018.08.085] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 08/17/2018] [Accepted: 08/27/2018] [Indexed: 10/28/2022]
Abstract
Pentacyclic triterpenes play an important role in plant defense and have demonstrated beneficial effects in human health acting in disease prevention. In the present study, the determination of triterpenes compounds in olive leaves of six different cultivars grown at four dates was assessed in order to corroborate the influence of olive growth cycle on triterpenes content and to evaluate if the highest amounts are detected in correspondence to the olive oil production period when the leaves are one of the most important by-product. A GC-QTOF-MS methodology was optimized and validated, and five triterpenes were identified and quantified in all olive leaves samples analysed. ANOVA analyses revealed quantitative differences among sampling times and cultivars. Principal Component Analyses showed a good separation among triterpenes content for the different collecting seasons and cultivars. Picual, the most commonly grown olive today for olive oil production, was the cultivar that presented the highest concentrations of triterpenes and oleanolic acid the major triterpene in all cultivars at all sampling times (54-76.5% of total triterpenes). The triterpenes concentration is higher in June than in the other sampling times. Unfortunately, the leaves sampled at the stage that corresponded to the olive oil production were not the best one in terms of triterpenes content; however the decrease was never >15.5%. Thus, the present results confirm olive leaves a suitable source of bioactive compounds that can be used to obtain high added-value products enriched in triterpenes.
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Affiliation(s)
- Beatriz Martín-García
- Department of Analytical Chemistry, Faculty of Sciences, University of Granada, Avd. Fuentenueva s/n, 18071 Granada, Spain
| | - Vito Verardo
- Department of Nutrition and Food Science, University of Granada, Campus Universitario de Cartuja, E-18071 Granada, Spain; Institute of Nutrition and Food Technology 'José Mataix', Biomedical Research Centre, University of Granada, Avenida del Conocimiento s/n, E-18071 Granada, Spain.
| | - Lorenzo León
- IFAPA Centro Alameda del Obispo, Avda Menéndez Pidal, s/n, E-14004 Córdoba, Spain
| | - Raúl De la Rosa
- IFAPA Centro Alameda del Obispo, Avda Menéndez Pidal, s/n, E-14004 Córdoba, Spain
| | - David Arráez-Román
- Department of Analytical Chemistry, Faculty of Sciences, University of Granada, Avd. Fuentenueva s/n, 18071 Granada, Spain; Functional Food Research and Development Center, Health Science Technological Park, Avd. del Conocimiento, Bioregion building, 18100, Granada, Spain
| | - Antonio Segura-Carretero
- Department of Analytical Chemistry, Faculty of Sciences, University of Granada, Avd. Fuentenueva s/n, 18071 Granada, Spain; Functional Food Research and Development Center, Health Science Technological Park, Avd. del Conocimiento, Bioregion building, 18100, Granada, Spain
| | - Ana María Gómez-Caravaca
- Department of Analytical Chemistry, Faculty of Sciences, University of Granada, Avd. Fuentenueva s/n, 18071 Granada, Spain
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Ying J, Zhang M, Qiu X, Lu Y. The potential of herb medicines in the treatment of esophageal cancer. Biomed Pharmacother 2018; 103:381-390. [PMID: 29674273 DOI: 10.1016/j.biopha.2018.04.088] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 04/08/2018] [Accepted: 04/12/2018] [Indexed: 02/07/2023] Open
Abstract
Esophageal cancer (EC) is one of common malignant neoplasms in the world. Due to dietary habits, environmental factors, stress and so on, larger numbers of person are diagnose with EC every year. Currently, the clinical treatment of EC mainly includes radiotherapy, chemotherapy, surgical resection alone or combined strategy. These treatment options are insufficient and often associated with a number of side effects. Medicinal herbs containing Traditional Chinese Medicine (TCM) have been used as an adjunct treatment for alleviating the side effects of chemotherapy or radiotherapy and for improving the quality of life of cancer patients. The monomer compounds obtained from medicinal herbs also exhibit potential anti-cancer activity against various type cancer cell lines including esophageal cancer, and have the ability to enhance cancer cells sensitizing to chemotherapy or radiotherapy. In this review, we summarize some monomers and composite of medicinal herbs with anti-cancer activity for EC, and elaborate their mechanism of action. Understanding the exact mechanism of their actions may provide valuable information for their possible application in cancer therapy and prevention. This is beneficial for the use and development of medicinal herbs for diseases therapy in the future.
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Affiliation(s)
- Jie Ying
- Department of Clinical Research Center, Xuyi People's Hospital, PR China
| | - Miaomiao Zhang
- Department of Clinical Research Center, Xuyi People's Hospital, PR China
| | - Xiaoyan Qiu
- Department of Clinical Research Center, Xuyi People's Hospital, PR China
| | - Yu Lu
- Department of Clinical Research Center, Xuyi People's Hospital, PR China.
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Vorobyova O, Deryabina O, Malygina D, Plotnikova N, Solovyeva A, Belyaeva K, Melnikova N. Betulin-3,28-diphosphate as a Component of Combination Cytostatic Drugs for the Treatment of Ehrlich Ascites Carcinoma In Vitro and In Vivo Experiments. Sci Pharm 2018; 86:E17. [PMID: 29690651 PMCID: PMC6027669 DOI: 10.3390/scipharm86020017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 04/17/2018] [Accepted: 04/18/2018] [Indexed: 12/18/2022] Open
Abstract
The activity of betulin-3,28-diphosphate (BDP) in combination with the cytostatics such as 5-fluorouracil (5-FU) and hydrazine sulfate (HS) was demonstrated by using the transplanted Ehrlich ascites carcinoma (EAC) in mice. The dose-dependent effect of combination drugs BDP + HS and BDP + 5-FU was revealed by in vitro experiments on rats. The synergetic effect of HS and BDP on oxidative stress and energy metabolism was established. The malonic dialdehyde (MDA) level both in plasma and erythrocytes decreased by 87 ± 2%, and the superoxide dismutase (SOD) activity increased by 105 ± 7% in comparison with the control. The combination of BDP + HS promoted the increase of lactate dehydrogenase (LDH) activity in the reverse reaction by 195 ± 21% compared to the control. The combination drug of 5-FU with BDP caused the synergetic decrease of the lipid peroxidation (LPO) intensity estimated by the MDA level decrease up to 14 ± 4% compared to pure compounds. Betulin-3,28-diphosphate in combination with cytostatics for EAC treatment improved the animal health status, as well as decreased the cytostatics dose that can be used in palliative therapy.
