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Liu J, Zhang W, Jin S, Zhang H, Xu Y, Xiong P, Qin X, Jia B. Plant-derived inducers in tumor differentiation therapy:A systematic review. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 130:155749. [PMID: 38763009 DOI: 10.1016/j.phymed.2024.155749] [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: 10/07/2023] [Revised: 02/27/2024] [Accepted: 05/14/2024] [Indexed: 05/21/2024]
Abstract
BACKGROUND Differentiation therapy, a highly regarded treatment method in tumor research, aims to induce tumor cells to differentiate back to normal cells, deviating from the malignant pathway and returning to a benign state. Its development relies on the continuous discovery of efficient and low-toxic differentiation inducers, including plant-derived active components that offer significant biological utilization and therapeutic potential. For this reason, the exploration of plant-derived inducers, particularly in their application in differentiation therapy, holds great promise in advancing cancer treatment strategies toward more effective and safer alternatives. PURPOSE This paper aims to provide a valuable reference for researchers seeking to identify natural, efficient, and low-toxic differentiation inducers from plants and highlights a promising research direction for the application of differentiation therapy in malignant tumor treatment. METHODS For the collection of pertinent information, an extensive search was conducted across diverse literature and electronic databases, including PubMed, ScienceDirect, Wiley, ACS, CNKI, Springer, Taylor & Francis, Web of Science, Google Scholar, and Baidu Scholar. This comprehensive approach aimed to retrieve and include all relevant literature from 1985 to 2023. Primary keywords such as "Natural medicinal plant," "Differentiation therapy," and "Differentiation inducer" were utilized, supplemented by secondary search terms including "Cancer," "Tumor," "Herbal medicine," "Induced differentiation," and "Cancer treatment." RESULTS This study systematically evaluated the application of plant-derived inducers in tumor-induced differentiation therapy. Through extensive literature review, specific plant components with confirmed differentiation-inducing properties were identified. Furthermore, potential molecular mechanisms underlying this process were outlined, shedding light on the future development of differentiation therapy in cancer treatment. CONCLUSION Plant-derived active components exhibit substantial biological utility and therapeutic potential. Delving deeper into the research on these components as differentiation inducers holds promise for the selection of novel cancer drugs and the unveiling of novel pathways for cancer treatment. These results emphasize the importance of continued exploration and in-depth research into natural, efficient, and low-toxic differentiation inducers from plants, which could significantly advance cancer treatment strategies. Moreover, the highlighted research direction underscores the relevance of differentiation therapy in the context of malignant tumor treatment, indicating its potential as a safer and more effective alternative in cancer therapy.
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Affiliation(s)
- Junyu Liu
- College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Wei Zhang
- College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Shenrui Jin
- College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Hua Zhang
- Nanbu Hospital of County Chinese Medicine, Nanchong, Sichuan, 637399, China
| | - Yi Xu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Peiyu Xiong
- College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Xuhua Qin
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China.
| | - Bo Jia
- College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China.
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Li X, Jiang Y, Wang Y, Li N, Zhang S, Lv K, Jia R, Wei T, Li X, Han C, Lin J. KLF4 suppresses anticancer effects of brusatol via transcriptional upregulating NCK2 expression in melanoma. Biochem Pharmacol 2024; 223:116197. [PMID: 38583810 DOI: 10.1016/j.bcp.2024.116197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 03/21/2024] [Accepted: 04/05/2024] [Indexed: 04/09/2024]
Abstract
Brusatol (Bru), a main extract from traditional Chinese medicine Brucea javanica, has been reported to exist antitumor effect in many tumors including melanoma. However, the underlying mechanism in its anti-melanoma effect still need further exploration. Here, we reported that the protein expression of KLF4 in melanoma cells were significantly downregulated in response to brusatol treatment. Overexpression of KLF4 suppressed brusatol-induced melanoma cell apoptosis; while knockdown of KLF4 enhanced antitumor effects of brusatol on melanoma cells not only in vitro but also in vivo. Further studies on the mechanism revealed that KLF4 bound to the promoter of NCK2 directly and facilitated NCK2 transcription, which suppressed the antitumor effect of brusatol on melanoma. Furthermore, our findings showed that miR-150-3p was dramatically upregulated under brusatol treatment which resulted in the downregulation of KLF4. Our results suggested that the miR-150-3p/KLF4/NCK2 axis might play an important role in the antitumour effects of brusatol in melanoma.
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Affiliation(s)
- Xiaodong Li
- Department of Dermatology, The First Affiliated Hospital of Dalian Medical University, Dalian 116044, PR China; Institute of Cancer Stem Cell of Dalian Medical University, Dalian 116044, PR China
| | - Yuankuan Jiang
- Department of Dermatology, The First Affiliated Hospital of Dalian Medical University, Dalian 116044, PR China
| | - Ying Wang
- Institute of Cancer Stem Cell of Dalian Medical University, Dalian 116044, PR China
| | - Na Li
- National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian 116044, PR China
| | - Shumeng Zhang
- Department of Dermatology, The First Affiliated Hospital of Dalian Medical University, Dalian 116044, PR China
| | - Kejia Lv
- Department of Dermatology, The First Affiliated Hospital of Dalian Medical University, Dalian 116044, PR China
| | - Renchuan Jia
- Department of Dermatology, The First Affiliated Hospital of Dalian Medical University, Dalian 116044, PR China
| | - Tianfu Wei
- Department of Dermatology, The First Affiliated Hospital of Dalian Medical University, Dalian 116044, PR China
| | - Xiaojie Li
- College of Stomatology Dalian Medical University, Dalian 116044, PR China.
| | - Chuanchun Han
- Institute of Cancer Stem Cell of Dalian Medical University, Dalian 116044, PR China.
| | - Jingrong Lin
- Department of Dermatology, The First Affiliated Hospital of Dalian Medical University, Dalian 116044, PR China.
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Chen J, Yu D, Li X, Deng Q, Yang H, Chen L, Bai L. A review of Brucea javanica: metabolites, pharmacology and clinical application. Front Pharmacol 2024; 14:1317620. [PMID: 38371913 PMCID: PMC10871038 DOI: 10.3389/fphar.2023.1317620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 12/27/2023] [Indexed: 02/20/2024] Open
Abstract
This review examines advances in the metabolites, pharmacological research, and therapeutic applications of the medicinal fruit of Brucea javanica (L.) Merr. Brucea javanica (BJ) is derived from the fruit of the Brucea javanica (L.) Merr. There are nearly 200 metabolites present in BJ, and due to the diversity of its metabolites, BJ has a wide range of pharmacological effects. The traditional pharmacological effects of BJ include anti-dysentery, anti-malaria, etc. The research investigating the contemporary pharmacological impacts of BJ mainly focuses on its anti-tumor properties. In the article, the strong monomeric metabolites among these pharmacological effects were preliminarily screened. Regarding the pharmacological mechanism of action, current research has initially explored BJ's pharmacological agent and molecular signaling pathways. However, a comprehensive system has yet to be established. BJ preparations have been utilized in clinical settings and have demonstrated effectiveness. Nevertheless, clinical research is primarily limited to observational studies, and there is a need for higher-quality research evidence to support its clinical application. There are still many difficulties and obstacles in studying BJ. However, it is indisputable that BJ is a botanical drugs with significant potential for application, and it is expected to have broader global usage.
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Affiliation(s)
- Jing Chen
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- The State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Department of Pharmacy, Guangyuan Central Hospital of Sichuan Province, Guangyuan, China
| | - Dongke Yu
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xinyu Li
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Qichuan Deng
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Hao Yang
- Power China Chengdu Engineering Corporation Limited, Chengdu, China
| | - Lu Chen
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Department of Pharmacy, Guanghan People's Hospital, Guanghan, China
| | - Lan Bai
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- The State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Viega BL, Rocha AM, Berti AP, Novello CR, Nicolin DJ, Almeida IV, Vicentini VEP, Düsman E. Cytotoxicity of isolated compounds from Picrasma crenata (Vell.) Engl. in animal tumor cell (HTC). BRAZ J BIOL 2023; 83:e273889. [PMID: 37436192 DOI: 10.1590/1519-6984.273889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 05/23/2023] [Indexed: 07/13/2023] Open
Abstract
The study aim was to evaluate the cytotoxic activity, using the MTT test [3-(4,5-Dimethilthiazol-2-yl)-2,5-diphenil tetrazolium bromide], from the crude extract of Picrasma crenata (Pau Tenente) and its isolated compounds, quassin and parain, in culture of rat liver tumor cells (HTC). The test was carried out exposing the cells for 24, 48 and 72 hours to concentrations of 5, 10, 50, 100, 200, 300, 400, 500 and 1000 μg of crude extract of Pau Tenente/mL of culture medium and 1, 5, 10, 15, 20, 40, 60, 80 and 100 μg of quassin or parain compounds/mL of culture medium. The absorbances averages results obtained showed that the crude extract did not present cytotoxicity for the HTC cells in all the concentrations and evaluated times. For quassin, the concentrations of 80 and 100 μg/mL were cytotoxic, after 72 hours of treatment. For parain, the concentrations of 1, 5, 20, 40, 60, 80 and 100 µg/mL, in 72 hours, were cytotoxic, revealing a new activity for this compound. Thus, the results demonstrate a first indication of the cytotoxic activity of compounds quassin and parain, adding an important social and economic value to them, and may have application in future research and in pharmaceutical industry.
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Affiliation(s)
- B L Viega
- Universidade Tecnológica Federal do Paraná - UTFPR, Francisco Beltrão, PR, Brasil
| | - A M Rocha
- Universidade Tecnológica Federal do Paraná - UTFPR, Francisco Beltrão, PR, Brasil
| | - A P Berti
- Universidade Estadual de Mato Grosso do Sul - UEMS, Dourados, MS, Brasil
| | - C R Novello
- Universidade Tecnológica Federal do Paraná - UTFPR, Francisco Beltrão, PR, Brasil
| | - D J Nicolin
- Universidade Tecnológica Federal do Paraná - UTFPR, Francisco Beltrão, PR, Brasil
| | - I V Almeida
- Universidade Federal Rural da Amazônia - UFRA, Capitão Poço, PA, Brasil
| | | | - E Düsman
- Universidade Tecnológica Federal do Paraná - UTFPR, Francisco Beltrão, PR, Brasil
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Brusatol: A potential sensitizing agent for cancer therapy from Brucea javanica. Biomed Pharmacother 2023; 158:114134. [PMID: 36525821 DOI: 10.1016/j.biopha.2022.114134] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 12/09/2022] [Accepted: 12/12/2022] [Indexed: 12/15/2022] Open
Abstract
Cancer is currently the most important problem endangering human health. As antitumor drugs have always been the most common methods for treating cancers, searching for new antitumor agents is of great significance. Brusatol, a quassinoid from the seeds of Brucea javanica, exhibits a potent tumor-suppressing effect with improved disease outcome. Studies have shown that brusatol not only shows potential tumor inhibition through multiple pharmacological effects, such as promoting apoptosis and inhibiting metastasis but also exhibits significant synergistic antitumor effects in combination with chemotherapeutic agents and overcoming chemical resistance in a wide range of cancer types. In this paper, the antitumor effects and mechanisms of brusatol were reviewed to provide evidence that brusatol has the exact antitumor efficacy of chemotherapeutic agents and show the potential of brusatol to be developed as a promising antitumor drug.
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Boretti A. Natural Products as Cancer Chemo Preventive Agents: Where We Stand. Nat Prod Commun 2022. [DOI: 10.1177/1934578x221144579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
This work briefly reviews cancer chemoprevention. This is a very challenging field, as products with a high level of toxicity such as chemotherapeutic agents may be proposed and accepted only under life-threatening conditions. Cancer chemoprevention is otherwise limited to completely safe substances, preferably having neither toxic nor side effects, administered in relatively low amounts. Phases of clinical trials, therapeutic end-points, and biomarkers of chemoprevention are difficult to be defined. The clinical trials needed to prove the efficacy of chemopreventive agents must be very long and extremely widespread to achieve significance, with many variables difficult to control, and therefore subjected to many confounding factors. This makes them almost impossible. It is, therefore, no surprise, if the progress of chemoprevention has been so far very limited. There are only a few examples of direct use of chemopreventive agents, under investigation, but with anything but established protocols, in addition to indirect uses such as general supplementation with antioxidant, anti-inflammatory, and immune-supportive agents. Cancer chemoprevention remains a potentially very rewarding approach, certainly worth further study, but extremely difficult to pursue, in need of different methodological approaches to producing valuable chemopreventive compounds of clear dosages and benefits.
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Liu KD, Yang WQ, Dai MZ, Xu Y, Qin YP, Dong YY, Fu J, Qu J. Phenolic constituents with anti-inflammatory and cytotoxic activities from the rhizomes of Iris domestica. PHYTOCHEMISTRY 2022; 203:113370. [PMID: 35977602 DOI: 10.1016/j.phytochem.2022.113370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 08/02/2022] [Accepted: 08/03/2022] [Indexed: 06/15/2023]
Abstract
Four undescribed flavonoid glucosides (iridins B-C, tectoridin A and ampelopsinin A); one undescribed phenolic glucoside (diplostephioside B); one undescribed phenolic compound (phenanthrenetriol A); and seventeen known compounds were isolated from the rhizomes of Iris domestica. The chemical structures of the undescribed compounds were established by spectroscopic/spectrometric data interpretation using HRESIMS, NMR, and ECD. Tectoridin A, nigricin A and naringenin exhibited anti-inflammatory activities with inhibition rates of 53.71%, 57.68% and 88.71%, respectively, against the NF-κB signaling pathway at a concentration of 10 μM. 4'-O-methylnyasol (10 μM) exhibited 84.91% antiproliferative activity against the K562 human leukemia cell line with an IC50 value of 4.20 μM.
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Affiliation(s)
- Kai-Dong Liu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People's Republic of China
| | - Wan-Qi Yang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People's Republic of China
| | - Ming-Zhu Dai
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People's Republic of China
| | - Yong Xu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People's Republic of China
| | - Yun-Peng Qin
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People's Republic of China
| | - Ying-Ying Dong
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People's Republic of China
| | - Jiang Fu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People's Republic of China
| | - Jing Qu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People's Republic of China.
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Huang CH, Wang FT, Chan WH. Role of caspase-3-cleaved/activated PAK2 in brusatol-triggered apoptosis of human lung cancer A549 cells. Toxicol Res (Camb) 2022; 11:791-803. [PMID: 36337251 PMCID: PMC9623572 DOI: 10.1093/toxres/tfac057] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 07/19/2022] [Accepted: 07/20/2022] [Indexed: 09/01/2023] Open
Abstract
Brusatol, a major quassinoid extract of Bruceae fructus, is an important bioactive component with antineoplastic capacity. Several beneficial pharmacological and biological properties of brusatol have been uncovered to date, including anti-inflammatory, anticolitis, antimalarial, and anticancer activities. To confer anticancer benefits, brusatol is reported to effectively inhibit the Nrf2-mediated antioxidant response and trigger apoptotic signaling. In this study, we investigated the regulatory mechanisms underlying apoptotic processes in brusatol-treated A549 cells in detail. Our experiments showed that brusatol induces cell death through intracellular ROS-triggered mitochondria-dependent apoptotic events and does not involve necrosis. Mechanistically, p21-activated protein kinase 2 (PAK2) was cleaved by caspase-3 to generate an activated p34 fragment involved in brusatol-induced apoptosis of A549 cells. Notably, PAK2 knockdown led to downregulation of caspase-3-mediated PAK2 activity, in turn, effectively attenuating brusatol-induced apoptosis, highlighting a crucial role of caspase-3-activated PAK2 in this process. Moreover, knockdown of PAK2 resulted in significant inhibition of c-Jun N-terminal kinase (JNK) activity in brusatol-treated A549 cells, clearly suggesting that JNK serves as a downstream substrate of caspase-3-cleaved/activated PAK2 in the apoptotic cascade. SP600125, a specific JNK inhibitor, significantly suppressed brusatol-induced JNK activity but only partially prevented apoptosis, implying that JNK serves as only one of a number of substrates for PAK2 in the brusatol-triggered apoptotic cascade. Based on the collective results, we propose a signaling cascade model for brusatol-induced apoptosis in human A549 cells involving ROS, caspases, PAK2, and JNK.
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Affiliation(s)
- Chien-Hsun Huang
- Department of Obstetrics and Gynecology, Taoyuan General Hospital, Ministry of Health & Welfare, Zhongshan Road, Taoyuan District, Taoyuan City 33004, Taiwan
| | - Fu-Ting Wang
- Rehabilitation and Technical Aid Center, Taipei Veterans General Hospital, Section 2, Shipai Road, Beitou District, Taipei City 11217, Taiwan
| | - Wen-Hsiung Chan
- Department of Bioscience Technology and Center for Nanotechnology, Chung Yuan Christian University, Zhongbei Road, Zhongli District, Taoyuan City 32023, Taiwan
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Jorge J, Magalhães N, Alves R, Lapa B, Gonçalves AC, Sarmento-Ribeiro AB. Antitumor Effect of Brusatol in Acute Lymphoblastic Leukemia Models Is Triggered by Reactive Oxygen Species Accumulation. Biomedicines 2022; 10:biomedicines10092207. [PMID: 36140308 PMCID: PMC9496058 DOI: 10.3390/biomedicines10092207] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 08/31/2022] [Accepted: 09/02/2022] [Indexed: 11/16/2022] Open
Abstract
Acute lymphoblastic leukemia (ALL) is one of the most common hematological malignancies at pediatric ages and is characterized by different chromosomal rearrangements and genetic abnormalities involved in the differentiation and proliferation of lymphoid precursor cells. Brusatol is a quassinoid plant extract extensively studied due to its antineoplastic effect through global protein synthesis and nuclear factor erythroid 2-related factor-2 (NRF2) signaling inhibition. NRF2 is the main regulator of cellular antioxidant response and reactive oxygen species (ROS), which plays an important role in oxidative stress regulation. This study aimed to evaluate the effect of brusatol in in vitro models of ALL. KOPN-8 (B-ALL), CEM (T-ALL), and MOLT-4 (T-ALL) cell lines were incubated with increasing concentrations of brusatol, and the metabolic activity was evaluated using the resazurin assay. Flow cytometry was used to evaluate cell death, cell cycle, mitochondrial membrane potential (Δψmit), and to measure ROS and reduced glutathione (GSH) levels. Our results show that brusatol promoted a decrease in metabolic activity in ALL cell lines in a time-, dose-, and cell-line-dependent manner. Brusatol induced a cytostatic effect by cell cycle arrest in G0/G1 in all cell lines; however, cell death mediated by apoptosis was only observed in T-ALL cells. Brusatol leads to an oxidative stress imbalance by the increase in ROS levels, namely, superoxide anion. Redox imbalance and cellular apoptosis induced by brusatol are highly modulated by mitochondria disruption as a decrease in mitochondrial membrane potential is detected. These data suggest that brusatol might represent a new therapeutic approach for acute lymphoblastic leukemia, particularly for ALL T-cell lineage.
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Affiliation(s)
- Joana Jorge
- Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research (iCBR)—Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3000-061 Coimbra, Portugal
| | - Nisa Magalhães
- Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
| | - Raquel Alves
- Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research (iCBR)—Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3000-061 Coimbra, Portugal
| | - Beatriz Lapa
- Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research (iCBR)—Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal
| | - Ana Cristina Gonçalves
- Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research (iCBR)—Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3000-061 Coimbra, Portugal
- Correspondence: (A.C.G.); (A.B.S.-R.); Tel.: +351-239-480-024 (A.C.G.)
| | - Ana Bela Sarmento-Ribeiro
- Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research (iCBR)—Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3000-061 Coimbra, Portugal
- Hematology Service, Centro Hospitalar e Universitário de Coimbra (CHUC), 3000-061 Coimbra, Portugal
- Correspondence: (A.C.G.); (A.B.S.-R.); Tel.: +351-239-480-024 (A.C.G.)
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Li F, Gao C, Li X, Wang J, Zhao Y, Ke Y, Liu Y, Liu HM, Hu Z, Wei L, Chen ZS. Jiyuan oridonin A induces differentiation of acute myeloid leukemia cells including leukemic stem-like cells. Front Pharmacol 2022; 13:1001552. [PMID: 36133825 PMCID: PMC9484275 DOI: 10.3389/fphar.2022.1001552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
Acute myeloid leukemia (AML) is an aggressive form of hematological neoplasia characterized by failure of myeloid differentiation. AML is a leading cause of death from leukemia. Cytarabine chemotherapy resistance is a major source of refractory/relapsed AML. A major obstacle to the successful treatment of AML results from residual disease maintained by leukemic stem cells (LSCs), which are mostly resistant to conventional chemotherapy. Here, we determined the effect of a natural compound, Jiyuan oridonin A (JOA), on the differentiation blockade in the M2 subtype [particularly t (8;21)] of AML cells, M3 subtype of AML cells (APL cells), and leukemic stem-like cells both in vitro and in vivo. We found that JOA induced cell differentiation and suppressed the colony formation capacity in various AML cell lines (Kasumi-1, KG-1, MUTZ-8, NB4, and HL-60) without eliciting apoptosis. The mechanism of JOA-induced cell differentiation depends on the specificity of cell type. JOA mediated the differentiation of Kasumi-1 cells by activating the hematopoietic cell lineage signaling pathway, while inhibition of c-MYC was involved in the JOA-induced differentiation of NB4 cells. Moreover, JOA was identified to target leukemic stem-like cells by induced cell differentiation in vivo. These findings demonstrated that JOA could inhibit the proliferation of M2 and M3 subtypes of AML cells and leukemic stem-like cells by overcoming the differentiation blockade, which may offer a novel therapeutic strategy for AML to overcome relapse and drug resistance in patients with AML. Our findings highlight the possibility of using compounds like JOA as a promising differentiation-induced agent for the treatment of AML.
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Affiliation(s)
- Fahui Li
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Congying Gao
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Xueming Li
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Jiangyun Wang
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Yao Zhao
- Laboratory for Stem Cell and Regenerative Medicine, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Yu Ke
- School of Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Ying Liu
- School of Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Hong-Min Liu
- School of Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Zhenbo Hu
- Laboratory for Stem Cell and Regenerative Medicine, Affiliated Hospital of Weifang Medical University, Weifang, China
- *Correspondence: Zhenbo Hu, ; Liuya Wei, ; Zhe-Sheng Chen,
| | - Liuya Wei
- School of Pharmacy, Weifang Medical University, Weifang, China
- *Correspondence: Zhenbo Hu, ; Liuya Wei, ; Zhe-Sheng Chen,
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, United States
- *Correspondence: Zhenbo Hu, ; Liuya Wei, ; Zhe-Sheng Chen,
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11
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Combining empirical knowledge, in silico molecular docking and ADMET profiling to identify therapeutic phytochemicals from Brucea antidysentrica for acute myeloid leukemia. PLoS One 2022; 17:e0270050. [PMID: 35895695 PMCID: PMC9328557 DOI: 10.1371/journal.pone.0270050] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 06/03/2022] [Indexed: 12/18/2022] Open
Abstract
Acute myeloid leukemia (AML) is one of the deadly cancers. Chemotherapy is the first-line treatment and the only curative intervention is stem cell transplantation which are intolerable for aged and comorbid patients. Therefore, finding complementary treatment is still an active research area. For this, empirical knowledge driven search for therapeutic agents have been carried out by long and arduous wet lab processes. Nonetheless, currently there is an accumulated bioinformatics data about natural products that enabled the use of efficient and cost effective in silico methods to find drug candidates. In this work, therefore, we set out to computationally investigate the phytochemicals from Brucea antidysentrica to identify therapeutic phytochemicals for AML. We performed in silico molecular docking of compounds against AML receptors IDH2, MCL1, FLT3 and BCL2. Phytochemicals were docked to AML receptors at the same site where small molecule drugs were bound and their binding affinities were examined. In addition, random compounds from PubChem were docked with AML targets and their docking score was compared with that of phytochemicals using statistical analysis. Then, non-covalent interactions between phytochemicals and receptors were identified and visualized using discovery studio and Protein-Ligand Interaction Profiler web tool (PLIP). From the statistical analysis, most of the phytochemicals exhibited significantly lower (p-value ≤ 0.05) binding energies compared with random compounds. Using cutoff binding energy of less than or equal to one standard deviation from the mean of the phytochemicals’ binding energies for each receptor, 12 phytochemicals showed considerable binding affinity. Especially, hydnocarpin (-8.9 kcal/mol) and yadanzioside P (-9.4 kcal/mol) exhibited lower binding energy than approved drugs AMG176 (-8.6 kcal/mol) and gilteritinib (-9.1 kcal/mol) to receptors MCL1 and FLT3 respectively, indicating their potential to be lead molecules. In addition, most of the phytochemicals possessed acceptable drug-likeness and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Based on the binding affinities as exhibited by the molecular docking studies supported by the statistical analysis, 12 phytochemicals from Brucea antidysentrica (1,11-dimethoxycanthin-6-one, 1-methoxycanthin-6-one, 2-methoxycanthin-6-one, beta-carboline-1-propionic acid, bruceanol A, bruceanol D, bruceanol F, bruceantarin, bruceantin, canthin-6-one, hydnocarpin, and yadanzioside P) can be considered as candidate compounds to prevent and manage AML. However, the phytochemicals should be further studied using in vivo & in vitro experiments on AML models. Therefore, this study concludes that combination of empirical knowledge, in silico molecular docking and ADMET profiling is useful to find natural product-based drug candidates. This technique can be applied to other natural products with known empirical efficacy.
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12
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Ardıl B, Alper M. Potential cancer treatment effects of brusatol or eriodictyol combined with 5-fluorouracil (5-FU) in colorectal cancer cell. Naunyn Schmiedebergs Arch Pharmacol 2022; 395:1109-1123. [PMID: 35857038 DOI: 10.1007/s00210-022-02270-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 07/07/2022] [Indexed: 10/17/2022]
Abstract
Colorectal cancer is among the most frequently diagnosed cancers in patients today. In the treatment of this disease, combination or multicomponent therapy has been identified as a potential method to improve patient response and delay side effects. The aim of this study was to determine the effects on cell viability of commercial Bru and Erio used together with the anticancer drug 5-FU in the human colorectal cancer (CRC) cell line (HT-29 cell line) for the first time, as far as can be determined from available literature at this time. Additionally, the research seeks to study any potential effects on apoptosis. For this purpose, the effects of independent and combined treatments of the aforementioned agents on cell viability were investigated through the MTT experiment. Apoptotic effects were determined by Annexin V/PI and real-time PCR methods. In addition, a cell cycle analysis was used to determine the distribution of cells in the cycle. Data from experiments for 48 h showed that Bru, alone or in combination with 5-FU, is capable of causing an increase in the percentage of apoptotic cells in HT-29 cells compared to those of Erio alone or in combination with 5-FU. A significant increase in the level of bax and caspase-3 apoptotic genes was also detected in combinations of IC50 concentrations of Bru and 5-FU. These findings suggest that unlike Erio, Bru alone or in combination with 5-FU may be useful for increasing the effects of 5-FU used in the treatment of CRC and to provide data on alternative treatment approaches.
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Affiliation(s)
- Buse Ardıl
- Faculty of Science, Department of Molecular Biology and Genetics, Muğla Sıtkı Koçman University, 48000, Mugla, Turkey
| | - Mehlika Alper
- Faculty of Science, Department of Molecular Biology and Genetics, Muğla Sıtkı Koçman University, 48000, Mugla, Turkey.
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13
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Mazumder K, Aktar A, Roy P, Biswas B, Hossain ME, Sarkar KK, Bachar SC, Ahmed F, Monjur-Al-Hossain ASM, Fukase K. A Review on Mechanistic Insight of Plant Derived Anticancer Bioactive Phytocompounds and Their Structure Activity Relationship. Molecules 2022; 27:3036. [PMID: 35566385 PMCID: PMC9102595 DOI: 10.3390/molecules27093036] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 05/04/2022] [Accepted: 05/05/2022] [Indexed: 11/16/2022] Open
Abstract
Cancer is a disorder that rigorously affects the human population worldwide. There is a steady demand for new remedies to both treat and prevent this life-threatening sickness due to toxicities, drug resistance and therapeutic failures in current conventional therapies. Researchers around the world are drawing their attention towards compounds of natural origin. For decades, human beings have been using the flora of the world as a source of cancer chemotherapeutic agents. Currently, clinically approved anticancer compounds are vincristine, vinblastine, taxanes, and podophyllotoxin, all of which come from natural sources. With the triumph of these compounds that have been developed into staple drug products for most cancer therapies, new technologies are now appearing to search for novel biomolecules with anticancer activities. Ellipticine, camptothecin, combretastatin, curcumin, homoharringtonine and others are plant derived bioactive phytocompounds with potential anticancer properties. Researchers have improved the field further through the use of advanced analytical chemistry and computational tools of analysis. The investigation of new strategies for administration such as nanotechnology may enable the development of the phytocompounds as drug products. These technologies have enhanced the anticancer potential of plant-derived drugs with the aim of site-directed drug delivery, enhanced bioavailability, and reduced toxicity. This review discusses mechanistic insights into anticancer compounds of natural origins and their structural activity relationships that make them targets for anticancer treatments.
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Affiliation(s)
- Kishor Mazumder
- Department of Pharmacy, Jashore University of Science and Technology, Jashore 7408, Bangladesh; (A.A.); (P.R.); (B.B.); (M.E.H.); (K.K.S.)
- School of Optometry and Vision Science, UNSW Medicine, University of New South Wales (UNSW), Sydney, NSW 2052, Australia
| | - Asma Aktar
- Department of Pharmacy, Jashore University of Science and Technology, Jashore 7408, Bangladesh; (A.A.); (P.R.); (B.B.); (M.E.H.); (K.K.S.)
| | - Priyanka Roy
- Department of Pharmacy, Jashore University of Science and Technology, Jashore 7408, Bangladesh; (A.A.); (P.R.); (B.B.); (M.E.H.); (K.K.S.)
| | - Biswajit Biswas
- Department of Pharmacy, Jashore University of Science and Technology, Jashore 7408, Bangladesh; (A.A.); (P.R.); (B.B.); (M.E.H.); (K.K.S.)
| | - Md. Emran Hossain
- Department of Pharmacy, Jashore University of Science and Technology, Jashore 7408, Bangladesh; (A.A.); (P.R.); (B.B.); (M.E.H.); (K.K.S.)
| | - Kishore Kumar Sarkar
- Department of Pharmacy, Jashore University of Science and Technology, Jashore 7408, Bangladesh; (A.A.); (P.R.); (B.B.); (M.E.H.); (K.K.S.)
| | - Sitesh Chandra Bachar
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka 1207, Bangladesh; (S.C.B.); (F.A.)
| | - Firoj Ahmed
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka 1207, Bangladesh; (S.C.B.); (F.A.)
| | - A. S. M. Monjur-Al-Hossain
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Dhaka, Dhaka 1207, Bangladesh;
| | - Koichi Fukase
- Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan
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14
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Kobayashi H, Imanaka S, Shigetomi H. Revisiting therapeutic strategies for ovarian cancer by focusing on redox homeostasis. Oncol Lett 2022; 23:80. [PMID: 35111249 PMCID: PMC8771630 DOI: 10.3892/ol.2022.13200] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 12/15/2021] [Indexed: 12/12/2022] Open
Abstract
Recent advances in molecular genetics have expanded our understanding of ovarian cancer. High levels of reactive oxygen species (ROS) and upregulation of antioxidant genes are common characteristic features of human cancers. This review reconsiders novel therapeutic strategies for ovarian cancer by focusing on redox homeostasis. A literature search was performed for preclinical and clinical studies published between January 1998 and October 2021 in the PubMed database using a combination of specific terms. ROS serves a central role in tumor suppression and progression by inducing DNA damage and mutations, genomic instability, and aberrant anti- and pro-tumorigenic signaling. Cancer cells increase their antioxidant capacity to neutralize the extra ROS. Additionally, antioxidants, such as CD44 variant isoform 9 (CD44v9) and nuclear factor erythroid 2-related factor 2 (Nrf2), mediate redox homeostasis in ovarian cancer. Furthermore, studies conducted on different cancer types revealed the dual role of antioxidants in tumor progression and inhibition. However, in animal models, genetic loss of antioxidant capacity in the host cannot block cancer initiation and progression. Host-derived antioxidant systems are essential to suppress carcinogenesis, suggesting that antioxidants serve a pivotal role in suppressing cancer development. By contrast, antioxidant activation in cancer cells confers aggressive phenotypes. Antioxidant inhibitors can promote cancer cell death by enhancing ROS levels. Concurrent inhibition of CD44v9 and Nrf2 may trigger apoptosis induction, potentiate chemosensitivity and enhance antitumor activities through the ROS-activated p38/p21 pathway. Antioxidants may have tumor-promoting and -suppressive functions. Therefore, an improved understanding of the role of antioxidants in redox homeostasis and developing antioxidant-specific inhibitors is necessary for treating ovarian cancer.
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Affiliation(s)
- Hiroshi Kobayashi
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Nara 634-8522, Japan.,Department of Obstetrics and Gynecology, Ms. Clinic MayOne, Kashihara, Nara 634-0813, Japan
| | - Shogo Imanaka
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Nara 634-8522, Japan.,Department of Obstetrics and Gynecology, Ms. Clinic MayOne, Kashihara, Nara 634-0813, Japan
| | - Hiroshi Shigetomi
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Nara 634-8522, Japan.,Department of Obstetrics and Gynecology, Aska Ladies Clinic, Nara 634-0001, Japan
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15
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Xing S, Nong F, Wang Y, Huang D, Qin J, Chen YF, He DH, Wu PE, Huang H, Zhan R, Xu H, Liu YQ. Brusatol has therapeutic efficacy in non-small cell lung cancer by targeting Skp1 to inhibit cancer growth and metastasis. Pharmacol Res 2022; 176:106059. [PMID: 34998973 DOI: 10.1016/j.phrs.2022.106059] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 12/30/2021] [Accepted: 01/03/2022] [Indexed: 11/23/2022]
Abstract
Skp1-Cul1-F-box protein (SCF) ubiquitin E3 ligases play important roles in cancer development and serve as a promising therapeutic target in cancer therapy. Brusatol (Bru), a known Nrf2 inhibitor, holds promise for treating a wide range of tumors; however, the direct targets of Bru and its anticancer mode of action remain unclear. In our study, 793 Bru-binding candidate proteins were identified by using a biotin-brusatol conjugate (Bio-Bru) followed by streptavidin-affinity pull down-based mass spectrometry. We found that Bru can directly bind to Skp1 and disrupt the interactions of Skp1 with the F-box protein Skp2, leading to the inhibition of the Skp2-SCF E3 ligase. Bru inhibited both proliferation and migration via promoting the accumulation of the substrates p27 and E-cadherin; Skp1 overexpression attenuated while Skp1 knockdown enhanced these effects of Bru in non-small cell lung cancer (NSCLC) cells. Moreover, Bru binding to Skp1 also inhibited the β-TRCP-SCF E3 ligase. In both subcutaneous and orthotopic NSCLC xenografts, Bru significantly inhibited the growth and metastasis of NSCLC through targeting SCF complex and upregulating p27 and E-cadherin protein levels. These data demonstrate that Bru is a Skp1-targeting agent that may have therapeutic potentials in lung cancer.
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Affiliation(s)
- Shangping Xing
- Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Feifei Nong
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Yaqin Wang
- Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Da Huang
- Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Jialiang Qin
- Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Yu-Fei Chen
- Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Dan-Hua He
- Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Pei-En Wu
- Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Huicai Huang
- Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Ruoting Zhan
- Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Hui Xu
- Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Yong-Qiang Liu
- Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
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16
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Ahanger AM, Kumar S, Arya A, Suryavanshi A, Kain D, Vandana. Synthesis and Encapsulation of Ajuga parviflora Extract with Zeolitic Imidazolate Framework-8 and Their Therapeutic Action against G + and G - Drug-Resistant Bacteria. ACS OMEGA 2022; 7:1671-1681. [PMID: 35071862 PMCID: PMC8772321 DOI: 10.1021/acsomega.1c03984] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 11/23/2021] [Indexed: 10/29/2023]
Abstract
Infectious diseases caused by bacteria have become a public health issue. Antibiotic therapy for infectious disorders, as well as antibiotic overuse, has resulted in antibiotic-resistant bacterial strains. Zeolitic imidazolate framework-8 (ZIF-8) possesses a wide surface area, high porosity, variable functionality, and potential drug carriers. We have established a clear method for making a nanoscale APE@ZIF-8 nanocomposite agent with outstanding antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and cephalosporin-carbapenem-resistant Escherichia coli (CCREC). We present a unique approach for encapsulating molecules ofAjuga parviflora extract (APE) with ZIF-8. APE@ZIF-8 has a positive charge. By electrostatic contact with the negatively charged bacterial surface of S. aureus and E. coli, APE@ZIF-8 NPs produce reactive oxygen species (ROS) that damage bacterial cell organelles. As a result, the APE@ZIF-8 nanocomposite offers limitless application potential in the treatment of infectious disorders caused by drug-resistant gram-positive and gram-negative bacteria.
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Affiliation(s)
- Ab Majeed Ahanger
- Medicinal
Plant Research Laboratory, Department of Botany, Ramjas College, University of Delhi, New Delhi 110007, India
| | - Suresh Kumar
- Medicinal
Plant Research Laboratory, Department of Botany, Ramjas College, University of Delhi, New Delhi 110007, India
| | - Atul Arya
- Medicinal
Plant Research Laboratory, Department of Botany, Ramjas College, University of Delhi, New Delhi 110007, India
| | - Amrita Suryavanshi
- Medicinal
Plant Research Laboratory, Department of Botany, Ramjas College, University of Delhi, New Delhi 110007, India
| | - Dolly Kain
- Medicinal
Plant Research Laboratory, Department of Botany, Ramjas College, University of Delhi, New Delhi 110007, India
| | - Vandana
- Medicinal
Plant Research Laboratory, Department of Botany, Ramjas College, University of Delhi, New Delhi 110007, India
- Department
of Chemistry, Dyal Singh College, University
of Delhi, New Delhi 110003, India
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17
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Abstract
A synthetic approach to quassinoids is described. The route to the tetracyclic core relies on an efficient and selective annulation between two unsaturated carbonyl components that is initiated by catalytic hydrogen atom transfer from an iron hydride to an alkene. Application of this strategy allows for enantioselective synthesis of quassin, which is prepared in 14 steps from commercially available starting material.
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Affiliation(s)
- William P Thomas
- Department of Chemistry, University of California, Irvine, California 92697-2025, United States
| | - Sergey V Pronin
- Department of Chemistry, University of California, Irvine, California 92697-2025, United States
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18
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Guo SB, Huang WJ, Tian XP. Brusatol modulates diverse cancer hallmarks and signaling pathways as a potential cancer therapeutic. ACTA MATERIA MEDICA 2022; 1. [DOI: 10.15212/amm-2022-0014] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/14/2024]
Abstract
Cancer is a consequence of uncontrolled cell proliferation that is associated with cell-cycle disruption. It is a multifactorial disease that depends on the modulation of numerous oncogenic signaling pathways and targets. Although a battle against cancer has been waged for centuries, this disease remains a major cause of death worldwide. Because of the development of resistance to current anticancer drugs, substantial effort has been focused on discovering more effective agents for tumor therapy. Natural products have powerful prospects as anticancer drugs. Brusatol, a component isolated from the plant Brucea javanica, has been demonstrated to efficiently combat a wide variety of tumors. Extensive studies have indicated that brusatol exhibits anticancer effects by arresting the cell cycle; promoting apoptosis; inducing autophagy; attenuating epithelial-mesenchymal transition; inhibiting migration, invasion and angiogenesis; and increasing chemosensitivity and radiosensitivity. These effects involve various oncogenic signaling pathways, including the MAPK, NF-κB, PI3K/AKT/mTOR, JAK/STAT and Keap1/Nrf2/ARE signaling pathways. This review describes the evidence suggesting that brusatol is a promising drug candidate for cancer therapeutics.
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Affiliation(s)
- Song-Bin Guo
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Wei-Juan Huang
- Department of Pharmacology, College of Pharmacy, Jinan University, Guangzhou, P.R. China
| | - Xiao-Peng Tian
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
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19
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Dai Z, Cai L, Chen Y, Wang S, Zhang Q, Wang C, Tu M, Zhu Z, Li Q, Lu X. Brusatol Inhibits Proliferation and Invasion of Glioblastoma by Down-Regulating the Expression of ECM1. Front Pharmacol 2022; 12:775680. [PMID: 34970146 PMCID: PMC8713816 DOI: 10.3389/fphar.2021.775680] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 11/30/2021] [Indexed: 12/13/2022] Open
Abstract
Brusatol (Bru), a Chinese herbal extract, has a variety of anti-tumor effects. However, little is known regarding its role and underlying mechanism in glioblastoma cells. Here, we found that Bru could inhibit the proliferation of glioblastoma cells in vivo and in vitro. Besides, it also had an inhibitory effect on human primary glioblastoma cells. RNA-seq analysis indicated that Bru possibly achieved these effects through inhibiting the expression of extracellular matrix protein 1 (ECM1). Down-regulating the expression of ECM1 via transfecting siRNA could weaken the proliferation and invasion of glioblastoma cells and promote the inhibitory effect of Bru treatment. Lentivirus-mediated overexpression of ECM1 could effectively reverse this weakening effect. Our findings indicated that Bru could inhibit the proliferation and invasion of glioblastoma cells by suppressing the expression of ECM1, and Bru might be a novel effective anticancer drug for glioblastoma cells.
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Affiliation(s)
- Zhang'an Dai
- Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lin Cai
- Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yingyu Chen
- Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Silu Wang
- Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qian Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chengde Wang
- Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ming Tu
- Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhangzhang Zhu
- Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qun Li
- Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xianghe Lu
- Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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20
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Cheng C, Yuan F, Chen XP, Zhang W, Zhao XL, Jiang ZP, Zhou HH, Zhou G, Cao S. Inhibition of Nrf2-mediated glucose metabolism by brusatol synergistically sensitizes acute myeloid leukemia to Ara-C. Biomed Pharmacother 2021; 142:111652. [PMID: 34112534 DOI: 10.1016/j.biopha.2021.111652] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 04/13/2021] [Accepted: 04/21/2021] [Indexed: 12/20/2022] Open
Abstract
Chemotherapy resistance remains to be the primary barrier to acute myeloid leukemia (AML) treatment failure. Nuclear factor-erythroid 2-related factor 2 (Nrf2) has been well established as a truly pleiotropic transcription factor. Inhibition of Nrf2 function increases the sensitivity of various chemotherapeutics and overcomes chemoresistance effectively. Brusatol (Bru) has been reported to decrease Nrf2 protein expression specifically by ubiquitin degradation of Nrf2. However, it remains elusive whether combination of Brusatol and Cytarabine (Ara-C) elicits a synergistic antitumor effect in AML. Our results demonstrated that combination of Ara-C and Brusatol synergistically exerted remarkable pro-apoptosis effect in HL-60 and THP-1 cells. Mechanistically, synergistic anti-tumor effect of Ara-C/Brusatol in AML cells is mediated by attenuating Nrf2 expression. To our surprise, Nrf2 inhibition by Brusatol causes downregulation of the expression of glycolysis-related proteins and decreased glucose consumption and lactate production, whereas the level of ROS production was unaffected. The activation of Nrf2 by Sulforaphane (SFP) could reverse the chemotherapeutic effect and changes of glycolysis of concomitant of Ara-C with Brusatol in AML cell lines. Additionally, Ara-C/Brusatol co-treatment decreased Glucose-6-phosphate dehydrogenase (G6PD) protein expression and increased the sensitivity of Ara-C. Moreover, the mouse xenograft in vivo experiment confirmed that combining Ara-C with Brusatol exerted stronger antileukemia than Ara-C alone. The efficacy, together with the mechanistic observations, reveals the potential of simultaneously giving these two drugs and provides a rational basis for targeting glucose catabolism in future clinical therapeutic approach.
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Affiliation(s)
- Cong Cheng
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha 410078, PR China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha 410078, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Center South University, Changsha 410008, Hunan, PR China
| | - Fang Yuan
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha 410078, PR China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha 410078, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Center South University, Changsha 410008, Hunan, PR China
| | - Xiao-Ping Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha 410078, PR China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha 410078, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Center South University, Changsha 410008, Hunan, PR China
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha 410078, PR China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha 410078, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Center South University, Changsha 410008, Hunan, PR China
| | - Xie-Lan Zhao
- Department of Hematology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, PR China
| | - Zhi-Ping Jiang
- Department of Hematology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, PR China
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha 410078, PR China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha 410078, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Center South University, Changsha 410008, Hunan, PR China
| | - Gan Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha 410078, PR China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha 410078, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Center South University, Changsha 410008, Hunan, PR China; National Institution of Drug Clinical Trial, Xiangya Hospital, Central South University, 110 Xiangya Road, Changsha, Hunan 410008, PR China.
| | - Shan Cao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha 410078, PR China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha 410078, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Center South University, Changsha 410008, Hunan, PR China.
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21
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Brusatol Inhibits Tumor Growth and Increases the Efficacy of Cabergoline against Pituitary Adenomas. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6696015. [PMID: 34221237 PMCID: PMC8221873 DOI: 10.1155/2021/6696015] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 05/15/2021] [Indexed: 12/03/2022]
Abstract
Cabergoline (CAB) is the first choice for treatment of prolactinoma and the most common subtype of pituitary adenoma. However, drug resistance and lack of effectiveness in other pituitary tumor types remain clinical challenges to this treatment. Brusatol (BT) is known to inhibit cell growth and promote apoptosis in a variety of cancer cells. In our present studies, we investigate the effects of BT on pituitary tumor cell proliferation in vitro and in vivo. BT treatment resulted in an increase in Annexin V-expressing cells and promoted the expression of apoptosis-related proteins in rat and human pituitary tumor cells. Investigation of the mechanism underlying this effect revealed that BT increased the production of reactive oxygen species (ROS) and inhibited the phosphorylation of 4EBP1 and S6K1. Furthermore, treatment with a combination of BT and CAB resulted in greater antitumor effects than either treatment alone in nude mice and pituitary tumor cells. Collectively, our results suggest that the BT-induced ROS accumulation and inhibition of mTORC1 signaling pathway leads to inhibition of tumor growth. Combined use of CAB and BT may increase the clinical effectiveness of treatment for human pituitary adenomas.
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22
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Burgers LD, Fürst R. Natural products as drugs and tools for influencing core processes of eukaryotic mRNA translation. Pharmacol Res 2021; 170:105535. [PMID: 34058326 DOI: 10.1016/j.phrs.2021.105535] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/02/2021] [Accepted: 03/02/2021] [Indexed: 12/19/2022]
Abstract
Eukaryotic protein synthesis is the highly conserved, complex mechanism of translating genetic information into proteins. Although this process is essential for cellular homoeostasis, dysregulations are associated with cellular malfunctions and diseases including cancer and diabetes. In the challenging and ongoing search for adequate treatment possibilities, natural products represent excellent research tools and drug leads for new interactions with the translational machinery and for influencing mRNA translation. In this review, bacterial-, marine- and plant-derived natural compounds that interact with different steps of mRNA translation, comprising ribosomal assembly, translation initiation and elongation, are highlighted. Thereby, the exact binding and interacting partners are unveiled in order to accurately understand the mode of action of each natural product. The pharmacological relevance of these compounds is furthermore assessed by evaluating the observed biological activities in the light of translational inhibition and by enlightening potential obstacles and undesired side-effects, e.g. in clinical trials. As many of the natural products presented here possess the potential to serve as drug leads for synthetic derivatives, structural motifs, which are indispensable for both mode of action and biological activities, are discussed. Evaluating the natural products emphasises the strong diversity of their points of attack. Especially the fact that selected binding partners can be set in direct relation to different diseases emphasises the indispensability of natural products in the field of drug development. Discovery of new, unique and unusual interacting partners again renders them promising tools for future research in the field of eukaryotic mRNA translation.
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Affiliation(s)
- Luisa D Burgers
- Institute of Pharmaceutical Biology, Faculty of Biochemistry, Chemistry and Pharmacy, Goethe University, Frankfurt, Germany
| | - Robert Fürst
- Institute of Pharmaceutical Biology, Faculty of Biochemistry, Chemistry and Pharmacy, Goethe University, Frankfurt, Germany; LOEWE Center for Translational Biodiversity Genomics (LOEWE-TBG), Frankfurt, Germany
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23
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Ren Y, Kinghorn AD. Development of Potential Antitumor Agents from the Scaffolds of Plant-Derived Terpenoid Lactones. J Med Chem 2020; 63:15410-15448. [PMID: 33289552 PMCID: PMC7812702 DOI: 10.1021/acs.jmedchem.0c01449] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Naturally occurring terpenoid lactones and their synthetic derivatives have attracted increasing interest for their promising antitumor activity and potential utilization in the discovery and design of new antitumor agents. In the present perspective article, selected plant-derived five-membered γ-lactones and six-membered δ-lactones that occur with terpenoid scaffolds are reviewed, with their structures, cancer cell line cytotoxicity and in vivo antitumor activity, structure-activity relationships, mechanism of action, and the potential for developing cancer chemotherapeutic agents discussed in each case. The compounds presented include artemisinin (ART, 1), parthenolide (PTL, 2), thapsigargin (TPG, 3), andrographolide (AGL, 4), ginkgolide B (GKL B, 5), jolkinolide B (JKL B, 6), nagilactone E (NGL E, 7), triptolide (TPL, 8), bruceantin (BRC, 9), dichapetalin A (DCT A, 10), and limonin (LMN, 11), and their naturally occurring analogues and synthetic derivatives. It is hoped that this contribution will be supportive of the future development of additional efficacious anticancer agents derived from natural products.
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Affiliation(s)
- Yulin Ren
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States
| | - A. Douglas Kinghorn
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States
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Yu XQ, Shang XY, Huang XX, Yao GD, Song SJ. Brusatol: A potential anti-tumor quassinoid from Brucea javanica. CHINESE HERBAL MEDICINES 2020; 12:359-366. [PMID: 36120179 PMCID: PMC9476775 DOI: 10.1016/j.chmed.2020.05.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 04/08/2020] [Accepted: 05/25/2020] [Indexed: 01/20/2023] Open
Abstract
Brusatol, a triterpene lactone compound mainly from Brucea javanica, sensitizes a broad spectrum of cancer cells. It is known as a specific inhibitor of nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway. In this review, we provide a comprehensive overview on the antitumor effect and molecular mechanisms of brusatol in vitro and in vivo. This review also covers pharmacokinetics studies, modification of dosages forms of brusatol. Increasing evidences have validated the value of brusatol as a chemotherapeutic agent in cancers, which may contribute to drug development and clinical application.
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25
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Quassinoid analogs with enhanced efficacy for treatment of hematologic malignancies target the PI3Kγ isoform. Commun Biol 2020; 3:267. [PMID: 32461675 PMCID: PMC7253423 DOI: 10.1038/s42003-020-0996-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 04/27/2020] [Indexed: 12/11/2022] Open
Abstract
Development of novel PI3K inhibitors is an important strategy to overcome their resistance and poor tolerability in clinical trials. The quassinoid family member Brusatol shows specific inhibitory activity against hematologic malignancies. However, the mechanism of its anti-cancer activity is unknown. We investigated the anti-cancer activity of Brusatol on multiple hematologic malignancies derived cell lines. The results demonstrated that the PI3Kγ isoform was identified as a direct target of Brusatol, and inhibition was dramatically reduced on cells with lower PI3Kγ levels. Novel synthetic analogs were also developed and tested in vitro and in vivo. They shared comparable or superior potency in their ability to inhibit malignant hematologic cell lines, and in a xenograft transplant mouse model. One unique analog had minimal toxicity to normal human cells and in a mouse model. These new analogs have enhanced potential for development as a new class of PI3K inhibitors for treatment of hematologic malignancies. Pei et al. demonstrate that PI3Kγ isoform is a direct target of Brusatol, a natural compound with inhibitory activity against hematologic malignancies. They further develop several Brusatol analogs with superior in vitro and in vivo anti-cancer activity.
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Abstract
The basic leucine zipper transcription factor Nrf2 is the primary regulator of cellular oxidative stress. Activation of Nrf2 is regarded as a potential preventive and therapeutic strategy. However, aberrant hyperactivation of Nrf2 is found in a variety of cancers and promotes cancer progression and metastasis. Moreover, constitutive activation of Nrf2 confers cancer cells resistance to chemo- and radio-therapy. Thus, inhibiting Nrf2 could be a new therapeutic strategy for cancer. With the aim of accelerating the discovery and development of novel Nrf2 inhibitors, we summarize the biological and pathological functions of Nrf2 in cancer. Furthermore, the recent studies of small molecular Nrf2 inhibitors and potential Nrf2 inhibitory mechanisms are also summarized in this review.
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27
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Cai SJ, Liu Y, Han S, Yang C. Brusatol, an NRF2 inhibitor for future cancer therapeutic. Cell Biosci 2019; 9:45. [PMID: 31183074 PMCID: PMC6554866 DOI: 10.1186/s13578-019-0309-8] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 05/30/2019] [Indexed: 11/10/2022] Open
Abstract
Background Natural products from herbal medicines have long been investigated for their potentials as cancer therapeutics. Besides the development of several herbal medicine-derived anti-cancer agents, such as paclitaxel, vincristine and podophyllotoxin, many recent laboratory findings demonstrated that brusatol, a quassinoid from the seeds of Brucea sumatrana, exhibits potent tumor suppressing effect with improved disease outcome. Our recent finding further demonstrated that brusatol synergizes with the intrinsic metabolic burden in cancer cells. Main body Here, we summarized the recent investigations of brusatol as an experimental therapeutic for human malignancies, such as leukemia, lung cancer, pancreatic cancer and brain tumor. We also discussed the molecular target brusatol, with a focus on the Nuclear factor erythroid 2-related factor 2 (NRF2)-guided gene transcription, as well as glutathione de novo synthesis. Further, we discussed the challenges and future applications of brusatol for cancer therapy. Conclusion In conclusion, we believe increasing evidences have shown the value of brusatol as a novel strategy for cancer treatment, which may indicate future drug development and clinical translation.
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Affiliation(s)
- Sabrina J Cai
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Building 37, Room 1142E, Bethesda, MD 20892 USA
| | - Yang Liu
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Building 37, Room 1142E, Bethesda, MD 20892 USA
| | - Sue Han
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Building 37, Room 1142E, Bethesda, MD 20892 USA
| | - Chunzhang Yang
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Building 37, Room 1142E, Bethesda, MD 20892 USA
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28
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Pharmacokinetic study on bruceoside A revealed the potential role of quassinoid glycosides for the anticancer properties of Fructus Bruceae. J Pharm Biomed Anal 2019; 170:264-272. [DOI: 10.1016/j.jpba.2019.03.052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 03/11/2019] [Accepted: 03/22/2019] [Indexed: 11/24/2022]
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Turpaev K, Krizhanovskii C, Wang X, Sargsyan E, Bergsten P, Welsh N. The protein synthesis inhibitor brusatol normalizes high-fat diet-induced glucose intolerance in male C57BL/6 mice: role of translation factor eIF5A hypusination. FASEB J 2019; 33:3510-3522. [PMID: 30462531 DOI: 10.1096/fj.201801698r] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The naturally occurring quassinoid compound brusatol improves the survival of insulin-producing cells when exposed to the proinflammatory cytokines IL-1β and IFN-γ in vitro. The aim of the present study was to investigate whether brusatol also promotes beneficial effects in mice fed a high-fat diet (HFD), and if so, to study the mechanisms by which brusatol acts. In vivo, we observed that the impaired glucose tolerance of HFD-fed male C57BL/6 mice was counteracted by a 2 wk treatment with brusatol. Brusatol treatment improved both β-cell function and peripheral insulin sensitivity of HFD-fed mice. In vitro, brusatol inhibited β-cell total protein and proinsulin biosynthesis, with an ED50 of ∼40 nM. In line with this, brusatol blocked cytokine-induced iNOS protein expression via inhibition of iNOS mRNA translation. Brusatol may have affected protein synthesis, at least in part, via inhibition of eukaryotic initiation factor 5A (eIF5A) hypusination, as eIF5A spermidine association and hypusination in RIN-5AH cells was reduced in a dose- and time-dependent manner. The eIF5A hypusination inhibitor GC7 promoted a similar effect. Both brusatol and GC7 protected rat RIN-5AH cells against cytokine-induced cell death. Brusatol reduced eIF5A hypusination and cytokine-induced cell death in EndoC-βH1 cells as well. Finally, hypusinated eIF5A was reduced in vivo by brusatol in islet endocrine and endothelial islet cells of mice fed an HFD. The results of the present study suggest that brusatol improves glucose intolerance in mice fed an HFD, possibly by inhibiting protein biosynthesis and eIF5A hypusination.-Turpaev, K., Krizhanovskii, C., Wang, X., Sargsyan, E., Bergsten, P., Welsh, N. The protein synthesis inhibitor brusatol normalizes high-fat diet-induced glucose intolerance in male C57BL/6 mice: role of translation factor eIF5A hypusination.
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Affiliation(s)
- Kyril Turpaev
- Science for Life Laboratory, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden; and
- Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, Russia
| | - Camilla Krizhanovskii
- Science for Life Laboratory, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden; and
| | - Xuan Wang
- Science for Life Laboratory, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden; and
| | - Ernest Sargsyan
- Science for Life Laboratory, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden; and
| | - Peter Bergsten
- Science for Life Laboratory, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden; and
| | - Nils Welsh
- Science for Life Laboratory, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden; and
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Brusatol ameliorates 2, 4, 6-trinitrobenzenesulfonic acid-induced experimental colitis in rats: Involvement of NF-κB pathway and NLRP3 inflammasome. Int Immunopharmacol 2018; 64:264-274. [DOI: 10.1016/j.intimp.2018.09.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 08/27/2018] [Accepted: 09/08/2018] [Indexed: 12/23/2022]
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Wei N, Li J, Fang C, Chang J, Xirou V, Syrigos NK, Marks BJ, Chu E, Schmitz JC. Targeting colon cancer with the novel STAT3 inhibitor bruceantinol. Oncogene 2018; 38:1676-1687. [DOI: 10.1038/s41388-018-0547-y] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 08/27/2018] [Accepted: 10/07/2018] [Indexed: 01/08/2023]
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32
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Corso CR, Acco A. Glutathione system in animal model of solid tumors: From regulation to therapeutic target. Crit Rev Oncol Hematol 2018; 128:43-57. [DOI: 10.1016/j.critrevonc.2018.05.014] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 04/10/2018] [Accepted: 05/16/2018] [Indexed: 02/07/2023] Open
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UVA Irradiation Enhances Brusatol-Mediated Inhibition of Melanoma Growth by Downregulation of the Nrf2-Mediated Antioxidant Response. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:9742154. [PMID: 29670684 PMCID: PMC5835260 DOI: 10.1155/2018/9742154] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 11/09/2017] [Accepted: 11/27/2017] [Indexed: 12/30/2022]
Abstract
Brusatol (BR) is a potent inhibitor of Nrf2, a transcription factor that is highly expressed in cancer tissues and confers chemoresistance. UVA-generated reactive oxygen species (ROS) can damage both normal and cancer cells and may be of potential use in phototherapy. In order to provide an alternative method to treat the aggressive melanoma, we sought to investigate whether low-dose UVA with BR is more effective in eliminating melanoma cells than the respective single treatments. We found that BR combined with UVA led to inhibition of A375 melanoma cell proliferation by cell cycle arrest in the G1 phase and triggers cell apoptosis. Furthermore, inhibition of Nrf2 expression attenuated colony formation and tumor development from A375 cells in heterotopic mouse models. In addition, cotreatment of UVA and BR partially suppressed Nrf2 and its downstream target genes such as HO-1 along with the PI3K/AKT pathway. We propose that cotreatment increased ROS-induced cell cycle arrest and cellular apoptosis and inhibits melanoma growth by regulating the AKT-Nrf2 pathway in A375 cells which offers a possible therapeutic intervention strategy for the treatment of human melanoma.
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34
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Chen HM, Lai ZQ, Liao HJ, Xie JH, Xian YF, Chen YL, Ip SP, Lin ZX, Su ZR. Synergistic antitumor effect of brusatol combined with cisplatin on colorectal cancer cells. Int J Mol Med 2018; 41:1447-1454. [PMID: 29328398 PMCID: PMC5819912 DOI: 10.3892/ijmm.2018.3372] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Accepted: 12/21/2017] [Indexed: 12/22/2022] Open
Abstract
Colorectal cancer (CRC) is a common and life-threatening type of malignant cancer, which is associated with a high mortality rate. Cisplatin (CDDP) is a commonly used chemotherapy drug with significant side effects. Brusatol (BR) is one of the principal chemical compounds isolated from the Chinese herb Bruceae Fructus, which has been reported to markedly inhibit the proliferation of numerous cancer cell lines. The present study aimed to investigate the possible synergistic anticancer effects of CDDP combined with BR on CT-26 cells, and to evaluate the underlying mechanisms of action. The growth inhibitory effects of BR, CDDP, and BR and CDDP cotreatment on CT-26 cells were assessed by MTT assay. Cell apoptosis were determined by flow cytometry and western blot analysis. The results indicated that compared with single-agent treatment, cotreatment of CT-26 cells with CDDP and BR synergistically inhibited cell proliferation and increased cellular apoptosis. Furthermore, treatment of CT-26 cells with CDDP and BR resulted in a marked increase in the release of cytosolic cytochrome c, decreased expression of procaspase-3 and procaspase-9, and upregulation of the B-cell lymphoma 2 (Bcl-2)-associated X protein/Bcl-2 ratio compared with treatment with BR or CDDP alone. These results strongly suggested that the combination of CDDP and BR was able to produce a synergistic antitumor effect in CRC cells, thus providing a solid foundation for further development of this combination regimen into an effective therapeutic method for CRC.
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Affiliation(s)
- Hai-Ming Chen
- The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Zheng-Quan Lai
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR 999077, P.R. China
| | - Hui-Jun Liao
- Department of Clinical Pharmacy and Pharmaceutical Services, Shenzhen Sixth People's Hospital (Nanshan Hospital), Shenzhen 518060, P.R. China
| | - Jian-Hui Xie
- The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Yan-Fang Xian
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR 999077, P.R. China
| | - Yun-Long Chen
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR 999077, P.R. China
| | - Siu-Po Ip
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR 999077, P.R. China
| | - Zhi-Xiu Lin
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR 999077, P.R. China
| | - Zi-Ren Su
- College of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
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35
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Lin Y, Sui LC, Wu RH, Ma RJ, Fu HY, Xu JJ, Qiu XH, Chen L. Nrf2 inhibition affects cell cycle progression during early mouse embryo development. J Reprod Dev 2017; 64:49-55. [PMID: 29249781 PMCID: PMC5830358 DOI: 10.1262/jrd.2017-042] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Brusatol, a quassinoid isolated from the fruit of Bruceajavanica, has recently been shown to inhibit nuclear factor erythroid 2-related factor 2 (Nrf2) via Keap1-dependent ubiquitination and
proteasomal degradation or protein synthesis. Nrf2 is a transcription factor that regulates the cellular defense response. Most studies have focused on the effects of Nrf2 in tumor development. Here, the critical roles
of Nrf2 in mouse early embryonic development were investigated. We found that brusatol treatment at the zygotic stage prevented the early embryo development. Most embryos stayed at the two-cell stage after 5 days of
culture (P < 0.05). This effect was associated with the cell cycle arrest, as the mRNA level of CDK1 and cyclin B decreased at the two-cell stage after brusatol treatment. The embryo
development potency was partially rescued by the injection of Nrf2 CRISPR activation plasmid. Thus, brusatol inhibited early embryo development by affecting Nrf2-related cell cycle transition from G2 to M
phase that is dependent on cyclin B-CDK1 complex.
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Affiliation(s)
- Ying Lin
- Reproductive Medical Center, Jinling Hospital, Clinical School of Medical College, Nanjing University, Jiangsu 210002, People's Republic of China.,School of Life Sciences, Nanjing Normal University, Jiangsu, People's Republic of China
| | - Liu-Cai Sui
- Reproductive Medical Center, Jinling Hospital, Clinical School of Medical College, Nanjing University, Jiangsu 210002, People's Republic of China
| | - Rong-Hua Wu
- Reproductive Medical Center, Jinling Hospital, Clinical School of Medical College, Nanjing University, Jiangsu 210002, People's Republic of China
| | - Ru-Jun Ma
- Reproductive Medical Center, Jinling Hospital, Clinical School of Medical College, Nanjing University, Jiangsu 210002, People's Republic of China
| | - Hai-Yan Fu
- Reproductive Medical Center, Jinling Hospital, Clinical School of Medical College, Nanjing University, Jiangsu 210002, People's Republic of China
| | - Juan-Juan Xu
- Reproductive Medical Center, Jinling Hospital, Clinical School of Medical College, Nanjing University, Jiangsu 210002, People's Republic of China
| | - Xu-Hua Qiu
- Reproductive Medical Center, Jinling Hospital, Clinical School of Medical College, Nanjing University, Jiangsu 210002, People's Republic of China
| | - Li Chen
- Reproductive Medical Center, Jinling Hospital, Clinical School of Medical College, Nanjing University, Jiangsu 210002, People's Republic of China
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Oh ET, Kim CW, Kim HG, Lee JS, Park HJ. Brusatol-Mediated Inhibition of c-Myc Increases HIF-1α Degradation and Causes Cell Death in Colorectal Cancer under Hypoxia. Am J Cancer Res 2017; 7:3415-3431. [PMID: 28912885 PMCID: PMC5596433 DOI: 10.7150/thno.20861] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 06/20/2017] [Indexed: 01/09/2023] Open
Abstract
HIF-1 (hypoxia-inducible factor-1) regulates the expression of ~100 genes involved in angiogenesis, metastasis, tumor growth, chemoresistance and radioresistance, underscoring the growing interest in targeting HIF-1 for cancer control. In the present study, we investigated the molecular mechanisms underlying brusatol-induced HIF-1α degradation and cell death in colorectal cancer under hypoxia (0.5% O2). Under hypoxia, pretreatment of cancer cells with brusatol increased HIF-1α degradation and cancer cell death in a dose-dependent manner. This effect was mediated by activation of prolyl hydroxylases (PHDs), as evidenced by the block of brusatol-induced HIF-1α degradation and cancer cell death by both pharmacological inhibition and siRNA-mediated knockdown of PHDs. In addition, a ferrous iron chelator (2,2'-bypyridyl) blocked brusatol-induced degradation of HIF-1α and cancer cell death in hypoxia by inhibiting PHD activation. We further found that brusatol inhibited c-Myc expression, and showed that overexpression of c-Myc prevented brusatol-induced degradation of HIF-1α and cancer cell death by increasing mitochondrial ROS production and subsequent ROS-mediated transition of ferrous iron to ferric iron. Consistent with these results, treatment of tumor-bearing mice with brusatol significantly suppressed tumor growth by promoting PHD-mediated HIF-1α degradation. Collectively, our results suggest that brusatol-mediated inhibition of c-Myc/ROS signaling pathway increases HIF-1α degradation by promoting PHD activity and induces cell death in colorectal cancer under hypoxia
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Guo N, Zhang X, Bu F, Wang L, Cao Z, Geng C, Guo R, Ren D, Wen Q. Determination of brusatol in plasma and tissues by LC-MS method and its application to a pharmacokinetic and distribution study in mice. J Chromatogr B Analyt Technol Biomed Life Sci 2017; 1053:20-26. [PMID: 28407533 DOI: 10.1016/j.jchromb.2017.04.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Revised: 03/30/2017] [Accepted: 04/01/2017] [Indexed: 10/19/2022]
Abstract
OBJECTIVES The quassinoid brusatol, which can be isolated from Brucea javanica (L.) Merr., becomes popularly studied because of its anti-tumor activity. In order to further investigate brusatol and extend its applications, a sensitive analytical method for determination of brusatol in biological samples is essential. However, few methods had been reported until now. In this study, a highly sensitive and reproducible LC-MS method for simultaneous quantification of brusatol in mouse plasma and tissues was developed and validated. METHOD Plasma samples and tissue homogenate were extracted with diethyl ether after addition of the internal standard solution(IS). The supernatant was blown to dryness with nitrogen and residual was reconstituted with 100μl of methanol. The separation was performed on an Intersil ODS-3 column and gradient elution was conducted with the mobile phase of water and methanol (0-5min 47:53, 5-5.5min 47:53-10:90, 5.5-9min 10:90, posttime 4min 47:53) at a flow rate of 0.8mL/min. Quantification was performed in the selected ion monitoring (SIM) mode at m/z 543.2 for brusatol and 220.0 for IS (ornidazole). The method was validated by analyzing quality control plasma and tissue homogenate samples, and was applied to analyze samples obtained from mice after injections of brusatol via the tail vein. RESULTS With ornidazole as the internal standard, calibration curve of the method ranged from 10 to 320ng/ml for plasma and 10-240ng/ml for tissues. Recovery rate of brusatol from plasma and tissues were between 71.09%-94.91%. Relative standard deviation (RSD) for inter- and intra-day precision was less than 15%, and the accuracy was between 96.1%-111.8%. The pharmacokinetics and distribution study of brusatol in mice after three single doses via the tail vein were carried out based on this method. The concentration of brusatol in plasma decreased rapidly and a more than 10 fold concentration of brusatol was found as compared to that in other tissues. CONCLUSIONS This is the first reported LC-MS method for detecting brusatol in tissues and can accurately determine the concentrations of these compounds in plasma and different tissues. Further research on the metabolism of brusatol in vivo is still needed.
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Affiliation(s)
- Nan Guo
- Institute of Clinical Pharmacology, Qilu Hospital of Shandong University, Jinan, China
| | - Xiaoran Zhang
- Jinan Central Hospital Affiliated to Shandong University, Jinan, China
| | - Fanlong Bu
- Institute of Clinical Pharmacology, Qilu Hospital of Shandong University, Jinan, China
| | - Lei Wang
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Zhanqi Cao
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Chunmei Geng
- Institute of Clinical Pharmacology, Qilu Hospital of Shandong University, Jinan, China
| | - Ruichen Guo
- Institute of Clinical Pharmacology, Qilu Hospital of Shandong University, Jinan, China
| | - Dongmei Ren
- Department of Natural Products, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Qing Wen
- Jinan Central Hospital Affiliated to Shandong University, Jinan, China.
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Sun Z, Cao Y, Zhai LZ. Java brucea and Chinese herbal medicine for the treatment of cholesterol granuloma in the suprasellar and sellar regions: A case report and literature review. Medicine (Baltimore) 2017; 96:e5930. [PMID: 28151875 PMCID: PMC5293438 DOI: 10.1097/md.0000000000005930] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Revised: 12/27/2016] [Accepted: 12/29/2016] [Indexed: 11/27/2022] Open
Abstract
RATIONALE A cholesterol granuloma (CG) is usually found in the middle ear, papilla, orbits, petrous apex, and choroid plexus, but is highly uncommon in the skull. In spite of benign clinicopathological lesions, bone erosion can be seen occasionally in the patient with CG. The optimal treatment strategy is radical surgery, but complete excision is usually impossible due to anatomical restrictions and a risk of injury to the key structures located nearby. Here, we report a patient with CGs in the suprasellar and sellar regions who was successfully treated with Java brucea and Chinese herbal medicine. PATIENT CONCERNS A 31-year-old man presenting with progressive decreased vision in both eyes was analyzed. DIAGNOSES A skull magnetic resonance imaging (MRI) scan showed a low-density tumor in the uprasellar and sellar regions and histopathological examination revealed a CG. INTERVENTIONS The patient was referred the surgery and radiotherapy. In the meantime, brucea soft capsules and herbal medicine combined were administered to him. OUTCOMES The related clinical symptoms and signs resolved significantly after several months, as his therapy progressed. The patient showed no sign of recurrence during the treatment period. Furthermore, he was still alive and disease-free at 37 months of follow-up visit. LESSONS Overall, brucea soft capsules and a Chinese herbal formula treatment combined could be beneficial in improving the patient's quality of life with CG in the skull.
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Affiliation(s)
- Zhe Sun
- First clinical medical college of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong,China
| | - Yang Cao
- Department of Oncology Center, the First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Lin-zhu Zhai
- Department of Oncology Center, the First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
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Issa ME, Berndt S, Carpentier G, Pezzuto JM, Cuendet M. Bruceantin inhibits multiple myeloma cancer stem cell proliferation. Cancer Biol Ther 2016; 17:966-75. [PMID: 27434731 DOI: 10.1080/15384047.2016.1210737] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Multiple myeloma (MM) continues to claim the lives of a majority of patients. MM cancer stem cells (CSCs) have been demonstrated to sustain tumor growth. Due to their ability to self-renew and to express detoxifying enzymes and efflux transporters, MM-CSCs are rendered highly resistant to conventional therapies. Therefore, managing MM-CSCs characteristics could have profound clinical implications. Bruceantin (BCT) is a natural product previously demonstrated to inhibit the growth of MM in RPMI 8226 cells-inoculated mouse xenograft models, and to cause regression in already established tumors. The objectives of the present study were to test the inhibitory effects of BCT on MM-CSCs growth derived from a human primary tumor, and to explore a mechanism of action underlying these effects. BCT exhibited potent antiproliferative activity in MM-CSCs starting at 25 nM. BCT induced cell cycle arrest, cell death and apoptosis in MM-CSCs as well as inhibited cell migration and angiogenesis in vitro. Using a qPCR screen, it was found that the gene expression of a number of Notch pathway members was altered. Pretreatment of MM-CSCs with the γ-secretase inhibitor RO4929097, a Notch pathway inhibitor, reversed BCT-induced effects on MM-CSCs proliferation. In this study, BCT was shown to be an effective agent in controlling the proliferation, viability and migration of MM-CSCs as well as angiogenesis in vitro. The effect on MM-CSCs proliferation may be mediated by the Notch pathway. These results warrant further investigation of BCT in a broader set of human-derived MM-CSCs and with in vivo models representative of MM.
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Affiliation(s)
- Mark E Issa
- a School of Pharmaceutical Sciences , University of Geneva, University of Lausanne, Rue Michel Servet , Geneva , Switzerland
| | - Sarah Berndt
- a School of Pharmaceutical Sciences , University of Geneva, University of Lausanne, Rue Michel Servet , Geneva , Switzerland
| | - Gilles Carpentier
- b Laboratoire CRRET, Faculté des Sciences et Technologie , Université Paris Est Créteil , Créteil Cedex , France
| | - John M Pezzuto
- c Arnold & Marie Schwartz College of Pharmacy and Health Sciences , Long Island University , Brooklyn , NY , USA
| | - Muriel Cuendet
- a School of Pharmaceutical Sciences , University of Geneva, University of Lausanne, Rue Michel Servet , Geneva , Switzerland
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Abstract
Brucea javanica, a Chinese herbal medicine, combined with conventional anticancer modalities, has been widely used for treatment of various cancers. Based on researches over the last decades, authors briefly summarized its active constituents, molecular mechanisms and clinical application for cancer treatment.
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Zhang Q, Yuan Y, Cui J, Xiao T, Deng Z, Jiang D. Determination of a potential antitumor quassinoid in rat plasma by UPLC-MS/MS and its application in a pharmacokinetic study. J Pharm Biomed Anal 2016; 124:143-148. [PMID: 26945636 DOI: 10.1016/j.jpba.2016.02.046] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Revised: 02/25/2016] [Accepted: 02/28/2016] [Indexed: 10/22/2022]
Abstract
A sensitive UPLC-MS/MS method was developed and validated for the determination of brusatol in rat plasma. Chromatographic separation was carried out on a C18 column using methanol and 10mM ammonium acetate containing 0.1% (v/v) formic acid (55:45, v/v). The lower limit of quantification (LLOQ) was 1.0 ng/mL for brusatol in plasma. The intra- and inter-day precision for the analyte ranged from 3.2% to 9.2% and 1.3% to 7.8%, and the accuracy was between 97.3% and 108.5%. The method was successfully applied in a pharmacokinetic study of brusatol following intravenous injection (0.5, 1.0, and 2.0mg/kg) of brusatol.
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Affiliation(s)
- Qiang Zhang
- Breast Surgery, Liaoning Cancer Hospital & Institute, