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Mei H, Yang J, Hao J, Ding Y, Wan X, Dong M, Zhang X, Luo L, Xiong T, Wang L, Yang T, Huang C. Mechanism of ethyl acetate fraction of Amorphophallus konjac against breast cancer based on network pharmacology, molecular docking and experimental validation. JOURNAL OF ETHNOPHARMACOLOGY 2025; 345:119648. [PMID: 40107477 DOI: 10.1016/j.jep.2025.119648] [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: 01/10/2025] [Revised: 02/19/2025] [Accepted: 03/16/2025] [Indexed: 03/22/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Amorphophallus konjac (Sheliugu), a medicinal and edible herb from East China and regions south of the Yangtze River, exhibits significant antitumor activity. However, its active constituents and mechanisms remain poorly understood. AIMS OF THE STUDY This study explores the therapeutic effects of the konjac ethyl acetate fraction (KEAF) in triple-negative breast cancer (TNBC) and elucidates its underlying mechanisms. MATERIALS AND METHODS UPLC-MS/MS identified KEAF's chemical components, and network pharmacology determined its key targets in TNBC. Survival curves of essential genes were analyzed using UALCAN, bc-GenExMiner, and Kaplan-Meier plotter databases. Protein expression and prognostic data identified TNBC-linked genes. Molecular docking assessed binding affinities of KEAF's bioactive components with these genes. In vitro experiments validated KEAF's effects on proliferation, migration, cell cycle regulation, and apoptosis. RESULTS KEAF contained 15 active compounds and 146 principal targets, with eight key targets identified: TP53, EGFR, AKT1, MYC, STAT3, HIF1A, ESR1, and JUN. GO and KEGG enrichment analyses highlighted the PI3K/Akt signaling pathway as central to KEAF's therapeutic effects. Protein expression and prognostic studies confirmed EGFR and ESR1 as critical in TNBC progression. Molecular docking revealed strong binding of scutellarein and genistein to EGFR and ESR1 (T score >5). In vitro, KEAF inhibited MDA-MB-231 cell proliferation and migration, modulated the cell cycle, and induced apoptosis by downregulating PI3K/Akt signaling. CONCLUSION Scutellarein and genistein in KEAF exhibit therapeutic potential against TNBC by targeting EGFR and ESR1 and suppressing the PI3K/Akt signaling pathway.
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Affiliation(s)
- Huimin Mei
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, PR China
| | - Jinglong Yang
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, PR China
| | - Jiapeng Hao
- Bijie Hospital of Traditional Chinese Medicine, Bijie, 551700, PR China
| | - Yushan Ding
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, PR China
| | - Xinliang Wan
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, PR China
| | - Minghong Dong
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, PR China
| | - Xudong Zhang
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, PR China
| | - Liying Luo
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, PR China
| | - Tongtong Xiong
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, PR China
| | - Lu Wang
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, PR China
| | - Tianming Yang
- Bijie Hospital of Traditional Chinese Medicine, Bijie, 551700, PR China.
| | - Cong Huang
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, PR China; Anshun Hospital of Traditional Chinese Medicine, Anshun, 561000, PR China.
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Sen K, Kumar Das S, Ghosh N, Sinha K, Sil PC. Lupeol: A dietary and medicinal triterpene with therapeutic potential. Biochem Pharmacol 2024; 229:116545. [PMID: 39293501 DOI: 10.1016/j.bcp.2024.116545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 09/04/2024] [Accepted: 09/13/2024] [Indexed: 09/20/2024]
Abstract
Lupeol, a triterpene derived from various plants, has emerged as a potent dietary supplement with extensive therapeutic potential. This review offers a comprehensive examination of lupeol's applications across diverse health conditions. By meticulously analyzing current scientific literature, we have synthesized findings that underscore lupeol's impact on cancer, diabetes, gastrointestinal disorders, neurological diseases, dermatological conditions, nephrological issues, and cardiovascular health. The review delves into molecular studies that reveal lupeol's ability to modulate disease pathways and alleviate symptoms, positioning it as a promising therapeutic agent. Moreover, we discuss the potential role of lupeol in clinical practice and public health strategies, emphasizing its substantial benefits as a natural compound. This thorough analysis serves as a critical resource for researchers, providing insights into the multifaceted therapeutic properties of lupeol and its potential to significantly enhance health outcomes.
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Affiliation(s)
- Koushik Sen
- Jhargram Raj College, Jhargram 721507, India
| | | | | | | | - Parames C Sil
- Division of Molecular Medicine, Bose Institute, Kolkata 700054, India.
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Fatma H, Jameel M, Siddiqui AJ, Kuddus M, Buali NS, Bahrini I, Siddique HR. Chemotherapeutic potential of lupeol against cancer in pre-clinical model: A systematic review and meta-analysis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 132:155777. [PMID: 38943695 DOI: 10.1016/j.phymed.2024.155777] [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: 03/25/2024] [Revised: 05/11/2024] [Accepted: 05/22/2024] [Indexed: 07/01/2024]
Abstract
BACKGROUND Extensive research on Lupeol's potential in cancer prevention highlights its ability to target various cancer-related factors. It regulates proliferative markers, modulates signaling pathways, including PI3K/AKT/mTOR, and influences inflammatory and apoptotic mechanisms. Additionally, Lupeol demonstrates selectivity in killing cancer cells while sparing normal cells, thus minimizing the risk of toxic effects on healthy tissues. HYPOTHESIS Therefore, we aimed to explore Lupeol's potential roles as a chemotherapeutic agent and as a sensitizer to chemotherapy by reviewing various animal-based studies published on its effects. STUDY DESIGN We conducted a comprehensive search across databases, including PubMed, PMC, Cochrane, EuroPMC, and ctri.gov.in to identify pertinent articles. Our focus was solely on published animal studies examining Lupeol's anti-cancer effects, with reviewers independently assessing bias risk and resolving discrepancies through consensus. RESULT 20 studies were shortlisted. The results demonstrated that Lupeol brings changes in the tumor volume by [Hedges's g: -6.62; 95 % CI: -8.68, -4.56; τ2: 24.36, I2: 96.50 %; p < 0.05] and tumor weight by [Hedges's g: -3.97; 95 % CI: -5.20, -2.49; τ2: 2.70, I2: 79.27 %; p <0.05]. The high I2, negative Egger's value, and asymmetrical funnel plot show the publication bias among the studies. Further, Lupeol in combination with other chemotherapeutic agents showed better outcomes as compared to them alone [Hedges's g: -6.38; 95 % CI: -11.82, -0.94; τ2: 46.91; I2: 98.68 %; p <0.05]. Lupeol also targets various signaling molecules and pathways to exert an anti-cancer effect. CONCLUSION In conclusion, Lupeol significantly reduces tumor volume and weight. Combining Lupeol with other chemotherapy agents shows promise for enhancing anti-cancer effects. However, high variability among studies and evidence of publication bias suggest caution in interpreting results.
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Affiliation(s)
- Homa Fatma
- Molecular Cancer Genetics & Translational Research Laboratory, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh-202002, Uttar Pradesh, India
| | - Mohd Jameel
- Molecular Cancer Genetics & Translational Research Laboratory, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh-202002, Uttar Pradesh, India
| | - Arif Jamal Siddiqui
- Department of Biology, College of Science, University of Ha'il, Hail, PO Box 2440, Kingdom of Saudi Arabia.
| | - Mohammed Kuddus
- Department of Biochemistry, College of Medicine, University of Ha'il, Hail, Kingdom of Saudi Arabia
| | - Nouha Saleh Buali
- Department of Biology, College of Science, University of Ha'il, Hail, PO Box 2440, Kingdom of Saudi Arabia
| | - Insaf Bahrini
- Department of Biology, College of Science, University of Ha'il, Hail, PO Box 2440, Kingdom of Saudi Arabia
| | - Hifzur R Siddique
- Molecular Cancer Genetics & Translational Research Laboratory, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh-202002, Uttar Pradesh, India.
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Yue X, Ling Ma N, Zhong J, Yang H, Chen H, Yang Y, Lam SS, Yan L, Styrishave B, Ciesielski TM, Peng WX, Sonne C. Ancient forest plants possess cytotoxic properties causing liver cancer HepG2 cell apoptosis. ENVIRONMENTAL RESEARCH 2024; 241:117474. [PMID: 37879390 DOI: 10.1016/j.envres.2023.117474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 10/20/2023] [Accepted: 10/21/2023] [Indexed: 10/27/2023]
Abstract
Here, we collected 154 plant species in China ancient forests looking for novel efficient bioactive compounds for cancer treatments. We found 600 bioactive phyto-chemicals that induce apoptosis of liver cancer cell in vitro. First, we screen the plant extract's in vitro cytotoxicity inhibition of cancer cell growth using in vitro HepG2 cell lines and MTT cytotoxicity. The results from these initial MTT in vitro cytotoxicity tests show that the most efficient plants towards hepatoma cytoxicity is Cephalotaxus sinensis, mint bush (Elsholtzia stauntonii) and winged spindle tree (Euonymus alatus). We then used in cell-counting kit-8 (CCK-8) to further understand in vivo tumor growth using nude mice and GC-MS and LC-QTOF-MS to analyze the composition of compounds in the extracts. Extracted chemically active molecules analyzed by network pharmacology showed inhibition on the growth of liver cancer cells by acting on multiple gene targets, which is different from the currently used traditional drugs acting on only one target of liver cancer cells. Extracts from Cephalotaxus sinensis, mint bush (Elsholtzia stauntonii) and winged spindle tree (Euonymus alatus) induce apoptosis in hepatoma cancer cell line HepG2 with a killing rate of more than 83% and a tumor size decrease by 62-67% and a killing rate of only 6% of normal hepatocyte LO2. This study highlight efficient candidate species for cancer treatment providing a basis for future development of novel plant-based drugs to help meeting several of the UN SDGs and planetary health.