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Affiliation(s)
- Olga Vorobyova
- Department of Pharmaceutical Chemistry, Federal State Budgetary Educational Institution of Higher Education "Privolzhsky Research Medical University", Ministry of Health of the Russian Federation, Minin sq., 10/1, 603005 Nizhny Novgorod, Russia.
| | - Olga Deryabina
- Department of Chemistry, N.P. Ogarev Mordovian State University, Bolshevistskaya St. 68, 430005 Saransk, Russia.
| | - Darina Malygina
- Department of Pharmaceutical Chemistry, Federal State Budgetary Educational Institution of Higher Education "Privolzhsky Research Medical University", Ministry of Health of the Russian Federation, Minin sq., 10/1, 603005 Nizhny Novgorod, Russia.
| | - Nadezhda Plotnikova
- Department of Chemistry, N.P. Ogarev Mordovian State University, Bolshevistskaya St. 68, 430005 Saransk, Russia.
| | - Anna Solovyeva
- Department of Pharmaceutical Chemistry, Federal State Budgetary Educational Institution of Higher Education "Privolzhsky Research Medical University", Ministry of Health of the Russian Federation, Minin sq., 10/1, 603005 Nizhny Novgorod, Russia.
| | - Kseniya Belyaeva
- Department of Pharmaceutical Chemistry, Federal State Budgetary Educational Institution of Higher Education "Privolzhsky Research Medical University", Ministry of Health of the Russian Federation, Minin sq., 10/1, 603005 Nizhny Novgorod, Russia.
| | - Nina Melnikova
- Department of Pharmaceutical Chemistry, Federal State Budgetary Educational Institution of Higher Education "Privolzhsky Research Medical University", Ministry of Health of the Russian Federation, Minin sq., 10/1, 603005 Nizhny Novgorod, Russia.
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Yanaki M, Kobayashi M, Aruga A, Nomura M, Ozaki M. In Vivo Antitumor Effects of MK615 Led by PD-L1 Downregulation. Integr Cancer Ther 2018; 17:646-653. [PMID: 29665734 PMCID: PMC6142083 DOI: 10.1177/1534735418766403] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background/Aim: MK615 extracted from Prunus mume
was reported to have anti-inflammatory effects. In this article, we examined the
in vivo antitumor effect of MK615 (an extract from Japanese apricot) using mouse
tumor xenografts and focusing on the downregulation of PD-L1 (programmed
death-ligand 1), a ligand of programmed cell death-1, a surface protein of
activated T cells. Materials and Methods: B16/BL6 melanoma cells
were injected into C57BL/6 or BALB/c-nu/nu mice to establish lung metastasis.
BALB/c-nu/nu mice (nude mice) were used as a T cell–deficient model. The mice
were given MK615 or saline orally every other day for approximately 8 weeks, and
their survival was observed. NF-κB (nuclear factor-κB) and PD-L1 expressions of
metastatic lung tissues were also examined. Results: The survival
rate was improved only in the MK615-treated C57BL/6 mice (P
< .05), not in the saline-given control mice or BALB/c-nu/nu mice. The
downregulations of NF-κB and PD-L1 were observed in both MK615-treated C57BL/6
and BALB/c-nu/nu mice. These results suggest that the antitumor effects of MK615
are associated with T cell–mediated immunity activated by MK-615-induced PD-L1
downregulation in tumor cells. Conclusion: MK615 is beneficial for
a prolonged host survival time in the B16/BL6 melanoma xenograft model
associated with T cell–mediated antitumor immunity.
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Affiliation(s)
| | | | | | | | - Makoto Ozaki
- 1 Tokyo Women's Medical University, Tokyo, Japan
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31
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Hattori M, Kawakami K, Akimoto M, Takenaga K, Suzumiya J, Honma Y. Antitumor Effect of Japanese Apricot Extract (MK615) on Human Cancer Cells in Vitro and in Vivo through a Reactive Oxygen Species-Dependent Mechanism. TUMORI JOURNAL 2018; 99:239-48. [DOI: 10.1177/030089161309900220] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Aims and background MK615 is produced from Japanese apricot and contains several cyclic triterpenes, such as oleanolic and ursolic acids. MK615 was shown to strongly suppress cutaneous in-transit metastasis in a patient with malignant melanoma. The present investigation was undertaken to clarify the antitumor effects of MK615 in vitro and in vivo. Methods Several human cancer cell lines were exposed to MK615 for 7 days to examine its antiproliferative effects. The effect of MK615 on in vivo growth of human pancreatic cancer MIAPaCa-2 cells was also examined. Results MK615 inhibited the growth of several human cancer cell lines in a concentration-dependent way. Pancreatic cancer MIAPaCa-2 cells were highly sensitive to the growth-inhibiting effects of MK615. Treatment with MK615 preferentially induced cell death in human cancer cells while sparing normal cells such as human umbilical vein endothelial cells (HUVEC) and mouse bone marrow cells. When MIAPaCa-2 cells were incubated with MK615 in the presence of antioxidant, growth-inhibition was significantly reduced, and MK615 induced the accumulation of reactive oxygen species in cancer cells but not in HUVEC. MK615, in both the presence and absence of gemcitabine, significantly inhibited the growth of human pancreatic cancer cells as xenografts without apparent adverse effects. Conclusions MK615, a supplement produced from Japanese apricot, may have therapeutic value in treating human cancers through a reactive oxygen species-dependent mechanism.
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Affiliation(s)
- Miho Hattori
- Department of Life Science, Shimane University, Izumo, Shimane, Japan
| | - Koshi Kawakami
- Department of Life Science, Shimane University, Izumo, Shimane, Japan
- Cancer Center, Faculty of Medicine, Shimane University, Izumo, Shimane, Japan
| | - Miho Akimoto
- Department of Life Science, Shimane University, Izumo, Shimane, Japan
| | - Keizo Takenaga
- Department of Life Science, Shimane University, Izumo, Shimane, Japan
| | - Junji Suzumiya
- Cancer Center, Faculty of Medicine, Shimane University, Izumo, Shimane, Japan
| | - Yoshio Honma
- Department of Life Science, Shimane University, Izumo, Shimane, Japan
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Deng JS, Chang JS, Liao JC, Chao W, Lee MM, Cheng CH, Huang GJ. Actinidia callosa var. callosa suppresses metastatic potential of human hepatoma cell SK-Hep1 by inhibiting matrix metalloproteinase-2 through PI3K/Akt and MAPK signaling pathways. BOTANICAL STUDIES 2018; 59:3. [PMID: 29356905 PMCID: PMC5778090 DOI: 10.1186/s40529-017-0216-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 12/07/2017] [Indexed: 06/07/2023]
Abstract
BACKGROUND Cancer cell metastasis involving multi-step procedures and cytophysiological property changes may make difficult in the clinical management and death rate increasing. RESULTS In this study, we first observed that ethyl acetate fraction of Actinidia callosa var. callosa (EAAC) carry out a dose-dependent inhibitory effect without cytotoxicity on the mobility and invasion of highly metastatic SK-Hep1 cells. To investigate the EAAC in cancer metastasis, SK-Hep1 cells were treated with EAAC at various concentrations and then subjected to gelatin zymography, casein zymography and western blot to study the impacts of EAAC on metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-1/2 (TIMP-1/2), respectively. Our results showed that EAAC treatment may decrease the expressions of MMP-2 and enhance the expression of TIMP-1/2 in a concentration-dependent manner. EAAC also inhibited effect on the phosphorylation of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase/serine/threonine protein kinase [or protein kinase B (PI3K/Akt)] and focal adhesion kinase (FAK). CONCLUSIONS These results indicate that EAAC inhibited SK-Hep1 cell of metastasis by reduced protein level of MMP-2 through the suppression of MAPK and FAK signaling pathway and of the activity of PI3K/Akt. These findings suggest that EAAC may be used as an antimetastatic agent.
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Affiliation(s)
- Jeng-Shyan Deng
- Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan
| | - Jui-Shu Chang
- School of Chinese Medicine, Graduate Institute of Integrated Medicine College of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Jung-Chun Liao
- School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan
| | - Wei Chao
- School of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Ming-Ming Lee
- Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan
| | - Chien-Hua Cheng
- Department of Visual Communication Design, Asia University, Taichung, Taiwan
| | - Guan-Jhong Huang
- School of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Chinese Medicine, China Medical University, Taichung, Taiwan
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Winkler K, Ramer R, Dithmer S, Ivanov I, Merkord J, Hinz B. Fatty acid amide hydrolase inhibitors confer anti-invasive and antimetastatic effects on lung cancer cells. Oncotarget 2017; 7:15047-64. [PMID: 26930716 PMCID: PMC4924770 DOI: 10.18632/oncotarget.7592] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 01/25/2016] [Indexed: 11/25/2022] Open
Abstract
Inhibition of endocannabinoid degradation has been suggested as tool for activation of endogenous tumor defense. One of these strategies lies in blockade of fatty acid amide hydrolase (FAAH) which catalyzes the degradation of endocannabinoids (anandamide [AEA], 2-arachidonoylglycerol [2-AG]) and endocannabinoid-like substances (N-oleoylethanolamine [OEA], N-palmitoylethanolamine [PEA]). This study addressed the impact of two FAAH inhibitors (arachidonoyl serotonin [AA-5HT], URB597) on A549 lung cancer cell metastasis and invasion. LC-MS analyses revealed increased levels of FAAH substrates (AEA, 2-AG, OEA, PEA) in cells incubated with either FAAH inhibitor. In athymic nude mice FAAH inhibitors were shown to elicit a dose-dependent antimetastatic action yielding a 67% and 62% inhibition of metastatic lung nodules following repeated administration of 15 mg/kg AA-5HT and 5 mg/kg URB597, respectively. In vitro, a concentration-dependent anti-invasive action of either FAAH inhibitor was demonstrated, accompanied with upregulation of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). Using siRNA approaches, a causal link between the TIMP-1-upregulating and anti-invasive action of FAAH inhibitors was confirmed. Moreover, knockdown of FAAH by siRNA was shown to confer decreased cancer cell invasiveness and increased TIMP-1 expression. Inhibitor experiments point toward a role of CB2 and transient receptor potential vanilloid 1 in conferring anti-invasive effects of FAAH inhibitors and FAAH siRNA. Finally, antimetastatic and anti-invasive effects were confirmed for all FAAH substrates with AEA and OEA causing a TIMP-1-dependent anti-invasive action. Collectively, the present study provides first-time proof for an antimetastatic action of FAAH inhibitors. As mechanism of its anti-invasive properties an upregulation of TIMP-1 was identified.
