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Li Y, Li Y, Yao Y, Li H, Gao C, Sun C, Zhuang J. Potential of cucurbitacin as an anticancer drug. Biomed Pharmacother 2023; 168:115707. [PMID: 37862969 DOI: 10.1016/j.biopha.2023.115707] [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: 07/18/2023] [Revised: 10/03/2023] [Accepted: 10/11/2023] [Indexed: 10/22/2023] Open
Abstract
In Chinese medicine, the Cucurbitaceae family contains many compounds known as cucurbitacins, which have been categorized into 12 classes ranging from A to T and more than 200 derivatives. Cucurbitacins are a class of highly oxidized tetracyclic triterpenoids with potent anticancer properties. The eight components of cucurbitacins with the strongest anticancer activity are cucurbitacins B, D, E, I, IIa, L-glucoside, Q, and R. Cucurbitacins have also been reported to suppress JAK-STAT 3, mTOR, VEGFR, Wnt/β-catenin, and MAPK signaling pathways, all of which are crucial for the survival and demise of cancer cells. In this paper, we review the progress in research on cucurbitacin-induced apoptosis, autophagy, cytoskeleton disruption, cell cycle arrest, inhibition of cell proliferation, inhibition of invasion and migration, inhibition of angiogenesis, epigenetic alterations, and synergistic anticancer effects in tumor cells. Recent studies have identified cucurbitacins as promising molecules for therapeutic innovation with broad versatility in immune response. Thus, cucurbitacin is a promising class of anticancer agents that can be used alone or in combination with chemotherapy and radiotherapy for the treatment of many types of cancer.Therefore, based on the research reports in the past five years at home and abroad, we further summarize and review the structural characteristics, chemical and biological activities, and studies of cucurbitacins based on the previous studies to provide a reference for further development and utilization of cucurbitacins.
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Affiliation(s)
- Yan Li
- College of Chinese Medicine, Weifang Medical University, Weifang, China
| | - Yingrui Li
- College of Chinese Medicine, Weifang Medical University, Weifang, China
| | - Yan Yao
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250022, China
| | - Huayao Li
- College of Chinese Medicine, Weifang Medical University, Weifang, China
| | - Chundi Gao
- College of Chinese Medicine, Weifang Medical University, Weifang, China
| | - Changgang Sun
- College of Chinese Medicine, Weifang Medical University, Weifang, China; Department of Oncology, Weifang Traditional Chinese Hospital, Weifang 261000, China
| | - Jing Zhuang
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang 261000, China.
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Liu H, Wang H, Dong A, Huo X, Wang H, Wang J, Si J. The Inhibition of Gastric Cancer Cells’ Progression by 23,24-Dihydrocucurbitacin E through Disruption of the Ras/Raf/ERK/MMP9 Signaling Pathway. Molecules 2022; 27:molecules27092697. [PMID: 35566048 PMCID: PMC9100127 DOI: 10.3390/molecules27092697] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/11/2022] [Accepted: 04/18/2022] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is considered to be one of the most common causes of cancer death worldwide due to its high recurrence and metastasis rates. The molecule 23,24-Dihydrocucurbitacin E (DHCE) is a cucurbitacin-derived tetracyclic triterpenoid compound that has anti-tumor activity, but the exact mechanism remains to be elucidated. This research aimed to explore the effects of DHCE on human gastric cancer cells and the possible mechanisms. The results showed that DHCE suppressed proliferation, migration, and invasion of gastric cancer cells, as well as induced apoptosis and G2/M phase arrest. Mechanistically, the potential targets and pathways of DHCE were predicted using database screening and verified using a molecular docking study, fluorescence staining, and Western blot. The results indicated that DHCE obviously inhibited the kinase activity of ERK2 via targeting its ATP-binding domain, destroyed F-actin microfilament, and reduced the expression levels of Ras, p-c-Raf, ERK, p-ERK, and MMP9 proteins. Collectively, our study demonstrated that DHCE suppressed gastric cancer cells’ proliferation, migration, and invasion through targeting ERK2 and disrupting the Ras/Raf/ERK/MMP9 signaling pathway. These properties make DHCE a promising candidate drug for the further design and development of novel and effective Ras/Raf/ERK/MMP9 pathway inhibitors for treating gastric cancer.
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Ahamad S, Mathew S, Khan WA, Mohanan K. Development of small-molecule PCSK9 inhibitors for the treatment of hypercholesterolemia. Drug Discov Today 2022; 27:1332-1349. [PMID: 35121175 DOI: 10.1016/j.drudis.2022.01.014] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 12/28/2021] [Accepted: 01/26/2022] [Indexed: 12/23/2022]
Abstract
When secreted into the circulation, proprotein convertase subtilisin kexin type 9 (PCSK9) blocks the low-density lipoprotein receptors (LDL-R) and, as a consequence, low-density lipoprotein cholesterol (LDL-C) levels increase. Therefore, PCSK9 has emerged as a potential therapeutic target for lowering LDL-C levels and preventing atherosclerosis. The US Food and Drug Administration (FDA) has approved two monoclonal antibodies (mAbs) against PCSK9, but the expensive manufacturing process limits their use. Subsequently, there have been tremendous efforts to develop cost-effective small molecules specific to PCSK9 over the past few years. These small molecules are promising therapeutics that act by preventing the synthesis of PCSK9, its secretion from cells, or the PCSK9-LDRL interaction. In this review, we summarize recent developments in the discovery of small-molecule PCSK9 inhibitors, focusing on their design, therapeutic effects, specific targets, and mechanisms of action.
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Affiliation(s)
- Shakir Ahamad
- Department of Chemistry, Aligarh Muslim University, Aligarh, 202002 UP, India.
| | - Shintu Mathew
- Medicinal and Process Chemistry Division CSIR-Central Drug Research Institute Lucknow, 226031 UP, India
| | - Waqas A Khan
- Department of Chemistry, Aligarh Muslim University, Aligarh, 202002 UP, India
| | - Kishor Mohanan
- Medicinal and Process Chemistry Division CSIR-Central Drug Research Institute Lucknow, 226031 UP, India.
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Alves CDS, Frias HV, Bonamin LV, Correia MSF, Corrêa MG, Bondan EF, de Fátima M Martins M, Coelho CP, Bernardi MM, Suffredini IB. Luffa operculata at a late period of gestation dysregulates melatonin and cytokines interfering with weight of dams and their male offspring. JOURNAL OF ETHNOPHARMACOLOGY 2021; 275:113867. [PMID: 33892067 DOI: 10.1016/j.jep.2021.113867] [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: 10/23/2020] [Revised: 12/20/2020] [Accepted: 01/18/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The tea made with the fruits of Luffa operculata (L.) Cogn. (Cucurbitaceae; EBN) is popularly used as abortive. AIM OF THE STUDY The present work aimed at accessing how the exposition of female Wistar rats to 1.0 mg/kg of EBN (experimental group, EG), or distilled water (control group, CG), by gavage, at gestational days (GD) 17-21 interfered with the reproductive performance, and with dams' behavior after weaning. MATERIALS AND METHODS At post-natal day 2 (PND2), the number of male and female pups was evaluated, as well as their weight. After weaning (PND21), dams were euthanized, and their liver and kidneys were removed for histological and biochemical analyses, while the blood was used in the evaluation of cytokines IL-1α, IL-1β, IL-6 and TNF-α, corticosterone, adrenocorticotrophic hormone, melatonin, AST, ALT and creatinine levels. RESULTS AND DISCUSSION Dams that were treated with EBN showed an anxiety-like behavior, weight loss at the end of gestation and weight gain at weaning, accompanied with a significant decrease in pro-inflammatory cytokines and in the melatonin level. No significant histological or biochemical alterations have occurred in the liver or kidneys. The number of female pups was significantly higher in the EG. The male pups showed weight gain at PND60. CONCLUSION The presence of cucurbitacins is probably involved in the dysregulations that were found, due to their polycyclic steroid triterpene structure.
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Affiliation(s)
- Cinthia Dos S Alves
- Programa de Pós-Graduação Em Patologia Ambiental e Experimental, Universidade Paulista - UNIP, Brazil
| | - Humberto V Frias
- Programa de Pós-Graduação Em Patologia Ambiental e Experimental, Universidade Paulista - UNIP, Brazil
| | - Leoni V Bonamin
- Programa de Pós-Graduação Em Patologia Ambiental e Experimental, Universidade Paulista - UNIP, Brazil
| | - Michelle S F Correia
- Programa de Pós-Graduação Em Patologia Ambiental e Experimental, Universidade Paulista - UNIP, Brazil
| | - Monica G Corrêa
- Programa de Pós-Graduação Em Odontologia, Universidade Paulista - UNIP, Brazil
| | - Eduardo F Bondan
- Programa de Pós-Graduação Em Patologia Ambiental e Experimental, Universidade Paulista - UNIP, Brazil
| | | | | | - Maria M Bernardi
- Programa de Pós-Graduação Em Patologia Ambiental e Experimental, Universidade Paulista - UNIP, Brazil; Programa de Pós-Graduação Em Odontologia, Universidade Paulista - UNIP, Brazil
| | - Ivana B Suffredini
- Programa de Pós-Graduação Em Patologia Ambiental e Experimental, Universidade Paulista - UNIP, Brazil; Programa de Pós-Graduação Em Odontologia, Universidade Paulista - UNIP, Brazil; Núcleo de Pesquisas Em Biodiversidade, Laboratório de Extração, Universidade Paulista - UNIP, Brazil.
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Alabi OA, Silva AH, Rode MP, Pizzol CD, de Campos AM, Filippin-Monteiro FB, Bakare AA, Creczynski-Pasa TB. In vitro cytotoxicity of co-exposure to superparamagnetic iron oxide and solid lipid nanoparticles. Toxicol Ind Health 2020; 37:77-89. [PMID: 33308053 DOI: 10.1177/0748233720977383] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Increased production and use of different types of nanoparticles (NPs) in the last decades has led to increased environmental release of these NPs with potential detrimental effects on both the environment and public health. Information is scarce in the literature on the cytotoxic effect of co-exposure to many NPs as this concern is relatively recent. Thus, in this study, we hypothesized scenarios of cell's co-exposure to two kinds of NPs, solid lipid nanoparticles (SLNs) and superparamagnetic iron oxide nanoparticles (SPIONs), to assess the potential cytotoxicity of exposure to NPs combination. Cytotoxicity of SPIONs, SLNs, and their 1:1 mixture (MIX) in six tumor and six non-tumor cell lines was investigated. The mechanisms underlining the induced cytotoxicity were studied through cell cycle analysis, detection of reactive oxygen species (ROS), and alterations in mitochondrial membrane potential (ΔΨM). Double staining with acridine orange and ethidium bromide was also used to confirm cell morphology alterations. The results showed that SPIONs induced low cytotoxicity compared to SLNs. However, the mixture of SPIONs and SLNs showed synergistic, antagonistic, and additive effects based on distinct tests such as viability assay, ROS generation, ΔΨM, and DNA damage, depending on the cell line. Apoptosis triggered by ROS and disturbances in ΔΨM are the most probable related mechanisms of action. As was postulated, there is possible cytotoxic interaction between the two kinds of NPs.
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Affiliation(s)
- Okunola A Alabi
- Department of Biology, Federal University of Technology, Akure, Ondo State, Nigeria.,Department of Pharmaceutical Sciences, 28117Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Adny H Silva
- Department of Biochemistry, 28117Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Michele P Rode
- Department of Pharmaceutical Sciences, 28117Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Carine Dal Pizzol
- Department of Pharmaceutical Sciences, 28117Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Angela Machado de Campos
- Department of Pharmaceutical Sciences, 28117Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Fabíola B Filippin-Monteiro
- Department of Clinical Analysis, 28117Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Adekunle A Bakare
- Cell Biology and Genetics Unit, Department of Zoology, University of Ibadan, Ibadan, Oyo State, Nigeria
| | - Tânia B Creczynski-Pasa
- Department of Pharmaceutical Sciences, 28117Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
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Ramezani M, Hasani M, Ramezani F, Karimi Abdolmaleki M. Cucurbitacins: A Focus on Cucurbitacin E As A Natural Product and Their Biological Activities. PHARMACEUTICAL SCIENCES 2020. [DOI: 10.34172/ps.2020.66] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
For the last years, different types of cucurbitacins have been extracted from various species of Cucurbitaceae family. For this review, all related papers were accumulated by searching electronic databases in the English language, including PubMed, Scopus, and Google Scholar. The keywords of cucurbitacin, cucumber anticancer therapy, cytotoxic effects, chemotherapy, and inhibitor effect were searched until February 2020. According to the result of this review, cucurbitacin E as a tetracyclic triterpenes compound, has been exhibited cell cycle arrest, anti-inflammatory and anticancer activities. It showed tumor proliferation prevention, induction of apoptosis or synergistically acts with other established antitumor compounds and cytokines throughout many molecular mechanisms. In a function-structure association manner, cucurbitacin E can inhibit Janus kinas2 (JAK2) phosphorylation, the signal transducer activator of transcription 3 (STAT3) and subsequently block these pathways, which seems to be the main mechanism of its activity. Future studies could target its detection in uninvestigated sources, subsequently its derivatives to improve their anticancer activity.
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Affiliation(s)
| | | | - Fatemeh Ramezani
- Physiology Research Center, Iran University of Medical Science, Tehran, Iran
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Wang LY, Zhao S, Lv GJ, Ma XJ, Zhang JB. Mechanisms of resveratrol in the prevention and treatment of gastrointestinal cancer. World J Clin Cases 2020; 8:2425-2437. [PMID: 32607320 PMCID: PMC7322414 DOI: 10.12998/wjcc.v8.i12.2425] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 05/20/2020] [Accepted: 05/23/2020] [Indexed: 02/05/2023] Open
Abstract
Gastrointestinal (GI) cancer is one of the leading causes of cancer-related deaths worldwide. According to the Global Cancer Statistics, colorectal cancer is the second leading cause of cancer-related mortality, closely followed by gastric cancer (GC). Environmental, dietary, and lifestyle factors including cigarette smoking, alcohol intake, and genetics are the most important risk factors for GI cancer. Furthermore, infections caused by Helicobacter pylori are a major cause of GC initiation. Despite improvements in conventional therapies, including surgery, chemotherapy, and radiotherapy, the length or quality of life of patients with advanced GI cancer is still poor because of delayed diagnosis, recurrence and side effect. Resveratrol (3, 4, 5-trihydroxy-trans-stilbene; Res), a natural polyphenolic compound, reportedly has various pharmacologic functions including anti-oxidant, anti-inflammatory, anti-cancer, and cardioprotective functions. Many studies have demonstrated that Res also exerts a chemopreventive effect on GI cancer. Research investigating the anti-cancer mechanism of Res for the prevention and treatment of GI cancer has implicated multiple pathways including oxidative stress, cell proliferation, and apoptosis. Therefore, this paper provides a review of the function and molecular mechanisms of Res in the prevention and treatment of GI cancer.
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Affiliation(s)
- Li-Yan Wang
- Department of Pharmacy, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
| | - Shan Zhao
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, Liaoning Province, China
| | - Guo-Jun Lv
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, Liaoning Province, China
| | - Xiao-Jun Ma
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, Liaoning Province, China
| | - Jian-Bin Zhang
- College of Pharmacy, Dalian Medical University, Dalian 116044, Liaoning Province, China
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Kaur R, Sharma P, Gupta GK, Ntie-Kang F, Kumar D. Structure-Activity-Relationship and Mechanistic Insights for Anti-HIV Natural Products. Molecules 2020; 25:E2070. [PMID: 32365518 PMCID: PMC7249135 DOI: 10.3390/molecules25092070] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 04/17/2020] [Accepted: 04/22/2020] [Indexed: 12/26/2022] Open
Abstract
Acquired Immunodeficiency Syndrome (AIDS), which chiefly originatesfroma retrovirus named Human Immunodeficiency Virus (HIV), has impacted about 70 million people worldwide. Even though several advances have been made in the field of antiretroviral combination therapy, HIV is still responsible for a considerable number of deaths in Africa. The current antiretroviral therapies have achieved success in providing instant HIV suppression but with countless undesirable adverse effects. Presently, the biodiversity of the plant kingdom is being explored by several researchers for the discovery of potent anti-HIV drugs with different mechanisms of action. The primary challenge is to afford a treatment that is free from any sort of risk of drug resistance and serious side effects. Hence, there is a strong demand to evaluate drugs derived from plants as well as their derivatives. Several plants, such as Andrographis paniculata, Dioscorea bulbifera, Aegle marmelos, Wistaria floribunda, Lindera chunii, Xanthoceras sorbifolia and others have displayed significant anti-HIV activity. Here, weattempt to summarize the main results, which focus on the structures of most potent plant-based natural products having anti-HIV activity along with their mechanisms of action and IC50 values, structure-activity-relationships and important key findings.
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Affiliation(s)
- Ramandeep Kaur
- Sri Sai College of Pharmacy, Manawala, Amritsar 143001, India; (R.K.); (P.S.)
| | - Pooja Sharma
- Sri Sai College of Pharmacy, Manawala, Amritsar 143001, India; (R.K.); (P.S.)
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala 147002, India
| | - Girish K. Gupta
- Department of Pharmaceutical Chemistry, Sri Sai College of Pharmacy, Badhani, Pathankot 145001, India;
| | - Fidele Ntie-Kang
- Department of Chemistry, Faculty of Science, University of Buea, P.O. Box 63 Buea, Cameroon
- Institute for Pharmacy, Martin-Luther-Universität Halle-Wittenberg, Kurt-Mothes-Str. 3, 06120 Halle (Saale), Germany
- Institut für Botanik, Technische Universität Dresden, Zellescher Weg 20b, 01062 Dresden, Germany
| | - Dinesh Kumar
- Sri Sai College of Pharmacy, Manawala, Amritsar 143001, India; (R.K.); (P.S.)
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Jiao R, Xu F, Huang X, Li H, Liu W, Cao H, Zang L, Li Z, Hua H, Li D. Antiproliferative chromone derivatives induce K562 cell death through endogenous and exogenous pathways. J Enzyme Inhib Med Chem 2020; 35:759-772. [PMID: 32183548 PMCID: PMC7144234 DOI: 10.1080/14756366.2020.1740696] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
A series of furoxan derivatives of chromone were prepared. The antiproliferative activities were tested against five cancer cell lines HepG2, MCF-7, HCT-116, B16, and K562, and two normal human cell lines L-02 and PBMCs. Among them, compound 15a exhibited the most potent antiproliferative activity. It was also found 15a produced more than 8 µM of NO at the peak time of 45 min by Griess assay. Generally, antiproliferative activity is positively related to NO release to some extent. Further in-depth studies on apoptosis-related mechanisms showed that 15a caused S-phase cell cycle arrest in a concentration-dependent manner and induced apoptosis significantly through mitochondria-related pathways. Human apoptosis protein array assay also demonstrated 15a increased the expression levels of pro-apoptotic Bax, Bad, HtrA2 and Trail R2/DR5. The expression of catalase and cell cycle blocker claspin were similarly up-regulated. In balance, 15a induced K562 cells death through both endogenous and exogenous pathways.
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Affiliation(s)
- Runwei Jiao
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Fanxing Xu
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Xiaofang Huang
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Haonan Li
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Weiwei Liu
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Hao Cao
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Linghe Zang
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Zhanlin Li
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Huiming Hua
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Dahong Li
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, P. R. China
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Li HH, Li J, Zhang XJ, Li JM, Xi C, Wang WQ, Lu YL, Xuan LJ. 23,24-Dihydrocucurbitacin B promotes lipid clearance by dual transcriptional regulation of LDLR and PCSK9. Acta Pharmacol Sin 2020; 41:327-335. [PMID: 31358898 PMCID: PMC7471448 DOI: 10.1038/s41401-019-0274-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 06/14/2019] [Indexed: 01/10/2023]
Abstract
23,24-Dihydrocucurbitacin B (designated as C95 in this article) is a cucurbitane triterpenoid that has been shown to possess a variety of pharmacological activities, such as anti-inflammatory and anti-HIV-1 activities etc. In this study, we investigated the effects of 23,24-dihydrocucurbitacin B on lipid regulation. We showed that 23,24-dihydrocucurbitacin B (1–5 μM) dose-dependently promoted DiI-LDL uptake in HepG2 cells by upregulating low-density lipoprotein receptor (LDLR) protein. In HepG2 cells, 23,24-dihydrocucurbitacin B (1–10 μM) dose-dependently enhanced LDLR promoter activity by elevating the mature form of SREBP2 (sterol regulatory element binding protein 2) protein levels on one hand, and inhibited PCSK9 (proprotein convertase subtilisin/kexin type 9) promoter activity by attenuating HNF1α (hepatocyte nuclear factor-1α) protein levels in nuclei on the other hand. Consequently, the expression of LDLR protein markedly increased, whereas the PCSK9-mediated LDLR protein degradation decreased. In a high-cholesterol LVG golden Syrian Hamster model, administration of 23,24-dihydrocucurbitacin B (30 mg · kg−1⋅ d−1, intragastric, for 3 weeks) significantly decreased the serum LDL-cholesterol (LDL-C) levels. PCSK9 protein levels in the serum and liver tissues were significantly decreased, whereas LDLR protein levels in liver tissues were significantly increased in the treated animals as compared with the control animals. In conclusion, our study demonstrates for the first time that 23,24-dihydrocucurbitacin B exhibits dual transcriptional regulation of LDLR and PCSK9 in HepG2 cells by increasing SREBP2 protein levels and decreasing HNF1α protein levels in the nuclei. These results propose a new strategy to simultaneously manage LDLR and PCSK9 protein expression and provide a promising lead compound for drug development.
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11
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Liu Y, Fan D. The Preparation of Ginsenoside Rg5, Its Antitumor Activity against Breast Cancer Cells and Its Targeting of PI3K. Nutrients 2020; 12:nu12010246. [PMID: 31963684 PMCID: PMC7019936 DOI: 10.3390/nu12010246] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/14/2020] [Accepted: 01/16/2020] [Indexed: 02/06/2023] Open
Abstract
Ginsenosides have been reported to possess various pharmacological effects, including anticancer effects. Nevertheless, there are few reports about the antitumor activity and mechanisms of ginsenoside Rg5 against breast cancer cells. In the present study, the major ginsenoside Rb1 was transformed into the rare ginsenoside Rg5 through enzymatic bioconversion and successive acid-assisted high temperature and pressure processing. Ginsenosides Rb1, Rg3, and Rg5 were investigated for their antitumor effects against five human cancer cell lines via the MTT assay. Among them, Rg5 exhibited the greatest cytotoxicity against breast cancer. Moreover, Rg5 remarkably suppressed breast cancer cell proliferation through mitochondria-mediated apoptosis and autophagic cell death. LC3B-GFP/Lysotracker and mRFP-EGFP-LC3B were utilized to show that Rg5 induced autophagosome-lysosome fusion. Western blot assays further illustrated that Rg5 decreased the phosphorylation levels of PI3K, Akt, mTOR, and Bad and suppressed the PI3K/Akt signaling pathway in breast cancer. Moreover, Rg5-induced apoptosis and autophagy could be dramatically strengthened by the PI3K/Akt inhibitor LY294002. Finally, a molecular docking study demonstrated that Rg5 could bind to the active pocket of PI3K. Collectively, our results revealed that Rg5 could be a potential therapeutic agent for breast cancer treatment.
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Affiliation(s)
- Yannan Liu
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi’an 710069, Shaanxi, China;
- Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi’an 710069, Shaanxi, China
- Biotech. & Biomed. Reserch Institute, Northwest University, Taibai North Road 229, Xi’an 710069, Shaanxi, China
| | - Daidi Fan
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi’an 710069, Shaanxi, China;
- Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi’an 710069, Shaanxi, China
- Biotech. & Biomed. Reserch Institute, Northwest University, Taibai North Road 229, Xi’an 710069, Shaanxi, China
- Correspondence:
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Wang Y, Liu M, Chen S, Wu Q. Avicularin inhibits cell proliferation and induces cell apoptosis in cutaneous squamous cell carcinoma. Exp Ther Med 2019; 19:1065-1071. [PMID: 32010270 PMCID: PMC6966122 DOI: 10.3892/etm.2019.8303] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Accepted: 11/19/2019] [Indexed: 01/22/2023] Open
Abstract
Avicularin (AL), quercetin-3-α-L-arabinofuranoside, has various pharmacological properties such as anticancer and anti-infective effects. However, the potential molecular mechanism via which AL exerts its anticancer activity is not fully understood. Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer, where metastasis has resulted in in effective clinical treatments. The aim of the present in vitro study was to investigate the anticancer effects and underlying mechanism of AL on human CSCC. The present results suggested that AL dose-dependently inhibited SCC13 cell viability and induced apoptosis. In addition, the present results suggested that AL induced apoptosis via repression of the mitogen-activated protein kinase kinase (MEK)/NF-κB signal pathway, thereby affecting the expression of apoptosis-related genes. Bax expression level was increased, while Bcl-2 expression level was decreased in SCC13 cells following AL treatment. In addition, the MEK/NF-κB signaling pathway-related genes p-MEK and phosphorylated-p65 were also decreased. The present results suggested that AL treatment increased the expression level of E-cadherin, but decreased the expression levels of N-cadherin, matrix metalloproteinase (MMP)-9 and vimentin in SCC13 cells. Collectively, the present results suggested that AL may have an anti-CSCC effect by inhibiting cell viability, inducing apoptosis and inhibiting epithelial-mesenchymal transition (EMT) of CSCC cells. The mechanism of these anti-CSCC effects was suggested to be via the regulation of apoptosis-related genes and EMT-related genes, and the inhibition of the MEK/NF-κB signaling pathway.
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Affiliation(s)
- Yan Wang
- College of Medical Technology, Jiangsu Vocational College of Medicine, Yancheng, Jiangsu 224000, P.R. China
| | - Mingzhu Liu
- Department of Dermatology, Nanjing Integrated Traditional Chinese and Western Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210014, P.R. China
| | - Shenglan Chen
- College of Medical Technology, Jiangsu Vocational College of Medicine, Yancheng, Jiangsu 224000, P.R. China
| | - Qin Wu
- College of Medical Technology, Jiangsu Vocational College of Medicine, Yancheng, Jiangsu 224000, P.R. China
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Wang QS, Gao LN, Zhu XN, Zhang Y, Zhang CN, Xu D, Cui YL. Co-delivery of glycyrrhizin and doxorubicin by alginate nanogel particles attenuates the activation of macrophage and enhances the therapeutic efficacy for hepatocellular carcinoma. Am J Cancer Res 2019; 9:6239-6255. [PMID: 31534548 PMCID: PMC6735516 DOI: 10.7150/thno.35972] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 07/26/2019] [Indexed: 12/19/2022] Open
Abstract
Nanocarrier drug delivery systems (NDDS) have been paid more attention over conventional drug delivery system for cancer therapy. However, the efficacy is hampered by the fast clearance of activated macrophage from the blood circulation system. In this study, glycyrrhizin (GL) was introduced into alginate (ALG) nanogel particles (NGPs) to construct multifunctional delivery vehicle to decrease the fast clearance of activated macrophage and enhance the anticancer efficacy with the combination therapy of GL and doxorubicin (DOX). Methods: We firstly synthesized the GL-ALG NGPs with intermolecular hydrogen bond and ionic bond as the multifunctional delivery vehicle. The immune response and phagocytosis of macrophage on GL-ALG NGPs were investigated on RAW 264.7 macrophages. The pharmacokinetic study of DOX loaded in GL-ALG NGPs was performed in rats. The active targeting effects of GL-ALG NGPs were further studied on hepatocellular carcinoma cell (HepG2) and H22 tumor-bearing mice. Moreover, the anticancer molecular mechanism of DOX/GL-ALG NGPs was investigated on HepG2 cells in vitro and tumor-bearing mice in vivo. Results: GL-ALG NGPs could not only avoid triggering the immuno-inflammatory responses of macrophages but also decreasing the phagocytosis of macrophage. The bioavailability of DOX was increased about 13.2 times by DOX/GL-ALG NGPs than free DOX in blood. The mice with normal immune functions used in constructing the tumor-bearing mice instead of the nude mouse also indicated the good biocompatibility of NGPs. GL-mediated ALG NGPs exhibited excellent hepatocellular carcinoma targeting effect in vitro and in vivo. The results suggested that the anticancer molecular mechanism of the combination therapy of glycyrrhizin and doxorubicin in ALG NGPs was performed via regulating apoptosis pathway of Bax/Bcl-2 ratio and caspase-3 activity, which was also verified in H22 tumor-bearing mice. Conclusion: DOX/GL-ALG NGPs could attenuate the activation of macrophage and enhance the therapeutic efficacy for hepatocellular carcinoma. Our results suggest that the combination therapy would provide a new strategy for liver cancer treatment.
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Chao X, Wang G, Tang Y, Dong C, Li H, Wang B, Wu J, Zhao J. The effects and mechanism of peiminine-induced apoptosis in human hepatocellular carcinoma HepG2 cells. PLoS One 2019; 14:e0201864. [PMID: 30615617 PMCID: PMC6322737 DOI: 10.1371/journal.pone.0201864] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 12/10/2018] [Indexed: 02/08/2023] Open
Abstract
Peiminine is a compound isolated from Bolbostemma paniculatum (Maxim) Franquet (Cucurbitaceae family), which has demonstrated antitumor activities. But its precise molecular mechanism underlying antitumor activity remain elusive. In this study, peiminine-induced apoptosis towards human hepatocellular carcinoma and its molecular mechanism were investigated. MTT assay was employed to assess anticancer effects of peiminine upon Hela, HepG2, SW480 and MCF-7 cell lines. Nuclear staining and flow cytometry were carried out to detect apoptosis induced by peiminine. Mitochondrial membrane potential evaluation and Western blot analysis were performed to investigate the mechanism of peiminine-induced apoptosis. The results showed peiminine reduced the viability of HepG2 cells in a time- and dose-dependent manner and had an IC50 of 4.58 μg/mL at 24h. Peiminine significantly increased the percentage of apoptotic cells and the mitochondrial membrane potential dose-dependently in HepG2 cells. The results of Western blotting indicated the expressions of Bcl-2, procaspase-3, procaspase-8, procaspase-9, and PARP decreased in HepG2 cells treated with peiminine, while the expressions of Bax, caspase-3, caspase-8, caspase-9, and cleaved PARP1 increased. The result suggests that peiminine can induce apoptosis in human hepatocellular carcinoma HepG2 cells through both extrinsic and intrinsic apoptotic pathways.
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Affiliation(s)
- Xu Chao
- The Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, P. R.China
- The College of Basic Medicine Sciences, Shaanxi University of Chinese Medicine, Xi’an, Shaanxi, P. R.China
| | - Guoquan Wang
- The College of Pharmacy, Shaanxi University of Chinese Medicine, Xi’an, Shaanxi, P. R.China
| | - Yuping Tang
- The College of Pharmacy, Shaanxi University of Chinese Medicine, Xi’an, Shaanxi, P. R.China
| | - Changhu Dong
- The Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, P. R.China
| | - Hong Li
- The Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, P. R.China
| | - Bin Wang
- The College of Pharmacy, Shaanxi University of Chinese Medicine, Xi’an, Shaanxi, P. R.China
| | - Jieqiong Wu
- The Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, P. R.China
| | - Jiarong Zhao
- The College of Basic Medicine Sciences, Shaanxi University of Chinese Medicine, Xi’an, Shaanxi, P. R.China
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Ha MT, Phan TN, Kim JA, Oh WK, Lee JH, Woo MH, Min BS. Trichosanhemiketal A and B: Two 13,14-seco-13,14-epoxyporiferastanes from the root of Trichosanthes kirilowii Maxim. Bioorg Chem 2018; 83:105-110. [PMID: 30343203 DOI: 10.1016/j.bioorg.2018.10.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 10/09/2018] [Accepted: 10/09/2018] [Indexed: 01/27/2023]
Abstract
Of the 32 Trichosanthes species in China, T. kirilowii Maxim. is the most renowned species used in traditional Chinese medicine and has diverse pharmacological properties. However, most of the phytochemical studies of T. kirilowii have focused on the fruits and seeds. In our investigation of the chemical constituents of T. kirilowii roots, two previously undescribed sterols [trichosanhemiketal A and B (1 and 2)], together with 13 known compounds, were isolated and their structures were elucidated. To the best of our knowledge, this represents the first isolation of compounds with a 13,14-seco-13,14-epoxyporiferastane (1-2) skeleton from the Cucurbitaceae family. The anti-inflammatory activity of the isolated compounds was determined through an analysis of their inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in macrophage RAW264.7 cells. Of the compounds, 4, 5, 6, and 8 showed significant inhibitory activities, with IC50 values of 8.5, 15.1, 25.4, and 28.5 µM, respectively. In addition, compound 4 inhibited inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 expression in a concentration-dependent manner.