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Affiliation(s)
- Xiaochen Yue
- Henan Province Engineering Research Center for Biomass Value-added Products, Forestry College, Henan Agricultural University, Zhengzhou, 450002, China
| | - Nyuk Ling Ma
- BIOSES Research Interest Group, Faculty of Science & Marine Environment, Universiti Malaysia Terengganu, 21030, Kuala Nerus, Terengganu, Malaysia; Center for Global Health Research (CGHR), Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, India
| | - Jiateng Zhong
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Han Yang
- Henan Province Engineering Research Center for Biomass Value-added Products, Forestry College, Henan Agricultural University, Zhengzhou, 450002, China
| | - Huiling Chen
- Henan Province Engineering Research Center for Biomass Value-added Products, Forestry College, Henan Agricultural University, Zhengzhou, 450002, China
| | - Yafeng Yang
- Henan Province Engineering Research Center for Biomass Value-added Products, Forestry College, Henan Agricultural University, Zhengzhou, 450002, China
| | - Su Shiung Lam
- Higher Institution Centre of Excellence (HICoE), Institute of Tropical Aquaculture and Fisheries (AKUATROP), Universiti Malaysia Terengganu, 21030, Kuala Nerus, Terengganu, Malaysia; Department of Chemical Engineering and Materials Science, Yuan Ze University, Taoyuan, Taiwan
| | - Lijun Yan
- Henan Province Engineering Research Center for Biomass Value-added Products, Forestry College, Henan Agricultural University, Zhengzhou, 450002, China
| | - Bjarne Styrishave
- Toxicology and Drug Metabolism Group, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Denmark
| | - Tomasz Maciej Ciesielski
- Department of Biology, Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491, Trondheim, Norway; Department of Arctic Technology, The University Center in Svalbard, 9171, Longyearbyen, Norway
| | - Wan-Xi Peng
- Henan Province Engineering Research Center for Biomass Value-added Products, Forestry College, Henan Agricultural University, Zhengzhou, 450002, China.
| | - Christian Sonne
- Aarhus University, Department of Ecoscience, Arctic Research Centre (ARC), Frederiksborgvej 399, PO Box 358, DK-4000, Roskilde, Denmark; Sustainability Cluster, School of Engineering, University of Petroleum & Energy Studies, Dehradun, Uttarakhand, 248007, India.
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Zhou L, Zhao Y, Pan LC, Wang J, Shi XJ, Du GS, He Q. Sirolimus increases the anti-cancer effect of Huai Er by regulating hypoxia inducible factor-1α-mediated glycolysis in hepatocellular carcinoma. World J Gastroenterol 2022; 28:4600-4619. [PMID: 36157928 PMCID: PMC9476881 DOI: 10.3748/wjg.v28.i32.4600] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 01/11/2022] [Accepted: 07/16/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Glycolysis caused by hypoxia-induced abnormal activation of hypoxia inducible factor-1α (HIF-1α) in the immune microenvironment promotes the progression of hepatocellular carcinoma (HCC), leading to enhanced drug resistance in cancer cells. Therefore, altering the immunosuppressive microenvironment by imp-roving the hypoxic state is a new goal in improving cancer treatment. AIM To analyse the role of HIF-1α, which is closely related to tumour proliferation, invasion, metastasis, and angiogenesis, in the proliferation and invasion of liver cancer, and to explore the HIF-1α pathway-mediated anti-cancer mechanism of sirolimus (SRL) combined with Huai Er. METHODS Previous studies on HCC tissues identified the importance of HIF-1α, glucose transporter 1 (GLUT1), and lactate dehydrogenase A (LDHA) expression. In this study, HepG2 and Huh7 cell lines were treated, under hypoxic and normoxic conditions, with a combination of SRL and Huai Er. The effects on proliferation, invasion, cell cycle, and apoptosis were analysed. Proteomics and genomics techniques were used to analyze the HIF-1α-related signalling pathway during SRL combined with Huai Er treatment and its inhibition of the proliferation of HCC cells. RESULTS High levels of HIF-1α, LDHA, and GLUT-1 were found in poorly differentiated HCC, with lower patient survival rates. Hypoxia promoted the proliferation of HepG2 and Huh7 cells and weakened the apoptosis and cell cycle blocking effects of the SRL/Huai Er treatment. This was achieved by activation of HIF-1α and glycolysis in HCC, leading to the upregulation of LDHA, GLUT-1, Akt/mammalian target of rapamycin (mTOR), vascular endothelial growth factor (VEGF), and Forkhead box P3 and downregulation of phosphatase and tensin homolog deleted on chromosome ten (PTEN) and p27. The hypoxia-induced activation of HIF-1α showed the greatest attenuation in the SRL/Huai Er (S50 + H8) group compared to the drug treatments alone (P < 0.001). The S50 + H8 treatment significantly downregulated the expression of mTOR and HIF-1α, and significantly reduced the expression of VEGF mRNA. Meanwhile, the combined blocking of mTOR and HIF-1α enhanced the downregulation of Akt/mTOR, HIF-1α, LDHA, and GLUT-1 mRNA and resulted in the downregulation of PTEN, p27, and VEGF mRNA (P < 0.001). CONCLUSION SRL increases the anti-cancer effect of Huai Er, which reduces the promotion of hypoxia-induced HIF-1α on the Warburg effect by inhibition of the PI3K/Akt/mTOR-HIF-1α and HIF-1α-PTEN signalling pathways in HCC.
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Affiliation(s)
- Lin Zhou
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing ChaoYang Hospital, Capital Medical University, Beijing 100020, China
| | - Yang Zhao
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing ChaoYang Hospital, Capital Medical University, Beijing 100020, China
| | - Li-Chao Pan
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Jing Wang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing ChaoYang Hospital, Capital Medical University, Beijing 100020, China
| | - Xian-Jie Shi
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Guo-Sheng Du
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Qiang He
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing ChaoYang Hospital, Capital Medical University, Beijing 100020, China
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Nisar S, Masoodi T, Prabhu KS, Kuttikrishnan S, Zarif L, Khatoon S, Ali S, Uddin S, Akil AAS, Singh M, Macha MA, Bhat AA. Natural products as chemo-radiation therapy sensitizers in cancers. Biomed Pharmacother 2022; 154:113610. [PMID: 36030591 DOI: 10.1016/j.biopha.2022.113610] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/24/2022] [Accepted: 08/24/2022] [Indexed: 11/02/2022] Open
Abstract
Cancer is a devastating disease and is the second leading cause of death worldwide. Surgery, chemotherapy (CT), and/or radiation therapy (RT) are the treatment of choice for most advanced tumors. Unfortunately, treatment failure due to intrinsic and acquired resistance to the current CT and RT is a significant challenge associated with poor patient prognosis. There is an urgent need to develop and identify agents that can sensitize tumor cells to chemo-radiation therapy (CRT) with minimal cytotoxicity to the healthy tissues. While many recent studies have identified the underlying molecular mechanisms and therapeutic targets for CRT failure, using small molecule inhibitors to chemo/radio sensitize tumors is associated with high toxicity and increased morbidity. Natural products have long been used as chemopreventive agents in many cancers. Combining many of these compounds with the standard chemotherapeutic agents or with RT has shown synergistic effects on cancer cell death and overall improvement in patient survival. Based on the available data, there is strong evidence that natural products have a robust therapeutic potential along with CRT and their well-known chemopreventive effects in many solid tumors. This review article reports updated literature on different natural products used as CT or RT sensitizers in many solid tumors. This is the first review discussing CT and RT sensitizers together in cancer.
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Affiliation(s)
- Sabah Nisar
- Depertment of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Tariq Masoodi
- Laboratory of Cancer immunology and genetics, Sidra Medicine, Qatar
| | - Kirti S Prabhu
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Qatar
| | - Shilpa Kuttikrishnan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Qatar
| | - Lubna Zarif
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Qatar
| | - Summaiya Khatoon
- Depertment of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Shahid Ali
- International Potato Center (CIP), Shillong, Meghalaya, India
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Qatar; Laboratory Animal Research Center, Qatar University, Doha, Qatar
| | - Ammira Al-Shabeeb Akil
- Depertment of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Mayank Singh
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, AIIMS, New Delhi, India.
| | - Muzafar A Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Awantipora, Jammu & Kashmir, India.
| | - Ajaz A Bhat
- Depertment of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar.
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Sohag AAM, Hossain MT, Rahaman MA, Rahman P, Hasan MS, Das RC, Khan MK, Sikder MH, Alam M, Uddin MJ, Rahman MH, Tahjib-Ul-Arif M, Islam T, Moon IS, Hannan MA. Molecular pharmacology and therapeutic advances of the pentacyclic triterpene lupeol. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 99:154012. [PMID: 35286936 DOI: 10.1016/j.phymed.2022.154012] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 02/14/2022] [Accepted: 02/25/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND Plant triterpenoids are major sources of nutraceuticals that provide many health benefits to humans. Lupeol is one of the pentacyclic dietary triterpenoids commonly found in many fruits and vegetables, which is highly investigated for its pharmacological effect and benefit to human health. PURPOSE This systematic review critically discussed the potential pharmacological benefits of lupeol and its derivatives as evidenced by various cellular and animal model studies. To gain insight into the pharmacological effects of lupeol, the network pharmacological approach is applied. Pharmacokinetics and recent developments in nanotechnology-based approaches to targeted delivery of lupeol along with its safety use are also discussed. METHODS This study is dependent on the systematic and non-exhaustive literature survey for related research articles, papers, and books on the chemistry, pharmacological benefits, pharmacokinetics, and safety of lupeol published between 2011 and 2021. For online materials, the popular academic search engines viz. Google Scholar, PubMed, Science Direct, Scopus, ResearchGate, Springer, as well as official websites were explored with selected keywords. RESULTS Lupeol has shown promising benefits in the management of cancer and many other human diseases such as diabetes, obesity, cardiovascular diseases, kidney and liver problems, skin diseases, and neurological disorders. The pharmacological effects of lupeol primarily rely on its capacity to revitalize the cellular antioxidant, anti-inflammatory and anti-apoptotic mechanisms. Network pharmacological approach revealed some prospective molecular targets and pathways and presented some significant information that could help explain the pharmacological effects of lupeol and its derivatives. Despite significant progress in molecular pharmacology, the clinical application of lupeol is limited due to poor bioavailability and insufficient knowledge on its mode of action. Structural modification and nanotechnology-guided targeted delivery of lupeol improve the bioavailability and bioactivity of lupeol. CONCLUSION The pentacyclic triterpene lupeol possesses numerous human health-benefiting properties. This review updates current knowledge and critically discusses the pharmacological effects and potential applications of lupeol and its derivatives in human health and diseases. Future studies are needed to evaluate the efficacies of lupeol and its derivatives in the management and pathobiology of human diseases.