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Affiliation(s)
- Katrin Winkler
- Institute of Toxicology and Pharmacology, Rostock University Medical Center, Rostock, Germany
| | - Robert Ramer
- Institute of Toxicology and Pharmacology, Rostock University Medical Center, Rostock, Germany
| | - Sophie Dithmer
- Institute of Toxicology and Pharmacology, Rostock University Medical Center, Rostock, Germany
| | - Igor Ivanov
- Institute of Toxicology and Pharmacology, Rostock University Medical Center, Rostock, Germany
| | - Jutta Merkord
- Institute of Toxicology and Pharmacology, Rostock University Medical Center, Rostock, Germany
| | - Burkhard Hinz
- Institute of Toxicology and Pharmacology, Rostock University Medical Center, Rostock, Germany
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Sharma M, Sharma S, Sharma V, Sharma K, Yadav SK, Dwivedi P, Agrawal S, Paliwal SK, Dwivedi AK, Maikhuri JP, Gupta G, Mishra PR, Rawat AKS. Oleanolic–bioenhancer coloaded chitosan modified nanocarriers attenuate breast cancer cells by multimode mechanism and preserve female fertility. Int J Biol Macromol 2017; 104:1345-1358. [DOI: 10.1016/j.ijbiomac.2017.06.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Revised: 05/24/2017] [Accepted: 06/02/2017] [Indexed: 12/28/2022]
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35
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Paradigm shift in cancer treatment: Cancer treatment as a metabolic disease – fusion of Eastern and Western medicine. JOURNAL OF TRADITIONAL CHINESE MEDICAL SCIENCES 2017. [DOI: 10.1016/j.jtcms.2017.12.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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Inoue M, Honma Y, Urano T, Suzumiya J. Japanese apricot extract (MK615) potentiates bendamustine-induced apoptosis via impairment of the DNA damage response in lymphoma cells. Oncol Lett 2017; 14:792-800. [PMID: 28693235 PMCID: PMC5494765 DOI: 10.3892/ol.2017.6219] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 02/27/2017] [Indexed: 11/06/2022] Open
Abstract
Bendamustine, a hybrid molecule of a purine analog and alkylator, induces cell death by the activation of apoptosis and the DNA damage response. The agent MK615 is produced from Japanese apricot and contains a number of cyclic triterpenes that exhibit antitumor activities. In the present study, the combined effects of bendamustine and MK615 on lymphoma cells were investigated. The combined compounds synergistically induced apoptosis in all lymphoid cell lines examined. MK615 inhibited the bendamustine-induced phosphorylation of checkpoint kinase 1 and 2. As ataxia telangiectasia mutated (ATM) and ataxia telangiectasia- and Rad3-related (ATR) kinases are key mediators of the DNA damage response, the effects of the combination of bendamustine and ATM/ATR inhibitors (KU-60019 and VE-821) on lymphoma cells were investigated. KU-60019 and/or VE-821 potentiated bendamustine activity in all cell lines tested, but did not affect MK615 activity, suggesting that these inhibitors have the same underlying mechanism of action as that of MK615. The results of the present study suggest that it may be feasible to use ATM/ATR inhibitors in combination with bendamustine for treating malignant lymphoma.
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Affiliation(s)
- Masaya Inoue
- Department of Oncology/Hematology, Faculty of Medicine, Shimane University, Izumo, Shimane 693-8501, Japan
| | - Yoshio Honma
- Department of Oncology/Hematology, Faculty of Medicine, Shimane University, Izumo, Shimane 693-8501, Japan
| | - Takeshi Urano
- Department of Biochemistry, Faculty of Medicine, Shimane University, Izumo, Shimane 693-8501, Japan
| | - Junji Suzumiya
- Department of Oncology/Hematology, Faculty of Medicine, Shimane University, Izumo, Shimane 693-8501, Japan
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The adjuvant value of Andrographis paniculata in metastatic esophageal cancer treatment - from preclinical perspectives. Sci Rep 2017; 7:854. [PMID: 28405006 PMCID: PMC5429803 DOI: 10.1038/s41598-017-00934-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 03/17/2017] [Indexed: 01/27/2023] Open
Abstract
Esophageal cancer (EC) is the fourth and sixth leading cause of cancer-related deaths in China and United States, respectively. The dismal prognosis of EC is mainly attributed to distant metastases, which may not be overcome by chemotherapy alone. Hence, the use of alternative adjuvant treatments, such as herbal medicines, for metastatic EC remains a great desire of patients. Our previous study demonstrated the in vivo anti-tumor and in vitro anti-invasion activities of Andrographis paniculata (AP) in esophageal cancer. In the present study, the chemical constituents of absorbed AP components through human intestinal Caco-2 cell monolayer were verified for the first time. The anti-migratory activities and suppressive effects on metastasis-related factors such as HER2, MMP2, MMP9, TM4SF3, CXCR4 of the absorbed AP components were revealed in esophageal cancer cells EC-109. The anti-tumor and anti-metastatic effects of AP water extract (1600 mg/kg) were further confirmed in metastatic esophageal xenograft-bearing mice. Besides, AP water extract acted synergistically with cisplatin plus 5-fluorouracil on inhibiting tumor nodule growth (with combination index <0.7). Meanwhile, chemotherapeutics-induced side-effects could also be reduced by AP water extract. The present findings provide evidence on safety and advantages of the combined use of AP with chemotherapeutics in pre-clinical setting.
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Wang S, Meng X, Dong Y. Ursolic acid nanoparticles inhibit cervical cancer growth in vitro and in vivo via apoptosis induction. Int J Oncol 2017; 50:1330-1340. [PMID: 28259944 DOI: 10.3892/ijo.2017.3890] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Accepted: 01/12/2017] [Indexed: 11/06/2022] Open
Abstract
Cervical cancer is a cause of cancer death, making it one of the most common causes of death among women globally. Previously, a variety of studies have revealed the molecular mechanisms by which cervical cancer develops. However, there are still limitations in treatment for cervical cancer. Ursolic acid is a naturally derived pentacyclic triterpene acid, exhibiting broad anticancer effects. Nanoparticulate drug delivery systems have been known to better the bioavailability of drugs on intranasal administration compared with only drug solutions. Administration of ursolic acid nanoparticles is thought to be sufficient to lead to considerable suppression of cervical cancer progression. We loaded gold-ursolic acid into poly(DL-lactide-co-glycolide) nanoparticles to cervical cancer cell lines due to the properties of ursolic acid in altering cellular processes and the easier absorbance of nanoparticles. In addition, in this study, ursolic acid nanoparticles were administered to cervical cancer cells to find effective treatments for cervical cancer inhibition. In the present study, ELISA, western blotting, flow cytometry and immunohistochemistry assays were carried out to calculate the molecular mechanism by which ursolic acid nanoparticles modulated cervical cancer progression. Data indicated that ursolic acid nanoparticles, indeed, significantly suppress cervial cancer cell proliferation, invasion and migration compared to the control group, and apoptosis was induced by ursolic acid nanoparticles in cervical cancer cells through activating caspases, p53 and suppressing anti-apoptosis-related signals. Furthermore, tumor size was reduced by treatment of ursolic acid nanoparticles in in vivo experiments. In conclusion, this study suggests that ursolic acid nanoparticles inhibited cervical cancer cell proliferation via apoptosis induction, which could be a potential target for future therapeutic strategy clinically.
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Affiliation(s)
- Shaoguang Wang
- Department of Gynecology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Xiaomei Meng
- Department of Gynecology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Yaozhong Dong
- Department of Gynecology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
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39
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You J, Wu D, Zhao M, Li G, Gong P, Wu Y, Guo Y, Chen G, Zhao X, Sun Z, Xia L, Wu Y. Development of a facile and sensitive HPLC-FLD method via fluorescence labeling for triterpenic acid bioavailability investigation. Biomed Chromatogr 2017; 31. [DOI: 10.1002/bmc.3894] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 10/28/2016] [Accepted: 11/08/2016] [Indexed: 01/17/2023]
Affiliation(s)
- Jinmao You
- Key Laboratory of Life-Organic Analysis of Shandong Province; Qufu Normal University; Qufu People's Republic of China
| | - Di Wu
- School of Life Sciences; Xiamen University; Xiamen China
| | - Mei Zhao
- Key Laboratory of Life-Organic Analysis of Shandong Province; Qufu Normal University; Qufu People's Republic of China
| | - Guoliang Li
- Key Laboratory of Life-Organic Analysis of Shandong Province; Qufu Normal University; Qufu People's Republic of China
- Key Laboratory of Food Safety Risk Assessment, Ministry of Health; China National Centre for Food Safety Risk Assessment; Beijing China
| | - Peiwei Gong
- Key Laboratory of Life-Organic Analysis of Shandong Province; Qufu Normal University; Qufu People's Republic of China
| | - Yueyue Wu
- Key Laboratory of Life-Organic Analysis of Shandong Province; Qufu Normal University; Qufu People's Republic of China
| | - Yu Guo
- Key Laboratory of Life-Organic Analysis of Shandong Province; Qufu Normal University; Qufu People's Republic of China
| | - Guang Chen
- Key Laboratory of Life-Organic Analysis of Shandong Province; Qufu Normal University; Qufu People's Republic of China
| | - Xianen Zhao
- Key Laboratory of Life-Organic Analysis of Shandong Province; Qufu Normal University; Qufu People's Republic of China
| | - Zhiwei Sun
- Key Laboratory of Life-Organic Analysis of Shandong Province; Qufu Normal University; Qufu People's Republic of China
| | - Lian Xia
- Key Laboratory of Life-Organic Analysis of Shandong Province; Qufu Normal University; Qufu People's Republic of China
| | - Yongning Wu
- Key Laboratory of Food Safety Risk Assessment, Ministry of Health; China National Centre for Food Safety Risk Assessment; Beijing China
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40
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Lu YX, Chen DL, Wang DS, Chen LZ, Mo HY, Sheng H, Bai L, Wu QN, Yu HE, Xie D, Yun JP, Zeng ZL, Wang F, Ju HQ, Xu RH. Melatonin enhances sensitivity to fluorouracil in oesophageal squamous cell carcinoma through inhibition of Erk and Akt pathway. Cell Death Dis 2016; 7:e2432. [PMID: 27787516 PMCID: PMC5133993 DOI: 10.1038/cddis.2016.330] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2016] [Revised: 08/22/2016] [Accepted: 09/15/2016] [Indexed: 02/06/2023]
Abstract
Oesophageal squamous cell carcinoma (ESCC) is the sixth most common cause of cancer-associated death in the world and novel therapeutic alternatives are urgently warranted. In this study, we investigated the anti-tumour activity and underlying mechanisms of melatonin, an indoleamine compound secreted by the pineal gland as well as naturally occurring plant products, in ESCC cells and revealed that melatonin inhibited proliferation, migration, invasion and induced mitochondria-dependent apoptosis of ESCC cells in vitro and suppressed tumour growth in the subcutaneous mice model in vivo. Furthermore, after treatment with melatonin, the expressions of pMEK, pErk, pGSK3β and pAkt were significantly suppressed. In contrast, treatment of the conventional chemotherapeutic drug fluorouracil (5-Fu) resulted in activation of Erk and Akt, which could be reversed by co-treatment with melatonin. Importantly, melatonin effectively enhanced cytotoxicity of 5-Fu to ESCC in vitro and in vivo. Together, these results suggested that inhibition of Erk and Akt pathway by melatonin have an important role in sensitization of ESCC cells to 5-Fu. Combined 5-Fu and melatonin treatment may be appreciated as a useful approach for ESCC therapy that warrants further investigation.
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Affiliation(s)
- Yun-Xin Lu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Dong-Liang Chen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - De-Shen Wang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Le-Zong Chen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Hai-Yu Mo
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Hui Sheng
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Long Bai
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Qi-Nian Wu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Hong-En Yu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Dan Xie
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Jing-Ping Yun
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.,Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Zhao-Lei Zeng
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Feng Wang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Huai-Qiang Ju
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Rui-Hua Xu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
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41
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Lu YX, Chen DL, Wang DS, Chen LZ, Mo HY, Sheng H, Bai L, Wu QN, Yu HE, Xie D, Yun JP, Zeng ZL, Wang F, Ju HQ, Xu RH. Melatonin enhances sensitivity to fluorouracil in oesophageal squamous cell carcinoma through inhibition of Erk and Akt pathway. Cell Death Dis 2016. [PMID: 27787516 DOI: 10.1038/cddis.2016.330.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Oesophageal squamous cell carcinoma (ESCC) is the sixth most common cause of cancer-associated death in the world and novel therapeutic alternatives are urgently warranted. In this study, we investigated the anti-tumour activity and underlying mechanisms of melatonin, an indoleamine compound secreted by the pineal gland as well as naturally occurring plant products, in ESCC cells and revealed that melatonin inhibited proliferation, migration, invasion and induced mitochondria-dependent apoptosis of ESCC cells in vitro and suppressed tumour growth in the subcutaneous mice model in vivo. Furthermore, after treatment with melatonin, the expressions of pMEK, pErk, pGSK3β and pAkt were significantly suppressed. In contrast, treatment of the conventional chemotherapeutic drug fluorouracil (5-Fu) resulted in activation of Erk and Akt, which could be reversed by co-treatment with melatonin. Importantly, melatonin effectively enhanced cytotoxicity of 5-Fu to ESCC in vitro and in vivo. Together, these results suggested that inhibition of Erk and Akt pathway by melatonin have an important role in sensitization of ESCC cells to 5-Fu. Combined 5-Fu and melatonin treatment may be appreciated as a useful approach for ESCC therapy that warrants further investigation.
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Affiliation(s)
- Yun-Xin Lu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Dong-Liang Chen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - De-Shen Wang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Le-Zong Chen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Hai-Yu Mo
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Hui Sheng
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Long Bai
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Qi-Nian Wu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Hong-En Yu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Dan Xie
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Jing-Ping Yun
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.,Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Zhao-Lei Zeng
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Feng Wang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Huai-Qiang Ju
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Rui-Hua Xu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
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42
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Prasad S, Yadav VR, Sung B, Gupta SC, Tyagi AK, Aggarwal BB. Ursolic acid inhibits the growth of human pancreatic cancer and enhances the antitumor potential of gemcitabine in an orthotopic mouse model through suppression of the inflammatory microenvironment. Oncotarget 2016; 7:13182-96. [PMID: 26909608 PMCID: PMC4914350 DOI: 10.18632/oncotarget.7537] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 01/06/2016] [Indexed: 12/29/2022] Open
Abstract
The development of chemoresistance in human pancreatic cancer is one reason for the poor survival rate for patients with this cancer. Because multiple gene products are linked with chemoresistance, we investigated the ability of ursolic acid (UA) to sensitize pancreatic cancer cells to gemcitabine, a standard drug used for the treatment of pancreatic cancer. These investigations were done in AsPC-1, MIA PaCa-2, and Panc-28 cells and in nude mice orthotopically implanted with Panc-28 cells. In vitro, UA inhibited proliferation, induced apoptosis, suppressed NF-κB activation and its regulated proliferative, metastatic, and angiogenic proteins. UA (20 μM) also enhanced gemcitabine (200 nM)-induced apoptosis and suppressed the expression of NF-κB-regulated proteins. In the nude mouse model, oral administration of UA (250 mg/kg) suppressed tumor growth and enhanced the effect of gemcitabine (25 mg/kg). Furthermore, the combination of UA and gemcitabine suppressed the metastasis of cancer cells to distant organs such as liver and spleen. Immunohistochemical analysis showed that biomarkers of proliferation (Ki-67) and microvessel density (CD31) were suppressed by the combination of UA and gemcitabine. UA inhibited the activation of NF-κB and STAT3 and the expression of tumorigenic proteins regulated by these inflammatory transcription factors in tumor tissue. Furthermore, the combination of two agents decreased the expression of miR-29a, closely linked with tumorigenesis, in the tumor tissue. UA was found to be bioavailable in animal serum and tumor tissue. These results suggest that UA can inhibit the growth of human pancreatic tumors and sensitize them to gemcitabine by suppressing inflammatory biomarkers linked to proliferation, invasion, angiogenesis, and metastasis.
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Affiliation(s)
- Sahdeo Prasad
- Department of Experimental Therapeutics, Cytokine Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vivek R. Yadav
- Department of Experimental Therapeutics, Cytokine Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bokyung Sung
- Department of Experimental Therapeutics, Cytokine Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Subash C. Gupta
- Department of Experimental Therapeutics, Cytokine Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Amit K. Tyagi
- Department of Experimental Therapeutics, Cytokine Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bharat B. Aggarwal
- Department of Experimental Therapeutics, Cytokine Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Anti-inflammatory Research Institute, San Deigo, CA, USA
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43
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Ali-Seyed M, Jantan I, Vijayaraghavan K, Bukhari SNA. Betulinic Acid: Recent Advances in Chemical Modifications, Effective Delivery, and Molecular Mechanisms of a Promising Anticancer Therapy. Chem Biol Drug Des 2015; 87:517-36. [PMID: 26535952 DOI: 10.1111/cbdd.12682] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
An important method of drug discovery is examination of diverse life forms, including medicinal plants and natural products or bioactive compounds isolated from these sources. In cancer research, lead structures of compounds from natural sources can be used to design novel chemotherapies with enhanced biological properties. Betulinic acid (3β-hydroxy-lup-20(29)-en-28-oic acid or BetA) is a naturally occurring pentacyclic triterpene with a wide variety of biological activities, including potent antitumor properties. Non-malignant cells and normal tissues are not affected by BetA. Because BetA exerts its effects directly on the mitochondrion and triggers death of cancerous cells, it is an important alternative when certain chemotherapy drugs fail. Mitochondrion-targeted agents such as BetA hold great promise to circumvent drug resistance in human cancers. BetA is being developed by a large network of clinical trial groups with the support of the U.S. National Cancer Institute. This article discusses recent advances in research into anticancer activity of BetA, relevant modes of delivery, and the agent's therapeutic efficacy, mechanism of action, and future perspective as a pipeline anticancer drug. BetA is a potentially important agent in cancer therapeutics.
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Affiliation(s)
- Mohamed Ali-Seyed
- Faculty of Pharmacy, Universiti, Kebangsaan Malaysia (UKM), The National University of Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, 50300, Malaysia.,School of Life Sciences, B.S. Abdur Rahman University, Vandalur, Chennai, 600048, India
| | - Ibrahim Jantan
- Faculty of Pharmacy, Universiti, Kebangsaan Malaysia (UKM), The National University of Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, 50300, Malaysia
| | | | - Syed Nasir Abbas Bukhari
- Faculty of Pharmacy, Universiti, Kebangsaan Malaysia (UKM), The National University of Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, 50300, Malaysia
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44
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Tétreault MP. Esophageal Cancer: Insights From Mouse Models. CANCER GROWTH AND METASTASIS 2015; 8:37-46. [PMID: 26380556 PMCID: PMC4558891 DOI: 10.4137/cgm.s21218] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 07/15/2015] [Accepted: 07/17/2015] [Indexed: 12/30/2022]
Abstract
Esophageal cancer is the eighth leading cause of cancer and the sixth most common cause of cancer-related death worldwide. Despite recent advances in the development of surgical techniques in combination with the use of radiotherapy and chemotherapy, the prognosis for esophageal cancer remains poor. The cellular and molecular mechanisms that drive the pathogenesis of esophageal cancer are still poorly understood. Hence, understanding these mechanisms is crucial to improving outcomes for patients with esophageal cancer. Mouse models constitute valuable tools for modeling human cancers and for the preclinical testing of therapeutic strategies in a manner not possible in human subjects. Mice are excellent models for studying human cancers because they are similar to humans at the physiological and molecular levels and because they have a shorter gestation time and life cycle. Moreover, a wide range of well-developed technologies for introducing genetic modifications into mice are currently available. In this review, we describe how different mouse models are used to study esophageal cancer.
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Affiliation(s)
- Marie-Pier Tétreault
- Department of Medicine, Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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45
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Delebinski CI, Twardziok M, Kleinsimon S, Hoff F, Mulsow K, Rolff J, Jäger S, Eggert A, Seifert G. A Natural Combination Extract of Viscum album L. Containing Both Triterpene Acids and Lectins Is Highly Effective against AML In Vivo. PLoS One 2015; 10:e0133892. [PMID: 26244918 PMCID: PMC4526680 DOI: 10.1371/journal.pone.0133892] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 07/02/2015] [Indexed: 12/28/2022] Open
Abstract
Aqueous Viscum album L. extracts are widely used in complementary cancer medicine. Hydrophobic triterpene acids also possess anti-cancer properties, but due to their low solubility they do not occur in significant amounts in aqueous extracts. Using cyclodextrins we solubilised mistletoe triterpenes (mainly oleanolic acid) and investigated the effect of a mistletoe whole plant extract on human acute myeloid leukaemia cells in vitro, ex vivo and in vivo. Single Viscum album L. extracts containing only solubilised triterpene acids (TT) or lectins (viscum) inhibited cell proliferation and induced apoptosis in a dose-dependent manner in vitro and ex vivo. The combination of viscum and TT extracts (viscumTT) enhanced the induction of apoptosis synergistically. The experiments demonstrated that all three extracts are able to induce apoptosis via caspase-8 and -9 dependent pathways with down-regulation of members of the inhibitor of apoptosis and Bcl-2 families of proteins. Finally, the acute myeloid leukaemia mouse model experiment confirmed the therapeutic effectiveness of viscumTT-treatment resulting in significant tumour weight reduction, comparable to the effect in cytarabine-treated mice. These results suggest that the combination viscumTT may have a potential therapeutic value for the treatment AML.
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Affiliation(s)
- Catharina I. Delebinski
- Department of Paediatric Oncology/Haematology, Otto Heubner Centre for Paediatric and Adolescent Medicine (OHC), Charité –Universitaetsmedizin, Berlin, Germany
| | - Monika Twardziok
- Department of Paediatric Oncology/Haematology, Otto Heubner Centre for Paediatric and Adolescent Medicine (OHC), Charité –Universitaetsmedizin, Berlin, Germany
| | - Susann Kleinsimon
- Department of Paediatric Oncology/Haematology, Otto Heubner Centre for Paediatric and Adolescent Medicine (OHC), Charité –Universitaetsmedizin, Berlin, Germany
| | - Florian Hoff
- Department of Cell Biology and Cell Pathology, Philipps University, Marburg, Germany
| | | | | | | | - Angelika Eggert
- Department of Paediatric Oncology/Haematology, Otto Heubner Centre for Paediatric and Adolescent Medicine (OHC), Charité –Universitaetsmedizin, Berlin, Germany
| | - Georg Seifert
- Department of Paediatric Oncology/Haematology, Otto Heubner Centre for Paediatric and Adolescent Medicine (OHC), Charité –Universitaetsmedizin, Berlin, Germany
- * E-mail:
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46
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Sharma K, Zafar R. Occurrence of taraxerol and taraxasterol in medicinal plants. Pharmacogn Rev 2015; 9:19-23. [PMID: 26009688 PMCID: PMC4441157 DOI: 10.4103/0973-7847.156317] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2014] [Revised: 05/25/2014] [Accepted: 05/05/2015] [Indexed: 01/28/2023] Open
Abstract
Indian soil germinates thousands of medicinal drugs that are cultivated with a purpose to obtain a novel drug. As it is a well-established fact that the structural analogs with greater pharmacological activity and fewer side-effects may be generated by the molecular modification of the functional groups of such lead compounds. This review throws light on two natural triterpenes - Taraxerol and Taraxasterol which have many important pharmacological actions including anti-cancer activity, their chemistry, biosynthesis aspects, and possible use of these compounds as drugs in treatment of cancer. A silent crisis persists in cancer treatment in developing countries, and it is intensifying every year. Although at least 50-60% of cancer victims can benefit from radiotherapy that destroys cancerous tumors, but search for the paramount therapy which will prove to be inexpensive with minimal side effects still persists. Various treatment modalities have been prescribed, along with conventional and non-conventional medicine but due to their adverse effects and dissatisfaction among users, these treatments are not satisfactory enough to give relief to patients. Hence, this review sparks the occurrence of Taraxerol (VI) and Taraxasterol (VII) in nature, so that the natural godowns may be harvested to obtain these potent compounds for novel drug development as well as discusses limitations of these lead compounds progressing clinical trials.
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Affiliation(s)
- Kiran Sharma
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India
| | - Rasheeduz Zafar
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India
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47
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Ng PL, Rajab NF, Then SM, Mohd Yusof YA, Wan Ngah WZ, Pin KY, Looi ML. Piper betle leaf extract enhances the cytotoxicity effect of 5-fluorouracil in inhibiting the growth of HT29 and HCT116 colon cancer cells. J Zhejiang Univ Sci B 2015; 15:692-700. [PMID: 25091987 DOI: 10.1631/jzus.b1300303] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The combination effect of Piper betle (PB) and 5-fluorouracil (5-FU) in enhancing the cytotoxic potential of 5-FU in inhibiting the growth of colon cancer cells was investigated. METHODS HT29 and HCT116 cells were subjected to 5-FU or PB treatment. 5-FU and PB were then combined and their effects on both cell lines were observed after 24 h of treatment. PB-5-FU interaction was elucidated by isobologram analysis. Apoptosis features of the treated cells were revealed by annexin V/PI stain. High-performance liquid chromatography (HPLC) was performed to exclude any possible chemical interaction between the compounds. RESULTS In the presence of PB extract, the cytotoxicity of 5-FU was observed at a lower dose (IC50 12.5 µmol/L) and a shorter time (24 h) in both cell lines. Both cell lines treated with 5-FU or PB alone induced a greater apoptosis effect compared with the combination treatment. Isobologram analysis indicated that PB and 5-FU interacted synergistically and antagonistically in inhibiting the growth of HT29 and HCT116 cells, respectively. CONCLUSIONS In the presence of PB, a lower dosage of 5-FU is required to achieve the maximum drug effect in inhibiting the growth of HT29 cells. However, PB did not significantly reduce 5-FU dosage in HCT116 cells. Our result showed that this interaction may not solely contribute to the apoptosis pathway.
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Affiliation(s)
- Pek Leng Ng
- Department of Biomedical Sciences, Faculty of Allied Health, Universiti Kebangsaan Malaysia (UKM), Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia; UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Jalan Yaacob Latiff, Bandar Tun Razak, Cheras, 56000 Kuala Lumpur, Malaysia; School of Biomedical Science, University of Nottingham Malaysia Campus, 43500 Semenyih, Selangor, Malaysia; Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia (UKM), Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia; Forest Research Institute Malaysia (FRIM), 52109 Kuala Lumpur, Kepong, Malaysia; School of Biosciences, Taylor's University, Lakeside Campus, 47500 Subang Jaya, Selangor, Malaysia
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Rada M, Castellano JM, Perona JS, Guinda Á. GC-FID determination and pharmacokinetic studies of oleanolic acid in human serum. Biomed Chromatogr 2015; 29:1687-92. [PMID: 25943913 DOI: 10.1002/bmc.3480] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Revised: 02/27/2015] [Accepted: 03/20/2015] [Indexed: 12/31/2022]
Abstract
Analytical interest of OA determination in human serum has increased owing to the increasing interest in pharmaceutical research by pharmaceutical properties. A simple, specific, precise and accurate GC method with flame ionization detector (FID) developed and validated for the determination of oleanolic acid (OA) in human serum (HS). To an aliquot of HS, internal standard was added and a combination of liquid-liquid extraction with a mixture of diethyl ether-isopropyl alcohol, filtration and consecutive GC resulted in separation and quantification of OA. The organic phase was analyzed using a GC system equipped with a 30 × 0.25 mm i.d. Rtx-65TG capillary column and FID detection. Total chromatographic time was 10 min and no interfering peaks from endogenous components in blank serum were observed. The OA/internal standard peak area ratio was linearly fitted to the OA concentration (r = 0.992) over the range 10-1500 ng/mL. The mean serum extraction recovery of OA was 96.7 ± 1.0% and the lower limit of quantification based on 5 mL of serum was 10.7 ng/mL. The intra-day coefficient of variation ranged from 1.3 to 3.6% and inter-day varied from 1.4 to 4.5%. The developed method was used to study the pharmacokinetics of OA after oral administration in humans. The assay was simple, sensitive, precise and accurate for the use in the study of the mechanisms of absorption and distribution of OA in humans.
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Affiliation(s)
- Mirela Rada
- Food and Health Department, Instituto de la Grasa - CSIC, Avda Padre García Tejero, 4., 41012, Seville, Spain
| | - José María Castellano
- Food and Health Department, Instituto de la Grasa - CSIC, Avda Padre García Tejero, 4., 41012, Seville, Spain
| | - Javier S Perona
- Food and Health Department, Instituto de la Grasa - CSIC, Avda Padre García Tejero, 4., 41012, Seville, Spain
| | - Ángeles Guinda
- Food and Health Department, Instituto de la Grasa - CSIC, Avda Padre García Tejero, 4., 41012, Seville, Spain
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New Insights into Antimetastatic and Antiangiogenic Effects of Cannabinoids. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2015; 314:43-116. [DOI: 10.1016/bs.ircmb.2014.10.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
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