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Affiliation(s)
- Manh Tuan Ha
- College of Pharmacy, Drug Research and Development Center, Daegu Catholic University, Gyeongbuk 38430, Republic of Korea; Laboratory of Research and Applied Biochemistry, Center for Research and Technology Transfer, Vietnam Academy of Science and Technology, Hanoi, Viet Nam
| | - Thanh Nam Phan
- College of Natural Science, Kangwon National University, Kangwon 200-701, Republic of Korea
| | - Jeong Ah Kim
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea.
| | - Won Keun Oh
- College of Pharmacy, Seoul National Univeristy, Seoul 08826, Republic of Korea
| | - Jeong Hyung Lee
- College of Natural Science, Kangwon National University, Kangwon 200-701, Republic of Korea
| | - Mi Hee Woo
- College of Pharmacy, Drug Research and Development Center, Daegu Catholic University, Gyeongbuk 38430, Republic of Korea
| | - Byung Sun Min
- College of Pharmacy, Drug Research and Development Center, Daegu Catholic University, Gyeongbuk 38430, Republic of Korea.
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16
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Yu X, Tang L, Wu H, Zhang X, Luo H, Guo R, Xu M, Yang H, Fan J, Wang Z, Su R. Trichosanthis Fructus: botany, traditional uses, phytochemistry and pharmacology. JOURNAL OF ETHNOPHARMACOLOGY 2018; 224:177-194. [PMID: 29842965 DOI: 10.1016/j.jep.2018.05.034] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 05/18/2018] [Accepted: 05/23/2018] [Indexed: 06/08/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Trichosanthis Fructus (ripe fruits of Trichosanthes kirilowii Maxim. and Trichosanthes rosthornii Harms) is an essential traditional Chinese medicine to treat thoracic obstruction, angina, cardiac failure, myocardial infarction, pulmonary heart disease, some cerebral ischaemic diseases, etc. The present report reviews the advancements in research on the botany, traditional uses, phytochemistry and pharmacology of Trichosanthis Fructus. Finally, perspectives on future research and its possible directions are discussed. AIM OF THE STUDY This review provides up-to-date information about the botany, traditional uses, phytochemistry, pharmacology, toxicity and quality control of Trichosanthis Fructus and discusses the perspectives on future research and possible directions of this traditional Chinese Medicine and its origin plants. MATERIALS AND METHODS The information on Trichosanthes kirilowii Maxim. and Trichosanthes rosthornii Harms was collected from published scientific materials, including books; monographs on medicinal plants; pharmacopoeia and electronic databases such as SCI finder, PubMed, Web of Science, ACS, Science Direct, Wiley, Springer, Taylor, CNKI and Google Scholar. RESULTS Approximately 162 compounds, including terpenoids, phytosterols, flavonoids, nitrogenous compounds and lignans, have been isolated and identified from Trichosanthes kirilowii Maxim. and Trichosanthes rosthornii Harms. Numerous studies have shown that the extracts and compounds isolated from these two plants exhibit pharmacological activities, including protection against myocardial ischaemia, calcium antagonist, endothelial cell protection, anti-hypoxic, anti-platelet aggregation, expectorant, anti-inflammatory, cytotoxic and antioxidant. CONCLUSIONS Trichosanthis Fructus is an essential traditional Chinese medicine with pharmacological activities that mainly affect the cardiovascular system. This review summarises its botany, traditional uses, phytochemistry and pharmacology. Future research is needed to clarify the different uses of the seeds, pericarps and fruits. Quality control of investigations of the fruits should be improved, and the potential uses of the flesh, leaves and twigs should be further explored.
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Affiliation(s)
- Xiankuo Yu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing 100700, China
| | - Liying Tang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing 100700, China
| | - Hongwei Wu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing 100700, China
| | - Xiao Zhang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing 100700, China
| | - Hanyan Luo
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing 100700, China
| | - Rixin Guo
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing 100700, China
| | - Mengying Xu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing 100700, China
| | - Hongjun Yang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing 100700, China
| | - Jianwei Fan
- State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Shandong 276006, China
| | - Zhuju Wang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing 100700, China.
| | - Ruiqiang Su
- State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Shandong 276006, China.
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17
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Structure-Based Classification and Anti-Cancer Effects of Plant Metabolites. Int J Mol Sci 2018; 19:ijms19092651. [PMID: 30200668 PMCID: PMC6163735 DOI: 10.3390/ijms19092651] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 09/04/2018] [Accepted: 09/05/2018] [Indexed: 12/28/2022] Open
Abstract
A variety of malignant cancers affect the global human population. Although a wide variety of approaches to cancer treatment have been studied and used clinically (surgery, radiotherapy, chemotherapy, and immunotherapy), the toxic side effects of cancer therapies have a negative impact on patients and impede progress in conquering cancer. Plant metabolites are emerging as new leads for anti-cancer drug development. This review summarizes these plant metabolites with regard to their structures and the types of cancer against which they show activity, organized by the organ or tissues in which each cancer forms. This information will be helpful for understanding the current state of knowledge of the anti-cancer effects of various plant metabolites against major types of cancer for the further development of novel anti-cancer drugs.
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18
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Akhtar MF, Ashraf M, Javeed A, Anjum AA, Sharif A, Saleem M, Mustafa G, Ashraf M, Saleem A, Akhtar B. Association of textile industry effluent with mutagenicity and its toxic health implications upon acute and sub-chronic exposure. ENVIRONMENTAL MONITORING AND ASSESSMENT 2018; 190:179. [PMID: 29492685 DOI: 10.1007/s10661-018-6569-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 02/20/2018] [Indexed: 06/08/2023]
Abstract
Complex industrial discharges pose certain risks to the ecosystem. This study was aimed at identifying acute and sub-chronic toxicological effects of the textile industry wastewater. The textile wastewater was evaluated for the metals and organic pollutants by atomic absorption spectrophotometer and GC-MS respectively. In vitro genotoxicity and mutagenicity were assessed by Comet assay in peripheral lymphocytes isolated from Ovis aries and Ames test in Salmonella typhimurium strains TA-100 and 102 respectively. Physiological and behavioral changes along with systemic toxicity were determined in Rattus norvegicus albinus following acute and sub-chronic exposure. High amount of heavy metals such as Cr, Pb, Hg, As, and Cd were detected in textile wastewater. Organic pollutants such as 25-deacetoxy cucurbitacin-b, E-14-Hexadecenal, 11-Tricosene, and phthalates were also found. In vitro genotoxicity assessment in lymphocytes showed statistically significant DNA damaging potential of textile wastewater. Textile wastewater also showed significantly higher (p˂ 0.05) mutagenic potential in Salmonella TA-100 and TA-102 strains than sodium azide and 2-amino anthracycline. Acute exposure of textile wastewater to Rattus norvegicus was associated with several physiological changes and behavioral symptoms. Sub-chronic exposure of textile wastewater in Rattus norvegicus instigated the degeneration and necrosis of epithelial cells in renal tubules, hydropic degeneration and necrosis of hepatocytes, peri-bronchiolar infiltration and emphysema of the alveoli, and the degradation of myocardial cells. This study concludes that the textile wastewater may cause genotoxicity and mutagenicity, result in physiological and behavioral changes upon acute exposure, and inflict various pathological lesions upon sub-chronic exposure.
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Affiliation(s)
- Muhammad Furqan Akhtar
- Department of Pharmacology and Toxicology, University of Veterinary and Animal Sciences, Lahore, Pakistan.
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan.
| | - Muhammad Ashraf
- Department of Pharmacology and Toxicology, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Aqeel Javeed
- Department of Pharmacology and Toxicology, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Aftab Ahmad Anjum
- Department of Microbiology, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Ali Sharif
- Department of Pharmacology and Toxicology, University of Veterinary and Animal Sciences, Lahore, Pakistan
- Faculty of Pharmacy, University of Lahore, Lahore, Pakistan
| | - Mohammad Saleem
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan
| | - Ghulam Mustafa
- Department of Pathology, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Moneeb Ashraf
- Post Graduate Medical Institute, Jail Road, Lahore, Pakistan
| | - Ammara Saleem
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan
| | - Bushra Akhtar
- Institute of Pharmacy, Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan
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Yang Y, Huang X, Chen S, Ma G, Zhu M, Yan F, Yu J. Resveratrol induced apoptosis in human gastric carcinoma SGC-7901 cells via activation of mitochondrial pathway. Asia Pac J Clin Oncol 2018; 14:e317-e324. [PMID: 29316254 DOI: 10.1111/ajco.12841] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 12/05/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Resveratrol is a natural polyphenolic compound and its anticancer effect has been receiving considerable attention. Previous studies showed that resveratrol could inhibited the growth of human gastric carcinoma cells and apoptosis induction was an important mechanism. However, whether mitochondrial pathway was involved in resveratrol-induced apoptosis in human gastric cancer was not very clear. METHODS The cells were examined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, Annexin V/PI staining assay, mitochondrial membrane depolarization, cell morphological assessment, cytochrome c release assay, and Western blotting assay. RESULTS In this study, we found that resveratrol induced apoptosis in human gastric carcinoma SGC-7901 cells. Cleaved PARP was observed and caspase-3 was activated by resveratrol. Next, the mitochondrial membrane potential of cells dissipated after the cells were treated by resveratrol. Moreover, we found that pro-caspase 9 was downregulated and cytochrome c released from mitochondrial to the cytosol. We also found that the expression ratio of Bax/Bcl-2 was increased in the treated cells. We finally showed that resveratrol inhibited the proliferation of SGC-7901 xerograph in vivo. CONCLUSIONS Collectively, our findings demonstrate that resveratrol triggers apoptosis via mitochondrial pathway in SGC-7901 cells, which provide more basis for resveratrol acting as antitumor agents in cancer therapy.
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Affiliation(s)
- Yining Yang
- Department of Molecular Biology, Jiangsu Institute of Cancer Research, Nanjing, China
| | - Xinen Huang
- Department of Molecular Biology, Jiangsu Institute of Cancer Research, Nanjing, China
| | - Senqing Chen
- Department of Molecular Biology, Jiangsu Institute of Cancer Research, Nanjing, China
| | - Guojian Ma
- Department of Molecular Biology, Jiangsu Institute of Cancer Research, Nanjing, China
| | - Ming Zhu
- Department of Molecular Biology, Jiangsu Institute of Cancer Research, Nanjing, China
| | - Feng Yan
- Department of Molecular Biology, Jiangsu Institute of Cancer Research, Nanjing, China
| | - Jun Yu
- Department of Molecular Biology, Jiangsu Institute of Cancer Research, Nanjing, China
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20
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Zhang JX, Wei-Tan H, Hu CY, Wang WQ, Chu GH, Wei LH, Chen L. Anticancer activity of 23,24-dihydrocucurbitacin B against the HeLa human cervical cell line is due to apoptosis and G 2/M cell cycle arrest. Exp Ther Med 2018; 15:2575-2582. [PMID: 29456661 DOI: 10.3892/etm.2018.5710] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 11/17/2017] [Indexed: 12/30/2022] Open
Abstract
Cervical cancer is one of the primary causes of cancer-associated mortality worldwide. Due to the increasing incidence of cervical cancer, multiple treatment options are required. Initial responses to chemotherapy and surgical interventions are generally positive, however patients often experience relapse and tumor recurrence. Currently, the effects of cucurbitacins on different types of cancer are being investigated, as they exhibit a wide variety of bioactivities. The anticancer activity of the cucurbitacin 23,24-dihydrocucurbitacin B against a panel of human cervical cancer cell lines was investigated in the current study. Cell viability was determined using an MTT assay and apoptosis was detected using DAPI staining. The proportion of apoptotic cells, cell cycle distribution, mitochondrial membrane potential (ΔΨm) and reactive oxygen species (ROS) levels were estimated using flow cytometry. Protein expression was determined using western blot analysis. The results of the current study indicated that 23,24-dihydrocucurbitacin B inhibited the viability of human cervical cancer cell lines and had an IC50 of 40-60 µM. However, its cytotoxic effects were much less pronounced in normal epithelial fr2 and HerEpiC cells, where it had an IC50 of 125 µM. The underlying mechanisms of this were further studied and the results demonstrated that 23,24-dihydrocucurbitacin B induced apoptosis in HeLa cells and caused ROS-mediated shifts in the ΔΨm. Additionally, it caused the cell cycle arrest of HeLa cells at the G2/M checkpoint. The phosphoinositide 3 kinase/protein kinase B/mechanistic target of rampamycin (PI3K/AKT/mTOR) cascade may serve an important role in cancer tumorigenesis, progression and resistance to chemotherapy. The results indicated that 23,24-dihydrocucurbitacin B significantly decreased the expression of important proteins in the PI3K/Akt/mTOR cascade. Taken together, these results suggest that 23,24-dihydrocucurbitacin B may be novel method of treating cervical cancer.
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Affiliation(s)
- Jun-Xiao Zhang
- Department of Gynecology, Northwest Women and Children's Hospital, Xi'an, Shaanxi 710061, P.R. China
| | - Hong Wei-Tan
- Department of Gynecology, Northwest Women and Children's Hospital, Xi'an, Shaanxi 710061, P.R. China
| | - Chun-Yan Hu
- Department of Gynecology, Northwest Women and Children's Hospital, Xi'an, Shaanxi 710061, P.R. China
| | - Wei-Qiang Wang
- Department of Gynecology, Northwest Women and Children's Hospital, Xi'an, Shaanxi 710061, P.R. China
| | - Guang-Hua Chu
- Department of Gynecology, Northwest Women and Children's Hospital, Xi'an, Shaanxi 710061, P.R. China
| | - Li-Hui Wei
- Department of Gynecology, Peking University People's Hospital, Beijing 100044, P.R. China
| | - Liu Chen
- Department of Gynecology, Northwest Women and Children's Hospital, Xi'an, Shaanxi 710061, P.R. China
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Shen S, Li W, Ouyang MA, Wang J. Structure-activity relationship of Triterpenes and derived Glycosides against cancer cells and mechanism of apoptosis induction. Nat Prod Res 2017; 32:654-661. [PMID: 28662592 DOI: 10.1080/14786419.2017.1335725] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Triterpenoids possess a wide range of biological effects. Here, the cytotoxic activities of 55 triterpenes and derived glycosides against BEL-7404 and SGC-7901 cells were assessed, and structure-activity relationships were analysed accordingly. Nine of them effectively inhibited the two cell lines. In particular, compounds 49 and 52 inhibited BEL-7404 cells as efficiently as 5'-fluorouracil (IC50 values 0.46 and 1.48, respectively). Moreover, we found that compounds 49 and 52 induced apoptosis in BEL-7404 cells. Indeed, DNA fragmentation assay showed a time-dependent degradation of DNA after treatment of cells with compounds 49 and 52. In addition, Bax gene expression levels were increased after treatment with these compounds, in a concentration-dependent manner. Taken together, our findings suggested that compounds 49 and 52 induce apoptosis in BEL-7404 cells by upregulating the Bax gene without affecting Bcl-2 gene expression.
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Affiliation(s)
- Shuo Shen
- a Academy of Agriculture and Forestry Sciences of Qinghai University (Qinhai Academy of Agriculture and Forestry Sciences) , Xining , China.,b State Key Laboratory of Plateau Ecology and Agriculture , Qinghai University , Xining , China.,c Institute of Plant Virology , Fujian Agriculture and Forestry University , Fuzhou , China.,d Key Laboratory of the Tibet Plateau Biotechnology , Ministry of Education , Xining , China
| | - Wei Li
- a Academy of Agriculture and Forestry Sciences of Qinghai University (Qinhai Academy of Agriculture and Forestry Sciences) , Xining , China.,b State Key Laboratory of Plateau Ecology and Agriculture , Qinghai University , Xining , China.,c Institute of Plant Virology , Fujian Agriculture and Forestry University , Fuzhou , China.,d Key Laboratory of the Tibet Plateau Biotechnology , Ministry of Education , Xining , China
| | - Ming-An Ouyang
- c Institute of Plant Virology , Fujian Agriculture and Forestry University , Fuzhou , China
| | - Jian Wang
- a Academy of Agriculture and Forestry Sciences of Qinghai University (Qinhai Academy of Agriculture and Forestry Sciences) , Xining , China.,b State Key Laboratory of Plateau Ecology and Agriculture , Qinghai University , Xining , China.,d Key Laboratory of the Tibet Plateau Biotechnology , Ministry of Education , Xining , China
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22
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Allylic isothiouronium salts: The discovery of a novel class of thiourea analogues with antitumor activity. Eur J Med Chem 2017; 129:151-158. [DOI: 10.1016/j.ejmech.2017.02.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 01/19/2017] [Accepted: 02/06/2017] [Indexed: 12/15/2022]
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23
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Biodegradable and Biocompatible Systems Based on Hydroxyapatite Nanoparticles. APPLIED SCIENCES-BASEL 2017. [DOI: 10.3390/app7010060] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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24
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Yang Z, Hu X, Wu S. Preparative isolation of a cytotoxic principle of a forest mushroomSuillus luteusby sodium dodecyl sulfate based “salting-in” countercurrent chromatography. J Sep Sci 2016; 39:732-40. [DOI: 10.1002/jssc.201501028] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 11/19/2015] [Accepted: 11/22/2015] [Indexed: 11/11/2022]
Affiliation(s)
- Zhi Yang
- Research Center of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences; Zhejiang University, Hangzhou 310058; China
| | - Xueqian Hu
- School of Medicine; Zhejiang University; Hangzhou 310058 China
| | - Shihua Wu
- Research Center of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences; Zhejiang University, Hangzhou 310058; China
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Reyes-Zurita FJ, Rufino-Palomares EE, García-Salguero L, Peragón J, Medina PP, Parra A, Cascante M, Lupiáñez JA. Maslinic Acid, a Natural Triterpene, Induces a Death Receptor-Mediated Apoptotic Mechanism in Caco-2 p53-Deficient Colon Adenocarcinoma Cells. PLoS One 2016; 11:e0146178. [PMID: 26751572 PMCID: PMC4709006 DOI: 10.1371/journal.pone.0146178] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 12/14/2015] [Indexed: 01/08/2023] Open
Abstract
Maslinic acid (MA) is a natural triterpene present in high concentrations in the waxy skin of olives. We have previously reported that MA induces apoptotic cell death via the mitochondrial apoptotic pathway in HT29 colon cancer cells. Here, we show that MA induces apoptosis in Caco-2 colon cancer cells via the extrinsic apoptotic pathway in a dose-dependent manner. MA triggered a series of effects associated with apoptosis, including the cleavage of caspases -8 and -3, and increased the levels of t-Bid within a few hours of its addition to the culture medium. MA had no effect on the expression of the Bax protein, release of cytochrome-c or on the mitochondrial membrane potential. This suggests that MA triggered the extrinsic apoptotic pathway in this cell type, as opposed to the intrinsic pathway found in the HT29 colon-cancer cell line. Our results suggest that the apoptotic mechanism induced in Caco-2 may be different from that found in HT29 colon-cancer cells, and that in Caco-2 cells MA seems to work independently of p53. Natural antitumoral agents capable of activating both the extrinsic and intrinsic apoptotic pathways could be of great use in treating colon-cancer of whatever origin.
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Affiliation(s)
- Fernando J. Reyes-Zurita
- Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, 18071, Granada, Spain
| | - Eva E. Rufino-Palomares
- Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, 18071, Granada, Spain
| | - Leticia García-Salguero
- Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, 18071, Granada, Spain
| | - Juan Peragón
- Department of Experimental Biology, Biochemistry and Molecular Biology Section. University of Jaen, 23071, Jaén, Spain
| | - Pedro P. Medina
- Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, 18071, Granada, Spain
| | - Andrés Parra
- Department of Organic Chemistry, Section of Natural Products, Faculty of Sciences, University of Granada, 18071, Granada, Spain
| | - Marta Cascante
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028, Barcelona, Spain
- * E-mail: (JAL); (MC)
| | - José A. Lupiáñez
- Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, 18071, Granada, Spain
- * E-mail: (JAL); (MC)
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Sung MH, Kwon OK, Oh SR, Lee J, Park SH, Han SB, Ahn KS. Azorella compacta methanolic extract induces apoptosis via activation of mitogen-activated protein kinase. Mol Med Rep 2015; 12:6821-8. [PMID: 26397193 DOI: 10.3892/mmr.2015.4317] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Accepted: 06/30/2015] [Indexed: 11/06/2022] Open
Abstract
Azorella compacta Phil. (AC) is an alpine medicinal plant used traditionally for antibacterial treatment. Recent studies have revealed that this plant also has anti‑diabetic effects, but that it is toxic. The present study investigated the underlying mechanisms of action of AC extract against human leukemia HL60 cells. Apoptosis induction was measured by MTT assay, fluorescence microscopy, DNA fragmentation assay, flow cytometric analysis, reverse transcription quantitative polymerase chain reaction and western blot analyses. It was found that AC extract inhibited the growth of HL60 and other cancer cell lines in a dose‑dependent manner. The cytotoxic effects of AC extract on HL60 cells were associated with apoptosis characterized by DNA fragmentation and dose‑dependent increases in Annexin V‑positive cells, as determined by flow cytometric analysis. AC‑extract‑induced apoptosis was accompanied by activated/cleaved caspase‑3, caspase‑9 and poly(adenosine diphosphate‑ribose) polymerase (PARP). The increases in apoptosis were also associated with decreases of the apoptosis-inhibitor B-cell lymphoma 2 (Bcl‑2), upregulation of pro‑apoptotic Bcl-2-associated X (Bax) protein and downregulation of anti‑apoptotic Bcl extra large protein. Furthermore, western blot analysis of mitogen-activated protein kinase (MAPK)-associated proteins indicated that treatment with AC extract increased the levels of c-Jun N-terminal kinase, extracellular signal-regulated kinase and p38. In addition, the expression of Bax and cleaved PARP was blocked when AC treatment was performed in the presence of MAPK inhibitors. It was therefore concluded that AC induced apoptosis in human leukemia HL60 cells via an intrinsic pathway controlled through MAPK-associated signaling.
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Affiliation(s)
- Min Hee Sung
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Chungbuk 363‑883, Republic of Korea
| | - Ok-Kyoung Kwon
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Chungbuk 363‑883, Republic of Korea
| | - Sei-Ryang Oh
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Chungbuk 363‑883, Republic of Korea
| | - Joongku Lee
- International Biological Material Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea
| | - Sang-Hong Park
- International Biological Material Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea
| | - Sang Bae Han
- College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361‑763, Republic of Korea
| | - Kyung-Seop Ahn
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Chungbuk 363‑883, Republic of Korea
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Pfaffosidic Fraction from Hebanthe paniculata Induces Cell Cycle Arrest and Caspase-3-Induced Apoptosis in HepG2 Cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2015; 2015:835796. [PMID: 26075002 PMCID: PMC4444582 DOI: 10.1155/2015/835796] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Revised: 03/26/2015] [Accepted: 04/17/2015] [Indexed: 12/02/2022]
Abstract
Hebanthe paniculata roots (formerly Pfaffia paniculata and popularly known as Brazilian ginseng) show antineoplastic, chemopreventive, and antiproliferative properties. Functional properties of these roots and their extracts are usually attributed to the pfaffosidic fraction, which is composed mainly by pfaffosides A–F. However, the therapeutic potential of this fraction in cancer cells is not yet entirely understood. This study aimed to analyze the antitumoral effects of the purified pfaffosidic fraction or saponinic fraction on the human hepatocellular carcinoma HepG2 cell line. Cellular viability, proliferation, and apoptosis were evaluated, respectively, by MTT assay, BrdU incorporation, activated caspase-3 immunocytochemistry, and DNA fragmentation assay. Cell cycle was analyzed by flow cytometry and the cell cycle-related proteins were analyzed by quantitative PCR and Western blot. The cells exposed to pfaffosidic fraction had reduced viability and cellular growth, induced G2/M at 48 h or S at 72 h arrest, and increased sub-G1 cell population via cyclin E downregulation, p27KIP1 overexpression, and caspase-3-induced apoptosis, without affecting the DNA integrity. Antitumoral effects of pfaffosidic fraction from H. paniculata in HepG2 cells originated by multimechanisms of action might be associated with cell cycle arrest in the S phase, by CDK2 and cyclin E downregulation and p27KIP1 overexpression, besides induction of apoptosis through caspase-3 activation.
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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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Zhang M, Bian ZG, Zhang Y, Wang JH, Kan L, Wang X, Niu HY, He P. Cucurbitacin B inhibits proliferation and induces apoptosis via STAT3 pathway inhibition in A549 lung cancer cells. Mol Med Rep 2014; 10:2905-11. [PMID: 25242136 PMCID: PMC4227420 DOI: 10.3892/mmr.2014.2581] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Accepted: 07/21/2014] [Indexed: 01/11/2023] Open
Abstract
Natural products are a great source of cancer chemotherapeutic agents. The present study was conducted to investigate whether cucurbitacin B (CuB), one of the most potent and widely used cucurbitacins, inhibits proliferation and induces apoptosis in the A549 lung cancer cell line. Furthermore, CuB induced apoptosis of A549 cells in a concentration-dependent manner, as determined by fluorescence microscopy, flow cytometry and transmission electron microscopy. The present study also demonstrated that CuB dose-dependently inhibited lung cancer cell proliferation, with cell cycle inhibition and cyclin B1 downregulation. Apoptosis induced by CuB was shown to be associated with cytochrome c release, B-cell lymphoma 2 downregulation and signal transducer and activator of transcription 3 pathway inhibition. CuB may prove to be a useful approach for the chemotherapy of lung cancer.
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Affiliation(s)
- Meng Zhang
- Department of Geriatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Zhi-Gang Bian
- Department of Otolaryngology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Yi Zhang
- Department of Geriatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Jia-He Wang
- Department of Geriatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Liang Kan
- Department of Geriatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Xin Wang
- Department of Geriatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Hui-Yan Niu
- Department of Geriatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Ping He
- Department of Geriatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
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Seo CS, Kim TW, Kim YJ, Park SR, Ha H, Shin HK, Jung JY. Trichosanthes kirilowiiameliorates cisplatin-induced nephrotoxicity in bothin vitroandin vivo. Nat Prod Res 2014; 29:554-7. [DOI: 10.1080/14786419.2014.952229] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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31
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Pizzol CD, Filippin-Monteiro FB, Restrepo JAS, Pittella F, Silva AH, Alves de Souza P, Machado de Campos A, Creczynski-Pasa TB. Influence of surfactant and lipid type on the physicochemical properties and biocompatibility of solid lipid nanoparticles. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2014; 11:8581-96. [PMID: 25141003 PMCID: PMC4143879 DOI: 10.3390/ijerph110808581] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Revised: 08/04/2014] [Accepted: 08/12/2014] [Indexed: 11/27/2022]
Abstract
Nine types of solid lipid nanoparticle (SLN) formulations were produced using tripalmitin (TPM), glyceryl monostearate (GM) or stearic acid (SA), stabilized with lecithin S75 and polysorbate 80. Formulations were prepared presenting PI values within 0.25 to 0.30, and the physicochemical properties, stability upon storage and biocompatibility were evaluated. The average particle size ranged from 116 to 306 nm, with a negative surface charge around −11 mV. SLN presented good stability up to 60 days. The SLN manufactured using SA could not be measured by DLS due to the reflective feature of this formulation. However, TEM images revealed that SA nanoparticles presented square/rod shapes with an approximate size of 100 nm. Regarding biocompatibility aspects, SA nanoparticles showed toxicity in fibroblasts, causing cell death, and produced high hemolytic rates, indicating toxicity to red blood cells. This finding might be related to lipid type, as well as, the shape of the nanoparticles. No morphological alterations and hemolytic effects were observed in cells incubated with SLN containing TPM and GM. The SLN containing TPM and GM showed long-term stability, suggesting good shelf-life. The results indicate high toxicity of SLN prepared with SA, and strongly suggest that the components of the formulation should be analyzed in combination rather than separately to avoid misinterpretation of the results.
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Affiliation(s)
- Carine Dal Pizzol
- Departamento de Ciências Farmacêuticas, Programa de Pós-Graduação em Farmácia, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil.
| | - Fabíola Branco Filippin-Monteiro
- Departamento de Ciências Farmacêuticas, Programa de Pós-Graduação em Farmácia, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil.
| | - Jelver Alexander Sierra Restrepo
- Progama de Pós-Graduação em Engenharia de Materiais, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil.
| | - Frederico Pittella
- Departamento de Análises Clínicas, Universidade Federal de Juiz de Fora, Juiz de Fora, MG 36036-900, Brazil.
| | - Adny Henrique Silva
- Departamento de Ciências Farmacêuticas, Programa de Pós-Graduação em Farmácia, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil.
| | - Paula Alves de Souza
- Departamento de Ciências Farmacêuticas, Programa de Pós-Graduação em Farmácia, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil.
| | - Angela Machado de Campos
- Departamento de Ciências Farmacêuticas, Programa de Pós-Graduação em Farmácia, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil.
| | - Tânia Beatriz Creczynski-Pasa
- Departamento de Ciências Farmacêuticas, Programa de Pós-Graduação em Farmácia, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil.
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Wu ZR, Liu J, Li JY, Zheng LF, Li Y, Wang X, Xie QJ, Wang AX, Li YH, Liu RH, Li HY. Synthesis and biological evaluation of hydroxycinnamic acid hydrazide derivatives as inducer of caspase-3. Eur J Med Chem 2014; 85:778-83. [PMID: 25147141 DOI: 10.1016/j.ejmech.2014.08.040] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2014] [Revised: 08/11/2014] [Accepted: 08/11/2014] [Indexed: 12/21/2022]
Abstract
In order to generate compounds with superior antitumor activity and reduced toxicity, twelve new hydroxycinnamic acid hydrazide derivatives were synthesized and evaluated for their antiproliferative activities against two cancer cell lines (H1299 lung carcinoma cells and MCF-7 breast cancer cells), and compared to two normal counterparts (NL-20 lung epithelial cells and H184B5F5/M10 breast cells) by MTT method. The results demonstrated that some of these compounds possessed good antiproliferative activity against the two cancer cell lines. Among them, compound 2c was active against the growth of H1299 lung carcinoma cells with IC50 values of 1.50 μM, which was more active than the positive topotecan (IC50 = 4.18 μM). Simultaneously, it showed lower cytotoxic effects on normal NL-20 lung epithelial cells (IC50 > 10 μM). Mechanism studies indicated that it induced cell cycle arrest at G2/M phase followed by activation of caspase-3, and consequently caused the cell death. Further studies on the structure optimization are ongoing.
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Affiliation(s)
- Zheng-Rong Wu
- School of Pharmaceutics, Lanzhou University, 222 Tian Shui South Road, Lanzhou 730000, People's Republic of China
| | - Jian Liu
- The First Hospital of Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Jian-Ying Li
- School of Pharmaceutics, Lanzhou University, 222 Tian Shui South Road, Lanzhou 730000, People's Republic of China
| | - Li-Fang Zheng
- School of Pharmaceutics, Lanzhou University, 222 Tian Shui South Road, Lanzhou 730000, People's Republic of China
| | - Yang Li
- School of Pharmaceutics, Lanzhou University, 222 Tian Shui South Road, Lanzhou 730000, People's Republic of China
| | - Xing Wang
- School of Pharmaceutics, Lanzhou University, 222 Tian Shui South Road, Lanzhou 730000, People's Republic of China
| | - Qing-Jian Xie
- Institute of Microbiology, School of Life Sciences, Lanzhou University, 222 Tian Shui South Road, Lanzhou 730000, People's Republic of China
| | - Ai-Xia Wang
- School of Pharmaceutics, Lanzhou University, 222 Tian Shui South Road, Lanzhou 730000, People's Republic of China
| | - Ying-Hui Li
- School of Pharmaceutics, Lanzhou University, 222 Tian Shui South Road, Lanzhou 730000, People's Republic of China
| | - Rong-Hui Liu
- Institute of Microbiology, School of Life Sciences, Lanzhou University, 222 Tian Shui South Road, Lanzhou 730000, People's Republic of China
| | - Hong-Yu Li
- School of Pharmaceutics, Lanzhou University, 222 Tian Shui South Road, Lanzhou 730000, People's Republic of China; Institute of Microbiology, School of Life Sciences, Lanzhou University, 222 Tian Shui South Road, Lanzhou 730000, People's Republic of China.
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Lang KL, Silva IT, Machado VR, Zimmermann LA, Caro MS, Simões CM, Schenkel EP, Durán FJ, Bernardes LS, de Melo EB. Multivariate SAR and QSAR of cucurbitacin derivatives as cytotoxic compounds in a human lung adenocarcinoma cell line. J Mol Graph Model 2014; 48:70-9. [DOI: 10.1016/j.jmgm.2013.12.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Revised: 11/18/2013] [Accepted: 12/03/2013] [Indexed: 01/11/2023]
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de Groot T, Alsady M, Jaklofsky M, Otte-Höller I, Baumgarten R, Giles RH, Deen PMT. Lithium causes G2 arrest of renal principal cells. J Am Soc Nephrol 2014; 25:501-10. [PMID: 24408872 DOI: 10.1681/asn.2013090988] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Vasopressin-regulated expression and insertion of aquaporin-2 channels in the luminal membrane of renal principal cells is essential for urine concentration. Lithium affects urine concentrating ability, and approximately 20% of patients treated with lithium develop nephrogenic diabetes insipidus (NDI), a disorder characterized by polyuria and polydipsia. Lithium-induced NDI is caused by aquaporin-2 downregulation and a reduced ratio of principal/intercalated cells, yet lithium induces principal cell proliferation. Here, we studied how lithium-induced principal cell proliferation can lead to a reduced ratio of principal/intercalated cells using two-dimensional and three-dimensional polarized cultures of mouse renal collecting duct cells and mice treated with clinically relevant lithium concentrations. DNA image cytometry and immunoblotting revealed that lithium initiated proliferation of mouse renal collecting duct cells but also increased the G2/S ratio, indicating G2/M phase arrest. In mice, treatment with lithium for 4, 7, 10, or 13 days led to features of NDI and an increase in the number of principal cells expressing PCNA in the papilla. Remarkably, 30%-40% of the PCNA-positive principal cells also expressed pHistone-H3, a late G2/M phase marker detected in approximately 20% of cells during undisturbed proliferation. Our data reveal that lithium treatment initiates proliferation of renal principal cells but that a significant percentage of these cells are arrested in the late G2 phase, which explains the reduced principal/intercalated cell ratio and may identify the molecular pathway underlying the development of lithium-induced renal fibrosis.
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Affiliation(s)
- Theun de Groot
- Department of Physiology, Nijmegen Centre for Molecular Life Sciences, and
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35
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Synthesis of 1,3-thiazine-2,4-diones with potential anticancer activity. Eur J Med Chem 2013; 70:411-8. [DOI: 10.1016/j.ejmech.2013.10.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2013] [Revised: 10/03/2013] [Accepted: 10/07/2013] [Indexed: 01/04/2023]
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36
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Alabi OA, Bakare AA, Filippin-Monteiro FB, Sierra JA, Creczynski-Pasa TB. Electronic waste leachate-mediated DNA fragmentation and cell death by apoptosis in mouse fibroblast (NIH/3T3) cell line. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2013; 94:87-93. [PMID: 23726292 DOI: 10.1016/j.ecoenv.2013.05.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Revised: 05/03/2013] [Accepted: 05/06/2013] [Indexed: 05/15/2023]
Abstract
This study investigated the apoptotic effect of electronic waste on fibroblast cell line. Cells were treated with different concentrations of the leachate for 24h. Cell viability was detected by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test, nuclear morphology of cells was explored by acridine orange (AO)/ethidium bromide (EB) double staining, mitochondrial membrane potential was evaluated using JC-1 probe while cell cycle analysis was conducted using flow cytometry. The oxidative status was detected using DCFH-DA (dichlorofluorescin diacetate) probe and the relationship between cell death and ROS (reactive oxygen species) was investigated using N-acetylcysteine. Results showed an increased cell death as detected by MTT assay and AO/EB staining. Cell cycle analysis indicated an induction of sub/G1 events while JC-1 probe showed significant disruption of mitochondrial membrane potential. There was significant induction of ROS, while N-acetylcysteine protected the cells from DNA damage. These suggest apoptotic pathway as a possible mechanism of e-waste induced cyto-genotoxicity.
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Affiliation(s)
- Okunola A Alabi
- Department of Biosciences and Biotechnology, Babcock University, Ilisan Remo, Ogun State, Nigeria
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37
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The effectiveness of cucurbitacin B in BRCA1 defective breast cancer cells. PLoS One 2013; 8:e55732. [PMID: 23393598 PMCID: PMC3564916 DOI: 10.1371/journal.pone.0055732] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2012] [Accepted: 12/30/2012] [Indexed: 11/26/2022] Open
Abstract
Cucurbitacin B (CuB) is one of the potential agents for long term anticancer chemoprevention. Cumulative evidences has shown that cucurbitacin B provides potent cellular biological activities such as hepatoprotective, anti-inflammatory and antimicrobial effects, but the precise mechanism of this agent is not clearly understood. We examine the biological effects on cancer cells of cucurbitacin B extracted from a Thai herb, Trichosanthes cucumerina L. The wild type (wt) BRCA1, mutant BRCA1, BRCA1 knocked-down and BRCA1 overexpressed breast cancer cells were treated with the cucurbitacin B and determined for the inhibitory effects on the cell proliferation, migration, invasion, anchorage-independent growth. The gene expressions in the treated cells were analyzed for p21/Waf1, p27Kip1 and survivin. Our previous study revealed that loss of BRCA1 expression leads to an increase in survivin expression, which is responsible for a reduction in sensitivity to paclitaxel. In this work, we showed that cucurbitacin B obviously inhibited knocked-down and mutant BRCA1 breast cancer cells rather than the wild type BRCA1 breast cancer cells in regards to the cellular proliferation, migration, invasion and anchorage-independent growth. Furthermore, forcing the cells to overexpress wild type BRCA1 significantly reduced effectiveness of cucurbitacin B on growth inhibition of the endogenous mutant BRCA1 cells. Interestingly, cucurbitacin B promotes the expression of p21/Waf1 and p27Kip1 but inhibit the expression of survivin. We suggest that survivin could be an important target of cucurbitacin B in BRCA1 defective breast cancer cells.
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38
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Sohn SH, Yoon M, Kim J, Choi HL, Shin M, Hong M, Bae H. Screening herbal medicines for the recovery of alpha-synuclein-induced Parkinson’s disease model of yeast. Mol Cell Toxicol 2013. [DOI: 10.1007/s13273-012-0042-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Biological activities and potential molecular targets of cucurbitacins: a focus on cancer. Anticancer Drugs 2012; 23:777-87. [PMID: 22561419 DOI: 10.1097/cad.0b013e3283541384] [Citation(s) in RCA: 111] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Cucurbitacin and its derivatives (cucurbitacins) are a class of highly oxidized tetracyclic triterpenoids. They are widely distributed in the plant kingdom, where they act as heterologous chemical pheromones that protect plants from external biological insults. Their bioactivities first attracted attention in the 1960s. Documented data demonstrate that cucurbitacins possess strong pharmacological properties, such as antitumor, anti-inflammatory, and hepatoprotective effects, etc. Several molecular targets for cucurbitacins have been discovered, such as fibrous-actin, signal transducer and activator of transcription 3, cyclooxygenase-2, etc. The present study summarizes the achievements of the 50 years of research on cucurbitacins. The aim was to systematically analyze their bioactivities with an emphasis on their anticancer effects. Research and development has shed new insight into the beneficial properties of these compounds.
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40
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Sultana N, Saify ZS. Enzymatic biotransformation of terpenes as bioactive agents. J Enzyme Inhib Med Chem 2012; 28:1113-28. [DOI: 10.3109/14756366.2012.727411] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Affiliation(s)
- Nighat Sultana
- Pharmaceutical Research Center, PCSIR Laboratories Complex,
Karachi, Pakistan
| | - Zafar Saeed Saify
- International Center for Chemical Sciences, H.E.J. Research Institute of Chemistry, University of Karachi,
Karachi, Pakistan
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41
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Tong QY, He Y, Zhao QB, Qing Y, Huang W, Wu XH. Cytotoxicity and apoptosis-inducing effect of steroidal saponins from Dioscorea zingiberensis Wright against cancer cells. Steroids 2012; 77:1219-27. [PMID: 22575181 DOI: 10.1016/j.steroids.2012.04.019] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2012] [Revised: 04/10/2012] [Accepted: 04/29/2012] [Indexed: 02/05/2023]
Abstract
Steroidal saponins from Dioscorea zingiberensis Wright (DZW) have shown cytotoxic activity in cancer cells. In this study, we isolated and identified seven steroidal saponins from the rhizomes of DZW: diosgenin, trillin, diosgenin diglucoside, deltonin, zingiberensis saponin (ZS), protodeltonin and parvifloside. Our results showed that these seven compounds inhibited the proliferation of a panel of established human and murine cancer cell lines in vitro. ZS had more cytotoxic effect than the other saponins, even close to doxorubicin on the murine colon carcinoma cell line C26. The proliferation inhibitory effect of ZS was associated with its apoptosis-inducing effect by activation of caspase-3 and caspase-9 and specific proteolytic cleavage of poly (ADP-ribose) polymerase. Exposure of C26 to ZS also resulted in Bax upregulation and Bcl-2 downregulation. In conclusion, the findings of this study demonstrated that ZS is an effective natural agent for cancer therapy, which may be mediated, in part, by induction of apoptosis, and DZW's potential as an anticancer agent is worth being further investigated.
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Affiliation(s)
- Qing-Yi Tong
- Laboratory of Ethnopharmacology, Regenerative Medicine ResYarch Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Keyuan 4 Road No. 1,Gaopeng Avenue, Gaoxin District, Chengdu 610041, Sichuan, PR China
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Silva AH, Filippin-Monteiro FB, Mattei B, Zanetti-Ramos BG, Creczynski-Pasa TB. In vitro biocompatibility of solid lipid nanoparticles. THE SCIENCE OF THE TOTAL ENVIRONMENT 2012; 432:382-388. [PMID: 22750185 DOI: 10.1016/j.scitotenv.2012.06.018] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2011] [Revised: 06/01/2012] [Accepted: 06/06/2012] [Indexed: 06/01/2023]
Abstract
This study was undertaken to address the current deficient knowledge of cellular response to solid lipid nanoparticles (SLNs) exposure. We investigated the cytotoxicity of several SLNs formulations in two fibroblast cell lineages, Vero and MDCK. Several methods were used to explore the mechanisms involved in this cytotoxic process, including cell viability assays, flow cytometry and ROS generation assessment. Among nanoparticles tested, two of them (F4 and F5) demonstrated more cytotoxic effects in both cell lineages. The cell viability assays suggested that F4 and F5 interfere in cell mitochondrial metabolism and in lysosomal activity. In addition, F5 decreased the percentage of MDCK cells in G0/G1 and G2/M phases, with a marked increase in the Sub/G1 population, suggesting DNA fragmentation. Regarding F4, although IC(50) was higher (~700 μg/mL), this formulation affected mitochondrial membrane potential for Vero cells. However, the IC(50) of F5 was around 250 μg/mL, suggesting the effect of SDS (sodium dodecyl sulfate) present in the formulation. In summary, the nanoparticles tested here appears to be biocompatible, with the exception of F5. Further studies are required to elucidate the in vivo effects of these nanoscale structures, in order to evaluate or predict the connotation of their increased and widespread use.
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Affiliation(s)
- Adny Henrique Silva
- Departamento de Ciências Farmacêuticas, Universidade Federal de Santa Catarina P.O. Box 476, Florianópolis, SC, 88040-900, Brazil
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Anti-proliferative effect of 23,24-dihydrocucurbitacin F on human prostate cancer cells through induction of actin aggregation and cofilin-actin rod formation. Cancer Chemother Pharmacol 2012; 70:415-24. [DOI: 10.1007/s00280-012-1921-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2012] [Accepted: 07/04/2012] [Indexed: 10/28/2022]
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Lang KL, Silva IT, Zimmermann LA, Machado VR, Teixeira MR, Lapuh MI, Galetti MA, Palermo JA, Cabrera GM, Bernardes LSC, Simões CMO, Schenkel EP, Caro MSB, Durán FJ. Synthesis and cytotoxic activity evaluation of dihydrocucurbitacin B and cucurbitacin B derivatives. Bioorg Med Chem 2012; 20:3016-30. [DOI: 10.1016/j.bmc.2012.03.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2011] [Revised: 02/23/2012] [Accepted: 03/01/2012] [Indexed: 01/11/2023]
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Ganguly A, Banerjee K, Chakraborty P, Das S, Sarkar A, Hazra A, Banerjee M, Maity A, Chatterjee M, Mondal NB, Choudhuri SK. Overcoming multidrug resistance (MDR) in cancer in vitro and in vivo by a quinoline derivative. Biomed Pharmacother 2011; 65:387-94. [DOI: 10.1016/j.biopha.2011.04.024] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2011] [Accepted: 04/23/2011] [Indexed: 01/09/2023] Open
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Agrawal SK, Agrawal M, Sharma PR, Gupta BD, Arora S, Saxena AK. Induction of apoptosis in human promyelocytic leukemia HL60 cells by an extract from Erythrina suberosa stem bark. Nutr Cancer 2011; 63:802-13. [PMID: 21711175 DOI: 10.1080/01635581.2011.573900] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
In this study, the apoptosis-inducing effect of an alcoholic extract from Erythrina suberosa stem bark (ESB) was investigated using human promyelocytic leukemia HL60 cells. Cell viability was estimated by MTT assay. We found that the ESB inhibited cell proliferation in a dose- and time-dependent manner. A series of well-documented morphological changes, such as cell shrinkage, condensation of nuclear chromatin, and nuclear fragmentation, were observed by fluorescence microscopy. The gold standard scanning electron micrographs showed apoptotic bodies and formation of blebs. Cell cycle analysis showed a significant increase in Sub G(0) population of cells above 50 μg/ml. ESB treatment resulted in a dose-dependent increase in annexin V positive cells. Increase in intracellular ROS production up to sixfold was detected in ESB-treated HL60 cells by DCFH-DA assay. Dissipation of mitochondrial membrane potential of intact cells accompanied by increase in cytosolic cytochrome c was observed, which was followed by activation of caspase-9 and -3 but not caspase-8. DNA fragmentation analysis revealed typical ladders as early as 18 h indicative of caspase-3 role in the apoptotic pathway. The overall results suggest that ESB induces mitochondria-mediated intrinsic apoptotic pathway in HL60 cells and might have therapeutic value against human leukemia.
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Affiliation(s)
- Satyam Kumar Agrawal
- Cancer Pharmacology Division, Indian Institute of Integrative Medicine, Jammu, India.
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Zhao YY, Shen X, Chao X, Ho CC, Cheng XL, Zhang Y, Lin RC, Du KJ, Luo WJ, Chen JY, Sun WJ. Ergosta-4,6,8(14),22-tetraen-3-one induces G2/M cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells. Biochim Biophys Acta Gen Subj 2011; 1810:384-90. [PMID: 21241775 DOI: 10.1016/j.bbagen.2010.12.005] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2010] [Revised: 11/26/2010] [Accepted: 12/23/2010] [Indexed: 12/23/2022]
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Cucurbitacin IIa: a novel class of anti-cancer drug inducing non-reversible actin aggregation and inhibiting survivin independent of JAK2/STAT3 phosphorylation. Br J Cancer 2011; 104:781-9. [PMID: 21304528 PMCID: PMC3048206 DOI: 10.1038/bjc.2011.10] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Background: Cucurbitacin (Cuc) and triterpene-derived natural products exhibit anti-cancer potential in addition to their conspicuous anti-bacterial and anti-inflammatory activity. Recently, inhibition of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling was shown to underlie the effects of Cuc family on inducing cell death in cancer. Method: We purified Cuc IIa, the active component from the medicinal plant Hemsleya amalils Diels, which shows different structural modifications from other Cuc derivatives. We investigated the mechanisms of its inhibitory effects on cancer cells in vitro and tumour growth in vivo. Results: Cuc IIa induced the irreversible clustering of filamentous actin and arrested cell cycle by the increases in G2/M populations. Cuc IIa resulted in the reduced phospho-Histone H3 and markedly increased cleavage of poly-(ADP-ribose) polymerase or PARP, immediate upstream of DNA breakdown as the result of caspase activation, consistent with mitotic blockage-induced cell death. However, unlike other Cuc members, Cuc IIa did not suppress JAK2/STAT3 phosphorylation or alter phosphorylation of mitogen-activated protein kinases. Instead, the expression of the cell cycle-regulated Inhibitor of Apoptosis Protein (IAP) survivin was reduced. Introducing oncoprotein δ-catenin, which increased survivin expression and suppressed small GTPase RhoA, reduced efficacy of Cuc IIa to induce cell death. Supporting the effects of Cuc IIa on actin cytoskeletal signaling, RhoA phosphorylation was reduced suggesting its increased activity. Conclusion: Cuc IIa is a novel class of anti-cancer drug in suppression of cancer cell expansion by disrupting the actin cytoskeleton and directing the cell to undergo PARP-mediated apoptosis through the inhibition of survivin downstream of JAK2/STAT3.
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Bishayee A, Ahmed S, Brankov N, Perloff M. Triterpenoids as potential agents for the chemoprevention and therapy of breast cancer. FRONT BIOSCI-LANDMRK 2011; 16:980-96. [PMID: 21196213 PMCID: PMC3057757 DOI: 10.2741/3730] [Citation(s) in RCA: 203] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Breast cancer remains a major cause of death in the United States as well as the rest of the world. In view of the limited treatment options for patients with advanced breast cancer, preventive and novel therapeutic approaches play an important role in combating this disease. The plant-derived triterpenoids, commonly used for medicinal purposes in many Asian countries, posses various pharmacological properties. A large number of triterpenoids are known to exhibit cytotoxicity against a variety of tumor cells as well as anticancer efficacy in preclinical animal models. Numerous triterpenoids have been synthesized by structural modification of natural compounds. Some of these analogs are considered to be the most potent antiinflammatory and anticarcinogenic triterpenoids known. This review examines the potential role of natural triterpenoids and their derivatives in the chemoprevention and treatment of mammary tumors. Both in vitro and in vivo effects of these agents and related molecular mechanisms are presented. Potential challenges and future directions involved in the advancement of these promising compounds in the prevention and therapy of human breast cancer are also identified.
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Affiliation(s)
- Anupam Bishayee
- Cancer Therapeutics and Chemoprevention Group, Department of Pharmaceutical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, 4209 State Route 44, Rootstown, OH 44272, USA.
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Cucurbitacin B inhibits growth, arrests the cell cycle, and potentiates antiproliferative efficacy of cisplatin in cutaneous squamous cell carcinoma cell lines. Int J Oncol 2010; 37:737-43. [PMID: 20664943 DOI: 10.3892/ijo_00000723] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer with a substantial risk of metastasis which causes clinical treatment failure. This study investigated the anti-CSCC effects of a triterpenoid compound, Cucurbitacin B (CuB). Dose-response studies showed that CuB inhibited 50% growth (ED50) of the CSCC cell lines (SRB1, SRB12, SCC13, COLO16) in liquid culture at 4 x 10(-7)-10(-5) M. Soft-agar assays demonstrated that nearly all of the CSCC clonogenic cells were inhibited at 10(-7) M CuB. FACS analysis found that the compound (10(-7) M, 48 h) caused G2/M arrest. The CSCC cells underwent profound morphologic changes within 60 min after exposure to CuB (10(-7) M), rounding up and losing their pseudopodia. CuB (10(-7) M) caused prominent multinucleation of the cells after they were pulse-exposed (24 h) to the drug, washed and cultured in normal medium for an additional 24 h. The drug (10(-8)-10(-6) M, 3-24 h) decreased levels of CDC2 and cyclin B1 in SRB1 and SRB12 cell lines as seen by Western blot analysis. Migration of SRB1 and SRB12 cells was inhibited by 10(-7) M CuB. Interestingly, CuB synergistically potentiated the anti-proliferative effect of cisplatin in CSCC. In summary, CuB has a prominent anti-proliferative activity on CSCC cells. In vivo studies and clinical trials of this drug should be pursued in CSCC.
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