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Affiliation(s)
- Abdullah Al Mamun Sohag
- Department of Biochemistry and Molecular Biology, Bangladesh Agricultural University, Mymensingh-2202, Bangladesh
| | - Md Tahmeed Hossain
- Department of Biochemistry and Molecular Biology, Bangladesh Agricultural University, Mymensingh-2202, Bangladesh
| | - Md Arifur Rahaman
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh
| | - Papia Rahman
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh
| | | | - Rakhal Chandra Das
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh
| | - Md Kibria Khan
- Department of Pharmacy, Stamford University Bangladesh, Dhaka, Bangladesh
| | - Mahmudul Hasan Sikder
- Department of Pharmacology, Bangladesh Agricultural University, Mymensingh-2202, Bangladesh
| | - Mahboob Alam
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Korea; Division of Chemistry and Biotechnology, Dongguk University, Gyeongju, 780-714, Korea
| | - Md Jamal Uddin
- ABEx Bio-Research Center, East Azampur, Dhaka-1230, Bangladesh; Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, 03760, Korea
| | - Md Hasanur Rahman
- Department of Biotechnology and Genetic Engineering, Faculty of Life Sciences, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
| | - Md Tahjib-Ul-Arif
- Department of Biochemistry and Molecular Biology, Bangladesh Agricultural University, Mymensingh-2202, Bangladesh
| | - Tofazzal Islam
- Institute of Biotechnology and Genetic Engineering (IBGE), Bangabandhu Sheikh Mujibur Rahman Agricultural University, Gazipur 1706, Bangladesh
| | - Il Soo Moon
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Korea
| | - Md Abdul Hannan
- Department of Biochemistry and Molecular Biology, Bangladesh Agricultural University, Mymensingh-2202, Bangladesh.
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Malekinejad F, Kheradmand F, Khadem-Ansari MH, Malekinejad H. Lupeol synergizes with doxorubicin to induce anti-proliferative and apoptotic effects on breast cancer cells. Daru 2022; 30:103-115. [PMID: 35113358 PMCID: PMC9114251 DOI: 10.1007/s40199-022-00436-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 01/23/2022] [Indexed: 02/05/2023] Open
Abstract
PURPOSE Anti-cancer and anti-migration effects of lupeol as a biological pentacyclic triterpenoid were investigated individually and in combination with Doxorubicin (DOX) on MCF-7 and MDA-MB-231 breast cancer cells and human foreskin fibroblasts. METHODS To uncover the anticancer effect of lupeol and the impact of its combination with DOX, cell viability and scratch assays and dual acridine-orange apoptotic staining were performed. Moreover, the expression of proapoptotic caspase-3 and metastasis-related MMP-9 at the mRNA and protein levels was analyzed using qPCR and western blot techniques. RESULTS Lupeol synergistically increased the anti-proliferative effect of DOX with IC50 values of 42.55, 62.24 and 65.9 μM on MCF-7, MDA-MB-231 and HFF cells, respectively. Lupeol reduced the cell migration and lowered the DOX-induced cell migration, significantly (p < 0.05). The number of apoptotic cells elevated significantly (p < 0.05) when cancer cells were treated with the combination of lupeol and DOX. Lupeol individually and in combination with DOX up-regulated the expression of caspase-3. The proposed combination therapy synergized (3-4 fold) the down-regulation of MMP-9 expression in MCF-7 and MDA-MB-231 cells. CONCLUSION Our results indicate that lupeol could be considered as an anticancer agent and anticancer adjuvant in breast cancer-therapy. The anticancer properties of lupeol attribute to its antiproliferative, antimigrative and apoptotic effects.
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Affiliation(s)
- Faezeh Malekinejad
- grid.412763.50000 0004 0442 8645Department of Clinical Biochemistry, Urmia University of Medical Sciences, Urmia, Iran
| | - Fatemeh Kheradmand
- grid.412763.50000 0004 0442 8645Department of Clinical Biochemistry, Urmia University of Medical Sciences, Urmia, Iran
| | - Mohammad Hassan Khadem-Ansari
- grid.412763.50000 0004 0442 8645Department of Clinical Biochemistry, Urmia University of Medical Sciences, Urmia, Iran
| | - Hassan Malekinejad
- grid.412763.50000 0004 0442 8645Department of Pharmacology and Toxicology, School of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran ,grid.412763.50000 0004 0442 8645Experimental and Applied Pharmaceutical Sciences Research Center, Urmia University of Medical Sciences, Urmia, Iran
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Nurcahyanti ADR, Jap A, Lady J, Prismawan D, Sharopov F, Daoud R, Wink M, Sobeh M. Function of selected natural antidiabetic compounds with potential against cancer via modulation of the PI3K/AKT/mTOR cascade. Biomed Pharmacother 2021; 144:112138. [PMID: 34750026 DOI: 10.1016/j.biopha.2021.112138] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 08/19/2021] [Accepted: 08/31/2021] [Indexed: 12/12/2022] Open
Abstract
Diabetes mellitus (DM) is a metabolic disorder with growing global incidence, as 387 million people were diagnosed in 2014 with an expected projection of 642 million in 2040. Several complications are associated with DM including heart attack, stroke, kidney failure, blindness, and cancer. The latter is the second leading cause of death worldwide accounting for one in every six deaths, with liver, pancreas, and endometrium cancers are the most abundant among patients with diabetes. Phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway plays a vital role in developing a wide array of pathological disorders, among them diabetes and cancer. Natural secondary metabolites that counteract the deleterious effects of reactive oxygen species (ROS) and modulate PI3K/Akt/mTOR pathway could be a promising approach in cancer therapy. Here, 717 medicinal plants with antidiabetic activities were highlighted along with 357 bioactive compounds responsible for the antidiabetic activity. Also, 43 individual plant compounds with potential antidiabetic activities against cancer via the modulation of PI3K/Akt/mTOR cascade were identified. Taken together, the available data give an insight of the potential of repurposing medicinal plants and/or the individual secondary metabolites with antidiabetic activities for cancer therapy.
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Affiliation(s)
- Agustina Dwi Retno Nurcahyanti
- Department of Pharmacy, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Pluit Raya 2, 14440 Jakarta, Indonesia.
| | - Adeline Jap
- Department of Pharmacy, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Pluit Raya 2, 14440 Jakarta, Indonesia
| | - Jullietta Lady
- Department of Pharmacy, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Pluit Raya 2, 14440 Jakarta, Indonesia
| | - Deka Prismawan
- Department of Pharmacy, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Pluit Raya 2, 14440 Jakarta, Indonesia
| | - Farukh Sharopov
- Chinese-Tajik Innovation Center for Natural Products, National Academy of Sciences of Tajikistan, Ayni str. 299/2, 734063, Dushanbe, Tajikistan
| | - Rachid Daoud
- African Genome Center, Mohammed VI Polytechnic University (UM6P), Lot 660, Hay Moulay Rachid, Ben Guerir 43150, Morocco
| | - Michael Wink
- Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany
| | - Mansour Sobeh
- AgroBiosciences Research, Mohammed VI Polytechnic University, Lot 660-Hay Moulay Rachid, 43150 Ben-Guerir, Morocco.
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10
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Kang H, Sun Y, Hu X, Liu L. Gigantol inhibits proliferation and enhanced oxidative stress-mediated apoptosis through modulating of Wnt/β-catenin signaling pathway in HeLa cells. J Biochem Mol Toxicol 2021; 36:e22944. [PMID: 34729850 DOI: 10.1002/jbt.22944] [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: 11/19/2020] [Revised: 08/10/2021] [Accepted: 10/18/2021] [Indexed: 11/07/2022]
Abstract
Cervical cancer is one of the leading malignant cancers that is the fourth prominent cause of malignancy-related mortality in women globally. There is a predominant validation to a beneficial target in Wnt/β-catenin signaling in cervical carcinogenesis as they are very much deregulated in cancer. Previous studies reported Gigantol (GG) showed suppressive properties on the Wnt/β-catenin pathway in other tumor cells, but no evidence is available regarding GG suppressing Wnt/β-catenin signaling cervical tumor cells. Hence, the current research was planned to examine the suppressive effects of GG on HeLa cells and investigate the mechanism of action. HeLa cells were treated by GG in various doses and then appraising cell viability, oxidant/antioxidant levels, ∆ѰM status, reactive oxygen species (ROS) generation, apoptosis, and cell proliferation via Wnt/β-catenin signaling. We observed that GG noticeably inhibits cell proliferation, increased ROS generation, lipid peroxidation, mitochondrial membrane depolarization (∆ѰM), and increased apoptotic morphological changes of nuclear fragmentation and condensation. Moreover, GG effectively enhances proapoptotic, decreased ∆ѰM and antioxidant amounts, and mitigated Wnt/β-catenin signaling. Concisely, these findings proved that activating apoptosis and suppression of cell proliferation in GG treated HeLa cells was documented by the alleviation of Wnt/β-catenin signaling. Therefore, this study suggested that GG might develop a therapeutic effect against cervical carcinogenesis.
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Affiliation(s)
- Huanan Kang
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Yiming Sun
- Department of Andrology, Heilongjiang Provincial Hospital of Traditional Chinese Medicine, Harbin, China
| | - Xijiao Hu
- Second Department of Gynecology, Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Li Liu
- Department of Hysteroscopy, First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, China
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11
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Sureda A, Martorell M, Capó X, Monserrat-Mesquida M, Quetglas-Llabrés MM, Rasekhian M, Nabavi SM, Tejada S. Antitumor Effects of Triterpenes in Hepatocellular Carcinoma. Curr Med Chem 2021; 28:2465-2484. [PMID: 32484765 DOI: 10.2174/0929867327666200602132000] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 04/22/2020] [Accepted: 05/06/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Triterpenes are a large group of secondary metabolites mainly produced by plants with a variety of biological activities, including potential antitumor effects. Hepatocellular carcinoma (HCC) is a very common primary liver disease spread worldwide. The treatment can consist of surgical intervention, radiotherapy, immunotherapy and chemotherapeutic drugs. These drugs mainly include tyrosine multikinase inhibitors, although their use is limited by the underlying liver disease and displays side effects. For that reason, the utility of natural compounds such as triterpenes to treat HCC is an interesting line of research. No clinical studies are reported in humans so far. OBJECTIVE The aim of the present work is to review the knowledge about the effects of triterpenes as a possible coadjuvant tool to treat HCC. RESULTS In vitro and xenograft models have pointed out the cytotoxic and anti-proliferative effects as well as improvements in tumor growth and development of many triterpenes. In addition, they have also shown to be chemosensitizing agents when co-administered with chemotherapeutic agents. The mechanisms of action are diverse and involve the participation of mitogen-activated protein kinases, including JNK, p38 MAPK and ERK, and the survival-associated PI3K / Akt signaling pathway. However, no clinical studies are still reported in humans. CONCLUSION Triterpenes could become a future strategy to address HCC or at least improve results when administered in combination with chemotherapeutic agents.
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Affiliation(s)
- Antoni Sureda
- Research Group in Community Nutrition and Oxidative Stress, Health Research Institute of Balearic Islands (IdISBa) and CIBEROBN (Physiopathology of Obesity and Nutrition), University of Balearic Islands, Balearic Islands, E-07122 Palma, Spain
| | - Miquel Martorell
- Department of Nutrition and Dietetics, Faculty of Pharmacy, Centre for Healthy Living, University of Concepcion, 4070386 Concepcion, Chile
| | - Xavier Capó
- Research Group in Community Nutrition and Oxidative Stress, Health Research Institute of Balearic Islands (IdISBa) and CIBEROBN (Physiopathology of Obesity and Nutrition), University of Balearic Islands, Balearic Islands, E-07122 Palma, Spain
| | - Margalida Monserrat-Mesquida
- Research Group in Community Nutrition and Oxidative Stress, Health Research Institute of Balearic Islands (IdISBa) and CIBEROBN (Physiopathology of Obesity and Nutrition), University of Balearic Islands, Balearic Islands, E-07122 Palma, Spain
| | - Maria Magdalena Quetglas-Llabrés
- Research Group in Community Nutrition and Oxidative Stress, Health Research Institute of Balearic Islands (IdISBa) and CIBEROBN (Physiopathology of Obesity and Nutrition), University of Balearic Islands, Balearic Islands, E-07122 Palma, Spain
| | - Mahsa Rasekhian
- Pharmaceutical Sciences Research Center Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Seyed M Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran 14359-16471, Iran
| | - Silvia Tejada
- Laboratory of Neurophysiology, Biology Department, Health Research Institute of Balearic Islands (IdISBa) and CIBEROBN (Physiopathology of Obesity and Nutrition), University of the Balearic Islands, Balearic Islands, E-07122 Palma, Spain
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12
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Eldohaji LM, Fayed B, Hamoda AM, Ershaid M, Abdin S, Alhamidi TB, Mohammad MG, Omar HA, Soliman SSM. Potential targeting of Hep3B liver cancer cells by lupeol isolated from Avicennia marina. Arch Pharm (Weinheim) 2021; 354:e2100120. [PMID: 34085721 DOI: 10.1002/ardp.202100120] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/29/2021] [Accepted: 05/14/2021] [Indexed: 11/08/2022]
Abstract
Medicinal plants are valuable sources of different active constituents that are known to have important pharmacological activities including anticancer effects. Lupeol, a pentacyclic triterpenoid, present in many medicinal plants, has a wide range of biological activities. Although the anticancer activity of lupeol was reported, the published data are inconsistent and the clear mechanism of action has never been assigned. The current study aims at investigating the anticancer specificity and mechanism of lupeol isolated from Avicennia marina, which grows in the desert of the United Arab Emirates. The compound was purified by chromatography and identified by spectroscopy. Compared with a negative control, lupeol caused significant (p < .001) growth inhibitory activity on MCF-7 and Hep3B parental and resistant cells by 45%, 46%, 72%, and 35%, respectively. The mechanism of action of lupeol was further explored by measuring its effect on key players in cancer development and progression, BCL-2 anti-apoptotic and BAX pro-apoptotic proteins. Lupeol significantly (p < .01) downregulated BCL-2 gene expression in parental and resistant Hep3B cells by 33 and 3.5 times, respectively, contributing to the induction of apoptosis in Hep3B cells, whereas it caused no effect on BAX. Furthermore, the immunoblotting analysis revealed that lupeol cleaved the executioner caspase-3 into its active form. Interestingly, lupeol showed no significant effect on the proliferation of monocytes, whereas it caused an increase in the sub-G1 population and a reduction in the apoptosis rates of monocytes at 48 and 72 h, indicative of no immuno-inflammatory responses. Collectively, lupeol can be considered as promising effective and safe anticancer agent, particularly against Hep3B cancer cells.
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Affiliation(s)
- Leen M Eldohaji
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, UAE
| | - Bahgat Fayed
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, UAE.,Chemistry of Natural and Microbial Product Department, National Research Centre, Cairo, Egypt
| | - Alshaimaa M Hamoda
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, UAE.,College of Medicine, University of Sharjah, Sharjah, UAE.,Department of Pharmacognosy, Faculty of Pharmacy, Assiut University, Assiut, Egypt
| | - Mai Ershaid
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, UAE
| | - Shifaa Abdin
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, UAE
| | - Tasneem B Alhamidi
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, UAE
| | - Mohammad G Mohammad
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, UAE.,Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah, UAE
| | - Hany A Omar
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, UAE.,College of Pharmacy, University of Sharjah, Sharjah, UAE
| | - Sameh S M Soliman
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, UAE.,College of Pharmacy, University of Sharjah, Sharjah, UAE
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13
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ShuoWang, Song Z, Gong X, Ou C, Zhang W, Wang J, Yao C, Qin S, Yan B, Li Q, Wei K, Hou X, Zhou X, Miao J. Chloroform extract from Sophora Tonkinensis Gagnep. inhibit proliferation, migration, invasion and promote apoptosis of nasopharyngeal carcinoma cells by silencing the PI3K/AKT/mTOR signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2021; 271:113879. [PMID: 33524509 DOI: 10.1016/j.jep.2021.113879] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 01/19/2021] [Accepted: 01/20/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Sophora Tonkinensis Gagnep. (STG) has been used as a folk medicine for the treatment of different cancers, especially for nasopharyngeal carcinoma, cervical cancer, liver cancer, stomach cancer, lung cancer and leukemia in China. However, the main chemical composition and anticancer mechanism of chloroform extract of STG (CESTG) were still not very clear. AIM OF STUDY This work was carried out to investigate the anticancer effects and mechanisms of chloroform extract of STG (CESTG) on NPC. METHODS Cultured NPC CNE1, CNE2 and Np69 cells were treated with CESTG. Cells were subjected to cell proliferation, colony-forming, migration and invasion assays. Cell cycle and apoptosis were measured by flow cytometry. Western blotting and morphological analysis were also performed. Tumor xenografts and drug treatments were made in BALB/c nude mice. The main compounds of CESTG was separated by HPLC. RESULTS CESTG inhibited cell viability, clonal growth and induced cell apoptosis in a dose-dependent manner by silencing the PI3K/AKT/mTOR signaling pathway, which is associated with upregulation of cleaved PARP, caspase 3/7/8/9, cleaved caspase 3/7/8/9, Bax and downregulation of PARP, P-PI3K, PI3K, P-AKT, AKT, P-mTOR, mTOR and Bcl-2. In addition, CESTG arrested cell cycle in the G1/S phase, correlating with decreased levels of cyclin D1/B1, CDK 4 and 6. CESTG decreased cell migration and invasion which correlated with decreased expression of β-catenin, vimentin and snail. CESTG significantly inhibited the tumor growth without toxicity. CONCLUSION The results presented here suggest that CESTG could be use as a potential source of NPC therapeutic drug.
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Affiliation(s)
- ShuoWang
- National Engineering Laboratory of Southwest Endangered Medicinal Resources Development, Guangxi Botanical Garden of Medicinal Plants, Nanning, 530023, PR China
| | - Zhijun Song
- National Engineering Laboratory of Southwest Endangered Medicinal Resources Development, Guangxi Botanical Garden of Medicinal Plants, Nanning, 530023, PR China.
| | - Xiaomei Gong
- National Engineering Laboratory of Southwest Endangered Medicinal Resources Development, Guangxi Botanical Garden of Medicinal Plants, Nanning, 530023, PR China
| | - Chunli Ou
- National Engineering Laboratory of Southwest Endangered Medicinal Resources Development, Guangxi Botanical Garden of Medicinal Plants, Nanning, 530023, PR China
| | - Wenyu Zhang
- Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, PR China
| | - Jie Wang
- National Engineering Laboratory of Southwest Endangered Medicinal Resources Development, Guangxi Botanical Garden of Medicinal Plants, Nanning, 530023, PR China
| | - Caiyun Yao
- National Engineering Laboratory of Southwest Endangered Medicinal Resources Development, Guangxi Botanical Garden of Medicinal Plants, Nanning, 530023, PR China
| | - Shuangshuang Qin
- National Engineering Laboratory of Southwest Endangered Medicinal Resources Development, Guangxi Botanical Garden of Medicinal Plants, Nanning, 530023, PR China
| | - Bingxiong Yan
- National Engineering Laboratory of Southwest Endangered Medicinal Resources Development, Guangxi Botanical Garden of Medicinal Plants, Nanning, 530023, PR China
| | - Qiuping Li
- National Engineering Laboratory of Southwest Endangered Medicinal Resources Development, Guangxi Botanical Garden of Medicinal Plants, Nanning, 530023, PR China
| | - Kunhua Wei
- National Engineering Laboratory of Southwest Endangered Medicinal Resources Development, Guangxi Botanical Garden of Medicinal Plants, Nanning, 530023, PR China
| | - Xiaoli Hou
- National Engineering Laboratory of Southwest Endangered Medicinal Resources Development, Guangxi Botanical Garden of Medicinal Plants, Nanning, 530023, PR China
| | - Xiaolei Zhou
- National Engineering Laboratory of Southwest Endangered Medicinal Resources Development, Guangxi Botanical Garden of Medicinal Plants, Nanning, 530023, PR China.
| | - Jianhua Miao
- National Engineering Laboratory of Southwest Endangered Medicinal Resources Development, Guangxi Botanical Garden of Medicinal Plants, Nanning, 530023, PR China.
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14
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Liu K, Zhang X, Xie L, Deng M, Chen H, Song J, Long J, Li X, Luo J. Lupeol and its derivatives as anticancer and anti-inflammatory agents: Molecular mechanisms and therapeutic efficacy. Pharmacol Res 2020; 164:105373. [PMID: 33316380 DOI: 10.1016/j.phrs.2020.105373] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 11/17/2020] [Accepted: 12/03/2020] [Indexed: 02/06/2023]
Abstract
Lupeol is a natural triterpenoid that widely exists in edible fruits and vegetables, and medicinal plants. In the last decade, a plethora of studies on the pharmacological activities of lupeol have been conducted and have demonstrated that lupeol possesses an extensive range of pharmacological activities such as anticancer, antioxidant, anti-inflammatory, and antimicrobial activities. Pharmacokinetic studies have indicated that absorption of lupeol by animals was rapid despite its nonpolar characteristics, and lupeol belongs to class II BCS (biopharmaceutics classification system) compounds. Moreover, the bioactivities of some isolated or synthesized lupeol derivatives have been investigated, and these results showed that, with modification to C-3 or C-19, some derivatives exhibit stronger activities, e.g., antiprotozoal or anticancer activity. This review aims to summarize the advances in pharmacological and pharmacokinetic studies of lupeol in the last decade with an emphasis on its anticancer and anti-inflammatory activities, as well as the research progress of lupeol derivatives thus far, to provide researchers with the latest information, point out the limitations of relevant research at the current stage and the aspects that should be strengthened in future research.
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Affiliation(s)
- Kai Liu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China
| | - Xumin Zhang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China
| | - Long Xie
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China
| | - Mao Deng
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China
| | - Huijuan Chen
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China
| | - Jiawen Song
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China
| | - Jiaying Long
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China
| | - Xiaofang Li
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China.
| | - Jia Luo
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China.
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15
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Maurya SK, Shadab G, Siddique HR. Chemosensitization of Therapy Resistant Tumors: Targeting Multiple Cell Signaling Pathways by Lupeol, A Pentacyclic Triterpene. Curr Pharm Des 2020; 26:455-465. [DOI: 10.2174/1381612826666200122122804] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Accepted: 12/13/2019] [Indexed: 12/12/2022]
Abstract
Background:
The resistance of cancer cells to different therapies is one of the major stumbling blocks
for successful cancer treatment. Various natural and pharmaceuticals drugs are unable to control drug-resistance
cancer cell's growth. Also, chemotherapy and radiotherapy have several side effects and cannot apply to the patient
in excess. In this context, chemosensitization to the therapy-resistant cells by non-toxic phytochemicals
could be an excellent alternative to combat therapy-resistant cancers.
Objective:
To review the currently available literature on chemosensitization of therapy resistance cancers by
Lupeol for clinically approved drugs through targeting different cell signaling pathways.
Methods:
We reviewed relevant published articles in PubMed and other search engines from 1999 to 2019 to
write this manuscript. The key words used for the search were “Lupeol and Cancer”, “Lupeol and Chemosensitization”,
“Lupeol and Cell Signaling Pathways”, “Cancer Stem Cells and Lupeol” etc. The published results on the
chemosensitization of Lupeol were compared and discussed.
Results:
Lupeol chemosensitizes drug-resistant cancer cells for clinically approved drugs. Lupeol alone or in
combination with approved drugs inhibits inflammation in different cancer cells through modulation of expression
of IL-6, TNF-α, and IFN-γ. Lupeol, through altering the expression levels of BCL-2, BAX, Survivin, FAS,
Caspases, and PI3K-AKT-mTOR signaling pathway, significantly induce cell deaths among therapy-resistant
cells. Lupeol also modulates the molecules involved in cell cycle regulation such as Cyclins, CDKs, P53, P21,
and PCNA in different cancer types.
Conclusion:
Lupeol chemosensitizes the therapy-resistant cancer cells for the treatment of various clinically
approved drugs via modulating different signaling pathways responsible for chemoresistance cancer. Thus, Lupeol
might be used as an adjuvant molecule along with clinically approved drugs to reduce the toxicity and increase
the effectiveness.
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Affiliation(s)
- Santosh K. Maurya
- Molecular Cancer Genetics & Translational Research Lab, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh-202002, Uttar Pradesh, India
| | - G.G.H.A. Shadab
- Molecular Toxicology & Cytogenetics Lab, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh-202002, Uttar Pradesh, India
| | - Hifzur R. Siddique
- Molecular Cancer Genetics & Translational Research Lab, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh-202002, Uttar Pradesh, India
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16
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Zhu L, Sun Y, Zhang S, Wang L. Rap2B knockdown suppresses malignant progression of hepatocellular carcinoma by inactivating the PTEN/PI3K/Akt and ERK1/2 pathways. Mol Cell Biochem 2020; 466:55-63. [PMID: 32052247 DOI: 10.1007/s11010-020-03687-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 01/18/2020] [Indexed: 01/06/2023]
Abstract
Rap2B, belonging to the Ras superfamily of small guanosine triphosphate-binding proteins, is upregulated and contributes to the progression of several tumors by acting as an oncogene, including hepatocellular carcinoma (HCC). However, the mechanism underlying the functional roles of Rap2B in HCC remains unclear. In this study, the evaluation of Rap2B expression in HCC cells and tissues was achieved by qRT-PCR and western blot assays. The effects of Rap2B on the malignant biological behaviors in HCC were explored by means of MTT assay, flow cytometry analysis, and Transwell invasion assay, respectively. Protein levels of Ki67, matrix metalloproteinase (MMP)-2, MMP-9, and cleaved caspase-3, together with the alternations of the ERK1/2 and PTEN/PI3K/Akt pathways were qualified by western blot assay. Further verification of the Rap2B function on HCC tumorigenesis was attained by performing in vivo assays. We found that Rap2B levels were upregulated in HCC tissues and cells. Rap2B silencing led to a reduction of cell-proliferative and invasive abilities, and an increase of apoptosis in HCC cells. In addition, xenograft tumor assay demonstrated that Rap2B silencing repressed HCC xenograft tumor growth in vivo. In addition, we found that Rap2B knockdown significantly inhibited the ERK1/2 and PTEN/PI3K/Akt cascades in HCC cells and xenograft tumor tissues. Together, Rap2B knockdown inhibited HCC-malignant progression, which was involved in inhibiting the ERK1/2 and PTEN/PI3K/Akt pathways. Our findings contribute to understanding of the molecular mechanism of Rap2B in HCC progression.
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Affiliation(s)
- Linchao Zhu
- Department of Pediatric Surgery, Henan Provincial People's Hospital, No.7, Wei Wu Road, Zhengzhou, 450003, Henan, People's Republic of China.
| | - Ying Sun
- Department of Clinical Laboratory, Third People's Hospital of Henan Province, Zhengzhou, Henan, People's Republic of China
| | - Shufeng Zhang
- Department of Pediatric Surgery, Henan Provincial People's Hospital, No.7, Wei Wu Road, Zhengzhou, 450003, Henan, People's Republic of China
| | - Lin Wang
- Department of Pediatric Surgery, Henan Provincial People's Hospital, No.7, Wei Wu Road, Zhengzhou, 450003, Henan, People's Republic of China
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17
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Biswas T, Dwivedi UN. Plant triterpenoid saponins: biosynthesis, in vitro production, and pharmacological relevance. PROTOPLASMA 2019; 256:1463-1486. [PMID: 31297656 DOI: 10.1007/s00709-019-01411-0] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 07/01/2019] [Indexed: 05/26/2023]
Abstract
The saponins are a diverse class of natural products, with a broad scale distribution across different plant species. Chemically characterized as triterpenoid glycosides, they posses a 30C oxidosqualene precursor-based aglycone moiety (sapogenin), to which glycosyl residues are subsequently attached to yield the corresponding saponin. Based on the chemically distinct aglycone moieties, broadly, they are divided into triterpenoid saponins (dammaranes, ursanes, oleananes, lupanes, hopanes, etc.) and the sterol glycosides. This review aims to present in detail the biosynthesis patterns of the different aglycones from a common precursor and their glycosylation patterns to yield the functionally active glycoside. The review also presents recent advances in the pharmacological activities of these saponins, particularly as potent anti-neoplastic pharmacophores, antioxidants, or anti-viral/antibacterial agents. Since alternate production pedestals for these pharmacologically important triterpenes via cell and tissue cultures are an attractive option for their sustainable production, recent trends in the variety and scale of in vitro production of plant triterpenoids have also been discussed.
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Affiliation(s)
- Tanya Biswas
- Department of Biochemistry, University of Lucknow, Lucknow, 226007, India
| | - Upendra N Dwivedi
- Department of Biochemistry, University of Lucknow, Lucknow, 226007, India.
- Institute for Development of Advanced Computing, ONGC Centre for Advanced Studies, University of Lucknow, Lucknow, 226007, India.
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18
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Soleymani S, Farzaei MH, Zargaran A, Niknam S, Rahimi R. Promising plant-derived secondary metabolites for treatment of acne vulgaris: a mechanistic review. Arch Dermatol Res 2019; 312:5-23. [PMID: 31448393 DOI: 10.1007/s00403-019-01968-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Revised: 08/13/2019] [Accepted: 08/16/2019] [Indexed: 02/06/2023]
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19
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Khatal L, More H. Development and validation of a liquid chromatography-tandem mass spectrometry method for quantification of Lupeol in plasma and its application to pharmacokinetic study in rats. J Chromatogr B Analyt Technol Biomed Life Sci 2019; 1121:58-65. [PMID: 31108322 DOI: 10.1016/j.jchromb.2019.05.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 04/26/2019] [Accepted: 05/08/2019] [Indexed: 10/26/2022]
Abstract
Lupeol, a phytosterol and triterpene, possesses numerous medicinal properties against cancer, inflammation, arthritis, diabetes, heart diseases, etc. A novel, sensitive, specific and reproducible method for quantification of Lupeol in rat plasma using liquid chromatography combined with atmospheric pressure chemical ionization (APCI) tandem mass spectrometry (LC-MS/MS) was developed and validated as per regulatory guidelines. Sample preparation was simple and fast which consisted of one-step protein precipitation using acetonitrile. Testosterone was used as an internal standard. HyPurity Advance column was used to develop the chromatography method using 0.1% formic acid in water and acetonitrile as mobile phases by gradient elution. APCI positive ion mode was used for mass spectrometric detection. Multiple reaction monitoring (MRM) transitions of m/z 409.5 [M + H - H2O]+→137.3 for Lupeol and m/z 289.1 [M + H]+→97.1 for Testosterone were used for quantification. The method was validated over a linear concentration range of 5-5000 ng/mL with a correlation coefficient (r2) of ≥ 0.99. This method showed acceptable accuracy (89.52-97.10%), precision (%CV ≤ 10.75%) and recovery with a negligible matrix effect. Lupeol was found to be stable in the stock solution, autosampler condition and also in plasma for four freeze-thaw cycles, 6 h at ambient temperature and 30 days at -20°C. This method was successfully applied to measurement of Lupeol in plasma samples from pharmacokinetic study in rats and can be easily extended to human pharmacokinetic studies.
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Affiliation(s)
- Laxman Khatal
- Bharati Vidyapeeth College of Pharmacy, Kolhapur, Near Chitranagri, Kolhapur 416013, Maharashtra, India.
| | - Harinath More
- Bharati Vidyapeeth College of Pharmacy, Kolhapur, Near Chitranagri, Kolhapur 416013, Maharashtra, India
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Wang Y, Hong D, Qian Y, Tu X, Wang K, Yang X, Shao S, Kong X, Lou Z, Jin L. Lupeol inhibits growth and migration in two human colorectal cancer cell lines by suppression of Wnt-β-catenin pathway. Onco Targets Ther 2018; 11:7987-7999. [PMID: 30519040 PMCID: PMC6235339 DOI: 10.2147/ott.s183925] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background Lupeol, a triterpene isolated from various herbal plants, possesses an anti-inflammatory function and has been proposed as a candidate for anticancer agents. The purpose of this research was to investigate the effect of lupeol on the viability, apoptosis, cell-cycle distribution, and migration of colorectal cancer cell lines and its molecular mechanism. Methods Lupeol was assessed for its anticancer effect using two human colorectal cancer cell lines: SW480 and HCT116. These cells were treated with lupeol, and their viability, apoptosis, migration, and cycle distribution were detected by CCK8, flow cytometry, and the transwell method. Quantitative PCR, Western blot, and immunofluorescence were applied to detect the expressions of CTNNB1, TCF4, cMYC, CCND1, CLDN1, and CCNA2. Results Lupeol suppressed cell viability and migration and induced cellular apoptosis of both cell lines, with increased p53 and decreased Bcl2 protein levels (P<0.05). Cell cycles of both lupeol-treated cell lines were arrested in the S phase (P<0.05). Quantitative PCR and Western blot analyses showed significantly reduced expressions of CTNNB1, TCF4, and downstream genes of the Wnt–β-catenin pathway, including the cell-cycle-regulated genes of cMYC and CCND1 of both cell lines upon lupeol treatment (P<0.05). mRNA and protein levels of CLDN1 decreased in HCT116 cells, plus the expression of CCNA2 mRNA and protein decreased in SW480 cells (P<0.05). Immunofluorescence analysis confirmed decreased expression of Wnt–β-catenin signaling. Conclusion Our findings indicate that lupeol effectively inhibits proliferation and migration and induces apoptosis and cell-cycle arrest of two colorectal cell lines by inactivation of the Wnt–β-catenin signaling pathway and downregulation of cMYC, CCND1, CCNA2, and CLDN1, thereby making it a promising anticancer candidate.
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Affiliation(s)
- Yihao Wang
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, Zhejiang, People's Republic of China, ; .,School of Ophthalmology and Optometry, Wenzhou Medical University, Zhejiang, People's Republic of China
| | - Dan Hong
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, Zhejiang, People's Republic of China, ;
| | - Yuqin Qian
- School of the first Clinical Medical Sciences, Wenzhou Medical University, Zhejiang, People's Republic of China
| | - Xuezi Tu
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, Zhejiang, People's Republic of China, ;
| | - Keke Wang
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, Zhejiang, People's Republic of China, ;
| | - Xianhong Yang
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, Zhejiang, People's Republic of China, ;
| | - Sijia Shao
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, Zhejiang, People's Republic of China, ;
| | - Xinlong Kong
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, Zhejiang, People's Republic of China, ;
| | - Zhefeng Lou
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, Zhejiang, People's Republic of China, ;
| | - Longjin Jin
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, Zhejiang, People's Republic of China, ;
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de Oliveira Júnior RG, Christiane Adrielly AF, da Silva Almeida JRG, Grougnet R, Thiéry V, Picot L. Sensitization of tumor cells to chemotherapy by natural products: A systematic review of preclinical data and molecular mechanisms. Fitoterapia 2018; 129:383-400. [DOI: 10.1016/j.fitote.2018.02.025] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Revised: 02/19/2018] [Accepted: 02/20/2018] [Indexed: 12/13/2022]
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Chen MC, Hsu HH, Chu YY, Cheng SF, Shen CY, Lin YJ, Chen RJ, Viswanadha VP, Lin YM, Huang CY. Lupeol alters ER stress-signaling pathway by downregulating ABCG2 expression to induce Oxaliplatin-resistant LoVo colorectal cancer cell apoptosis. ENVIRONMENTAL TOXICOLOGY 2018; 33:587-593. [PMID: 29436100 DOI: 10.1002/tox.22544] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Revised: 01/23/2018] [Accepted: 01/27/2018] [Indexed: 06/08/2023]
Abstract
Colorectal cancer (CRC) is one of the most common cancers and causes of cancer-related death. There are several first-line chemotherapeutic drugs used to treat CRC. Oxaliplatin (OXA) is an alkylating cytotoxic agent that is usually combined with other chemotherapeutic drugs to treat stage II and stage III CRC. However, cancer cells commonly acquire multidrug resistance (MDR), which is a major obstruction to cancer treatment. Recent studies have shown that natural components from traditional Chinese medicine or foods that have many biological functions may be new adjuvant therapies in clinical trials. We challenged LoVo CRC cell lines with OXA in a dose-dependent manner to create an OXA-resistant model. The expression of ABCG2 was significantly higher, and levels of endoplasmic reticulum (ER) stress markers were lower than those Parental cells. However, Lupeol, which is found in fruits and vegetables, has been shown to have bioactive properties, including anti-tumor properties that are relevant to many diseases. In our study, Lupeol downregulated cell viability and activated cell apoptosis. Moreover, Lupeol decreased the expression of ABCG2 and activated ER stress to induce OXA-resistant cell death. Importantly, the anti-tumor effect of Lupeol in OXA-resistant cells was higher than that of LoVo Parental cells. In addition, we also confirmed our results with a xenograft animal model, and the tumor size significantly decreased after Lupeol injections. Our findings show that Lupeol served as a strong chemoresistant sensitizer and could be a new adjuvant therapy method for chemoresistant patients.
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Affiliation(s)
- Ming-Cheng Chen
- Division of Colorectal Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
- Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Hsi-Hsien Hsu
- Division of Colorectal Surgery, Mackay Memorial Hospital, Taipei, Taiwan
- Mackay Medicine, Nursing and Management College, Taipei, Taiwan
| | - Yuan-Yuan Chu
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
| | - Sue-Fei Cheng
- Department of Pharmacy, Veterans General Hospital, Taipei, Taiwan
| | - Chia-Yao Shen
- Department of Nursing, Mei Ho University, Pingguang Road, Pingtung, Taiwan
| | - Yi-Jiun Lin
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
| | - Ray-Jade Chen
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | | | - Yueh-Min Lin
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan
- Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan
| | - Chih-Yang Huang
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
- Faculty of Applied Sciences, Ton Duc Thang University, Tan Phong Ward, District 7, Ho Chi Minh City, 700000, Vietnam
- Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan
- Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan
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Qian L, Li X, Ye P, Wang G, Dai W, Liu Y, Gao Q, Shen G. Oxymatrine induces apoptosis and inhibits invasion in Gallbladder carcinoma via PTEN/PI3K/AKT pathway. Cytotechnology 2018; 70:83-94. [PMID: 29170841 PMCID: PMC5809667 DOI: 10.1007/s10616-017-0153-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 03/12/2017] [Indexed: 12/31/2022] Open
Abstract
Oxymatrine extracted from Sophora flavescens Ait as a natural polyphenolic phytochemical has been demonstrated to exhibit anti-tumor effects on various cancers, including Gallbladder carcinoma (GBC). However, its underlying mechanisms of function are largely unknown in GBC cells. The present study is conducted to investigate the anti-tumor effects and the underlying mechanisms of oxymatrine on GBC cells in vitro and in vivo. The results showed that oxymatrine inhibited cell viability, metastatic ability and induced cell apoptosis in dose-dependent manners. Furthermore, we found that the expression of p-AKT, MMP-2, MMP-9 and the ratio of Bcl-2/Bax were significantly down-regulated, while the expression of PTEN was up-regulated in GBC cells. In addition, pretreatment with a specific PI3K/AKT activator (IGF-1) significantly antagonized the oxymatrine-mediated inhibition of GBC-SD cells. Subsequently, our in vivo studies showed that administration of oxymatrine induced a significant dose-dependent decrease in tumor growth. In conclusion, these findings indicated that the inhibition of cells proliferation, migration, invasion and the induction of apoptosis in response to oxymatrine in GBC cells, may function through the suppression of PTEN/PI3K/AKT pathway, which was considered as the vital signaling pathway in regulating tumorigenesis. These results suggested that oxymatrine might be a novel effective candidate as chemotherapeutic agent against GBC.
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Affiliation(s)
- Liqiang Qian
- Department of General Surgery, Wujiang No.1 People's Hospital, Suzhou, 215200, China
| | - Xiaqin Li
- Department of Gynaecology and Obstetrics, Health Center of Songling, Suzhou, 215200, China
| | - Penghui Ye
- Department of General Surgery, Wujiang No.1 People's Hospital, Suzhou, 215200, China
| | - Gang Wang
- Department of General Surgery, Wujiang No.1 People's Hospital, Suzhou, 215200, China
| | - Wei Dai
- Department of General Surgery, Wujiang No.1 People's Hospital, Suzhou, 215200, China
| | - Yan Liu
- Department of General Surgery, Wujiang No.1 People's Hospital, Suzhou, 215200, China
| | - Quangen Gao
- Department of General Surgery, Wujiang No.1 People's Hospital, Suzhou, 215200, China.
| | - Genhai Shen
- Department of General Surgery, Wujiang No.1 People's Hospital, Suzhou, 215200, China.
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Seervi M, Lotankar S, Barbar S, Sathaye S. Assessment of cytochrome P450 inhibition and induction potential of lupeol and betulin in rat liver microsomes. Drug Metab Pers Ther 2017; 31:115-22. [PMID: 26959552 DOI: 10.1515/dmpt-2015-0043] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Accepted: 01/19/2016] [Indexed: 11/15/2022]
Abstract
BACKGROUND Lupeol and betulin are triterpenoids that are majorly found in dietary substances. The aim of present study was to investigate the inhibition and induction potential of lupeol and betulin on cytochrome P450 (CYP)1A2, CYP2C11, CYP2D6 and CYP3A2 activities in rat liver microsomes. METHODS The inhibition and induction studies were conducted using ethoxy resorufin-O-deethylase (CYP1A2), tolbutamide hydroxylase (CYP2C9), and midazolam hydroxylase (CYP3A4) activity assays. In vitro inhibition study was evaluated by incubating lupeol and betulin (1, 3, 10, 30 and 100 μM) with rat liver microsomes, and the metabolite formation was analyzed by high-performance liquid chromatography. The induction study was conducted by administering lupeol (20 mg/kg) and betulin (50 mg/kg) intraperitoneally for 14 days to rats followed by liver isolation and microsome preparation. RESULTS The IC50 values in inhibition studies were found to be 59.42 μM (CYP1A2), >100 μM (CYP2C11, CYP2D6, CYP3A2) for lupeol, 52.24 μM (CYP1A2), and >100 μM (CYP2C9, CYP2D6, CYP3A2) for betulin. There was no significant modification observed in the CYP450 isoforms, indicating neither inhibition nor induction potential of lupeol and betulin. CONCLUSIONS Lupeol and betulin have very low propensity to interact with CYP enzyme, suggesting no CYP inhibitory and inducing potential in rat liver microsomes.
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Soares DCF, de Paula Oliveira DC, Barcelos LS, Barbosa AS, Vieira LC, Townsend DM, Rubello D, de Barros ALB, Duarte LP, Silva-Cunha A. Antiangiogenic activity of PLGA-Lupeol implants for potential intravitreal applications. Biomed Pharmacother 2017; 92:394-402. [PMID: 28558353 DOI: 10.1016/j.biopha.2017.05.093] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Revised: 05/19/2017] [Accepted: 05/22/2017] [Indexed: 02/06/2023] Open
Abstract
Uncontrolled angiogenesis is directly associated with ocular diseases such as macular degeneration and diabetic retinopathy. Implantable polymeric drug delivery systems have been proposed for intravitreal applications and in the present work, we evaluated the antiangiogenic potential of PLGA ocular implants loaded with the triterpene lupeol using in vitro and in vivo models. The drug/polymer physiochemical properties of the lupeol-loaded PLGA were validated as functionally similar using differential scanning calorimetry, Fourier transform infrared spectroscopy, and scanning electron microscopy. Interestingly, in an in vitro culture system, lupeol (100μg/mL and 250μg/mL) was capable to inhibited the proliferation as well as the migration of Human Umbilical Vein Endothelial Cells (HUVEC), without interfering in cell viability, promoting a significant reduction in the percentage of vessels (39.41% and 44.12%, respectively), compared with the control group. In vivo test, by using the chorioallantoic membrane (CAM) model, lupeol-loaded PLGA ocular implants showed antiangiogenic activity comparable to the FDA-approved anti-VEGF antibody Bevacizumab. Overall, our results suggest lupeol-loaded PLGA ocular implants were able to inhibit the angiogenic process by impairing both proliferation and migration of endothelial cells.
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Affiliation(s)
| | - Diogo Coelho de Paula Oliveira
- Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Luciola Silva Barcelos
- Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Alan Sales Barbosa
- Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Lorena Carla Vieira
- Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Danyelle M Townsend
- Department of Drug Discovery and Pharmaceutical Sciences, Medical University of South Carolina, United States
| | - Domenico Rubello
- Department of Nuclear Medicine, Imaging and Clinical Pathology, Santa Maria della Misericordia Hospital, Rovigo, Italy
| | - André Luis Branco de Barros
- Department of Clinical and Toxicological Analyses, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
| | - Lucienir Pains Duarte
- Department of Chemistry, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Armando Silva-Cunha
- Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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Weerapreeyakul N, Junhom C, Barusrux S, Thitimetharoch T. Induction of apoptosis in human hepatocellular carcinoma cells by extracts of Lannea coromandelica (Houtt.) Merr. and Diospyros castanea (Craib) Fletcher. Chin Med 2016; 11:19. [PMID: 27110278 PMCID: PMC4841969 DOI: 10.1186/s13020-016-0091-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 04/16/2016] [Indexed: 01/30/2023] Open
Abstract
Background Herbal plants are a preferred source of anticancer agents. This study aims to screen the anticancer activity of a crude extract of twigs of (a) Bombax anceps Pierre var. anceps (BA); (b) Catunaregam tomentosa (Blume ex DC.) Tirveng. (CT); (c) Erythrophleum succirubrum Gagnep. (ES); (d) Lannea coromandelica (Houtt.) Merr. (LC); and (e) leaves and (f) twigs of Diospyros castanea (Craib) Fletcher (DC). Methods The 50 % ethanol–water extracts were prepared from each plant sample. In vitro anticancer effects of six extracts on the human hepatocellular carcinoma cell line (HepG2) in terms of cytotoxicity were investigated by neutral red assay, apoptosis induction by 4′,6-diamidino-2-phenylindole (DAPI) staining, and DNA fragmentation by agarose gel electrophoresis. Normal Vero cells were tested for comparison and to determine cancer selectivity. Gas chromatography–mass spectrometry analysis was performed to identify the compounds in the extracts. Results The six crude extracts had different cytotoxicities and were classified into three groups based on their IC50 value and selectivity index (SI). DC (twig) crude extract had both a high cytotoxicity and SI toward HepG2 cells comparable to melphalan (P = 0.023). The crude extracts of DC (leaves), LC (twig), and BA (twig) had moderate cytotoxicity and a lower SI. Although all crude plant extracts induced apoptosis in more than 50 % of the DAPI-positive apoptotic HepG2 cells, only DC (twig) and LC (twig) showed laddering in the DNA fragmentation assay. 2-Palmitoylglycerol was the major compound common to both. Pyrogallol and lupeol were the major compounds in DC (twig) crude extract. Hexadecanoic acid and octadecenoic acid were the major compounds in LC (twig) crude extract, which had high toxicity but low selectivity. Conclusion Ethanolic extracts from DC and LC twigs induced apoptosis in the HepG2 cell line. Pyrogallol and lupeol in DC (twig) might be responsible for the cytotoxicity toward the HepG2 cancer cells.
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Affiliation(s)
| | - Cholpajsorn Junhom
- Graduate School, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, 40002 Thailand
| | - Sahapat Barusrux
- Faculty of Associate Medical Sciences, Khon Kaen University, Khon Kaen, 40002 Thailand
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Lupeol enhances inhibitory effect of 5-fluorouracil on human gastric carcinoma cells. Naunyn Schmiedebergs Arch Pharmacol 2016; 389:477-84. [PMID: 26892272 DOI: 10.1007/s00210-016-1221-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Accepted: 02/09/2016] [Indexed: 01/11/2023]
Abstract
Lupeol, a dietary triterpene present in many fruits and medicinal plants, has been reported to possess many pharmacological properties including cancer-preventive and anti-cancer effects in vitro and in vivo. Here, we investigated the anti-cancer efficacy and adjuvant chemotherapy action of lupeol in gastric cancer (GC) cells (SGC7901 and BGC823) and explored the underlying mechanisms. Cells were treated with lupeol and/or 5-fluorouracil (5-Fu) and subjected to cell viability, colony formation, apoptosis, western blot, semiquantitative RT-PCR, and xenograft tumorigenicity assay. Our results showed that lupeol and 5-Fu inhibited the proliferation of SGC7901 and BGC823 cells, and combination treatment with lupeol and 5-Fu resulted in a combination index < 1, indicating a synergistic effect. Co-treatment with lupeol and 5-Fu induced apoptosis through up-regulating the expressions of Bax and p53 and down-regulating the expressions of survivin and Bcl-2. Furthermore, co-treatment displayed more efficient inhibition of tumor weight and volume on BGC823 xenograft mouse model than single-agent treatment with 5-Fu or lupeol. Taken together, our findings highlight that lupeol sensitizes GC to 5-Fu treatment, and combination treatment with lupeol and 5-Fu would be a promising therapeutic strategy for human GC treatment.
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El-Far AH, Badria FA, Shaheen HM. Possible Anticancer Mechanisms of Some Costus speciosus Active Ingredients Concerning Drug Discovery. Curr Drug Discov Technol 2016; 13:123-143. [PMID: 27515456 PMCID: PMC5086671 DOI: 10.2174/1570163813666160802154403] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Revised: 07/18/2016] [Accepted: 07/26/2016] [Indexed: 04/23/2023]
Abstract
Costus speciosus is native to South East Asia, especially found in India, Srilanka, Indonesia and Malaysia. C. speciosus have numerous therapeutic potentials against a wide variety of complains. The therapeutic properties of C. speciosus are attributed to the presence of various ingredients such as alkaloids, flavonoids, glycosides, phenols, saponins, sterols and sesquiterpenes. This review presented the past, present, and the future status of C. speciosus active ingredients to propose a future use as a potential anticancer agent. All possible up-regulation of cellular apoptotic molecules as p53, p21, p27, caspases, reactive oxygen species (ROS) generation and others attribute to the anticancer activity of C. speciosus along the down-regulation of anti-apoptotic agents such as Akt, Bcl2, NFKB, STAT3, JAK, MMPs, actin, surviving and vimentin. Eventually, we recommend further investigation of different C. speciosus extracts, using some active ingredients and evaluate the anticancer effect of these chemicals against different cancers.
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Affiliation(s)
- Ali H. El-Far
- Department of Biochemistry, Faculty of Veterinary Medicine, Damanhour University, El-Beheira, Egypt
| | - Faried A. Badria
- Departments of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Egypt
| | - Hazem M. Shaheen
- Department of Pharmacology, Faculty of Veterinary Medicine, Damanhour University, El-Beheira, Egypt
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Liu Y, Bi T, Dai W, Wang G, Qian L, Shen G, Gao Q. Lupeol Induces Apoptosis and Cell Cycle Arrest of Human Osteosarcoma Cells Through PI3K/AKT/mTOR Pathway. Technol Cancer Res Treat 2015; 15:NP16-NP24. [PMID: 26443801 DOI: 10.1177/1533034615609014] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 08/22/2015] [Accepted: 09/03/2015] [Indexed: 12/20/2022] Open
Abstract
Lupeol, a dietary triterpene present in many fruits and medicinal plants, has been reported to possess many pharmacological properties including anticancer effect in vitro and in vivo However, the activity of lupeol against osteosarcoma remains unclear. The present study is conducted to investigate the anticancer activity and the underlying mechanisms of lupeol on human osteosarcoma cells (MNNG/HOS and MG-63) in vitro and in vivo MNNG/HOS and MG-63 cells were treated by lupeol and subjected to methyl thiazolyl tetrazolium analysis, Hoechst staining, annexin V/propidium iodide double staining, cell cycle analysis, and Western blot analysis. In addition, MNNG/HOS xenograft tumors were established in female nude BALB/c mice, and lupeol was intravenously administered to evaluate the anticancer capacity in vivo Our results showed that lupeol induced apoptosis as well as cell cycle arrest in G0/G1 phase of MNNG/HOS and MG-63 cells in a dose-dependent manner in vitro Furthermore, the protein expression levels of phospho-phosphatidylinositol 3-kinase (p-PI3K), phospho-protein kinase B (p-AKT), p-p70S6K, and cyclin D1 were significantly downregulated, whereas the expression levels of p21 and p27 were upregulated. These protein interactions may play a pivotal role in the regulation of apoptosis and cell cycle arrest. More importantly, our in vivo studies showed that administration of lupeol decreased tumor growth in a dose-dependent manner and has no significant effect on the function of liver and kidney. Taken together, our findings indicated that lupeol can induce apoptosis as well as cell cycle arrest of human osteosarcoma cells through phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway and might offer a promising new approach in the effective treatment of osteosarcoma.
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Affiliation(s)
- Yan Liu
- Department of General Surgery, Wujiang No.1 People's Hospital, Suzhou, China
| | - Tingting Bi
- Department of Geriatric Ward, Wujiang No.1 People's Hospital, Suzhou, China
| | - Wei Dai
- Department of General Surgery, Wujiang No.1 People's Hospital, Suzhou, China
| | - Gang Wang
- Department of General Surgery, Wujiang No.1 People's Hospital, Suzhou, China
| | - Liqiang Qian
- Department of General Surgery, Wujiang No.1 People's Hospital, Suzhou, China
| | - Genhai Shen
- Department of General Surgery, Wujiang No.1 People's Hospital, Suzhou, China
| | - Quangen Gao
- Department of General Surgery, Wujiang No.1 People's Hospital, Suzhou, China
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Kwon HH, Yoon JY, Park SY, Min S, Kim YI, Park JY, Lee YS, Thiboutot DM, Suh DH. Activity-Guided Purification Identifies Lupeol, a Pentacyclic Triterpene, As a Therapeutic Agent Multiple Pathogenic Factors of Acne. J Invest Dermatol 2015; 135:1491-1500. [DOI: 10.1038/jid.2015.29] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2014] [Revised: 01/12/2015] [Accepted: 01/21/2015] [Indexed: 12/25/2022]
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Jin Y, Lyu Y, Tang X, Zhang Y, Chen J, Zheng D, Liang Y. Lupeol enhances radiosensitivity of human hepatocellular carcinoma cell line SMMC-7721 in vitro and in vivo. Int J Radiat Biol 2015; 91:202-8. [DOI: 10.3109/09553002.2015.966209] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Chudzik M, Korzonek-Szlacheta I, Król W. Triterpenes as potentially cytotoxic compounds. Molecules 2015; 20:1610-25. [PMID: 25608043 PMCID: PMC6272502 DOI: 10.3390/molecules20011610] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 01/13/2015] [Indexed: 01/05/2023] Open
Abstract
Triterpenes are compounds of natural origin, which have numerously biological activities: anti-cancer properties, anti-inflammatory, anti-oxidative, anti-viral, anti-bacterial and anti-fungal. These substances can be isolated from plants, animals or fungi. Nowadays, when neoplasms are main cause of death, triterpenes can become an alternative method for treating cancer because of their cytotoxic properties and chemopreventive activities.
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Affiliation(s)
- Malwina Chudzik
- Chair and Department of Microbiology and Immunology, Medical University of Silesia in Katowice, Jordana 19, Zabrze 41-808, Poland.
| | - Ilona Korzonek-Szlacheta
- Department of Nutrition-Associated Disease Prevention, Faculty of Public Health, Medical University of Silesia in Katowice, Piekarska 18, Bytom 41-902, Poland.
| | - Wojciech Król
- Chair and Department of Microbiology and Immunology, Medical University of Silesia in Katowice, Jordana 19, Zabrze 41-808, Poland.
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Liu Y, Bi T, Wang G, Dai W, Wu G, Qian L, Gao Q, Shen G. Lupeol inhibits proliferation and induces apoptosis of human pancreatic cancer PCNA-1 cells through AKT/ERK pathways. Naunyn Schmiedebergs Arch Pharmacol 2014; 388:295-304. [PMID: 25418891 DOI: 10.1007/s00210-014-1071-4] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 11/13/2014] [Indexed: 01/05/2023]
Abstract
Lupeol, a dietary triterpene, present in many fruits and medicinal plants, has been reported to possess many pharmacological properties including anti-cancer activities both in vitro and in vivo. However, the precise mechanism involved remains largely unknown. The present study is conducted to investigate the anti-cancer activity and the underlying mechanisms of lupeol on human pancreatic cancer proliferating cell nuclear antigen 1 (PCNA-1) cells in vitro and in vivo. Lupeol significantly inhibited the proliferation of the cells in dose- and time-dependent manners and induced apoptosis as well as cell cycle arrest in G0/G1 phase by upregulating P21 and P27 and downregulating cyclin D1. The expression of apoptosis-related proteins in cells was evaluated by western blot analysis, and we found that lupeol induced cell apoptosis by decreasing the levels of p-AKT and p-ERK. In addition, pretreatment with a specific PI3K/AKT activator (IGF-1) significantly neutralized the pro-apoptotic activity of lupeol in PCNA-1 cells, demonstrating the important role of AKT in this process. More importantly, our in vivo studies showed that administration of lupeol decreased tumor growth in a dose-dependent manner. Immunohistochemistry analysis demonstrated the downregulation of p-AKT and p-ERK in tumor tissues following lupeol treatment, consistent with the in vitro results. Therefore, these findings indicate that lupeol can inhibit cell proliferation and induce apoptosis as well as cell cycle arrest of PCNA-1 cells and might offer a therapeutic potential advantage for human pancreatic cancer chemoprevention or chemotherapy.
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Affiliation(s)
- Yan Liu
- Department of General Surgery, Wujiang No.1 People's Hospital, Suzhou, 215200, China
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Pitchai D, Roy A, Ignatius C. In vitro evaluation of anticancer potentials of lupeol isolated from Elephantopus scaber L. on MCF-7 cell line. J Adv Pharm Technol Res 2014; 5:179-84. [PMID: 25364696 PMCID: PMC4215481 DOI: 10.4103/2231-4040.143037] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Lupeol is a triterpenoid, present in most of the medicinally effective plants and possess a wide range of biological activity against human diseases. The present study aims at evaluating the anticancer potentials of lupeol, isolated from the leaves of Elephantopus scaber L. and thereby explores its action on key cancer marker, Bcl-2. The effect of lupeol on the cell viability of MCF-7 was determined by MTT and lactate dehydrogenase assays at different concentrations. The efficacy of the compound to induce cell death was analyzed using AO/EtBr staining. Phase contrast microscopic analysis provided the changes in cell morphology of the compound treated normal breast cells (MCF-10A) and MCF-7 cells. The expression of Bcl-2 and Bcl-xL proteins in the normal, cancer and lupeol treated cancer cell was analyzed by western blotting. Lupeol induced an effective change in the cell viability of MCF-7 cells with IC50 concentration as 80 μM. Induction of cell death, change in cell morphology and population of the cancer cells was observed in the lupeol treated cells, but the normal cells were not affected. The compound effectively downregulated Bcl-2 and Bcl-xL protein expressions, which directly contribute for the induction of MCF-7 cell apoptosis. Conclusion: Thus, lupeol acts as an anticancer agent against MCF-7 cells and is a potent phytodrug to be explored further for its cytotoxic mechanism.
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Affiliation(s)
- Daisy Pitchai
- Department of Biotechnology, Bioinformatics and Zoology, Holy Cross College (Automonous), Tiruchirappalli, Tamil Nadu, India
| | - Anita Roy
- Department of Biotechnology and Bioinformatics, Holy Cross College (Automonous), Tiruchirappalli, Tamil Nadu, India
| | - Cybil Ignatius
- Department of Zoology, Holy Cross College (Automonous), Tiruchirappalli, Tamil Nadu, India
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Liu Y, Bi T, Shen G, Li Z, Wu G, Wang Z, Qian L, Gao Q. Lupeol induces apoptosis and inhibits invasion in gallbladder carcinoma GBC-SD cells by suppression of EGFR/MMP-9 signaling pathway. Cytotechnology 2014; 68:123-133. [PMID: 25037728 DOI: 10.1007/s10616-014-9763-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Accepted: 06/25/2014] [Indexed: 12/13/2022] Open
Abstract
The cytostatic drug from fruits and other plant derived products have acted as a chemotherapeutic agent used in treatment of a wide variety of cancers. Lupeol, a dietary triterpene, present in many fruits and medicinal plants, has been shown to possess many pharmacological properties including anti-cancer effect in both in vitro and in vivo assay systems. However, the cancer proliferative and invasive inhibitory effects and molecular mechanisms on gallbladder carcinoma GBC-SD cells have not been studied. In the present study, GBC-SD cells were treated by lupeol and subjected to methyl thiazolyl tetrazolium analysis, Hoechst 33342 staining, annexin V/propidium iodide double-staining, transwell chamber assay and Western blot analysis. In addition, GBC-SD xenograft tumors were established in male nude BALB/c mice, and lupeol was intravenously administered to evaluate the anti-cancer capacity in vivo. Our results showed that lupeol inhibited the proliferation, migration, invasion and induced apoptosis of GBC-SD cells in a dose-dependent manner in vitro. Furthermore, the expression of p-EGFR, p-AKT and MMP-9 levels were significantly down-regulated. These protein interactions may play a pivotal role in the regulation of apoptosis and invasion. More importantly, our in vivo studies showed that administration of lupeol decreased tumor growth in a dose-dependent manner. Immunohistochemistry analysis demonstrated the down-regulation of p-EGFR and MMP-9 in tumor tissues following lupeol treatment, consistent with the in vitro results. Taken together, our findings indicated that lupeol can induce apoptotic cell death and inhibit the migration as well as invasion of GBC-SD cells. The mechanism may be associated with the suppression of EGFR/MMP-9 signaling. These results might offer a therapeutic potential advantage for human gallbladder carcinoma chemoprevention or chemotherapy.
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Affiliation(s)
- Yan Liu
- Department of General Surgery, Wujiang No.1 People's Hospital, Suzhou, 215200, China
- Graduate School, Xuzhou Medical College, Xuzhou, 221004, China
| | - Tingting Bi
- Department of General Surgery, Wujiang No.1 People's Hospital, Suzhou, 215200, China
- Graduate School, Xuzhou Medical College, Xuzhou, 221004, China
| | - Genhai Shen
- Department of General Surgery, Wujiang No.1 People's Hospital, Suzhou, 215200, China
| | - Zhimin Li
- Department of General Surgery, Wujiang No.1 People's Hospital, Suzhou, 215200, China
| | - Guoliang Wu
- Department of General Surgery, Wujiang No.1 People's Hospital, Suzhou, 215200, China
| | - Zheng Wang
- Department of General Surgery, Wujiang No.1 People's Hospital, Suzhou, 215200, China
| | - Liqiang Qian
- Department of General Surgery, Wujiang No.1 People's Hospital, Suzhou, 215200, China
| | - Quangen Gao
- Department of General Surgery, Wujiang No.1 People's Hospital, Suzhou, 215200, China.
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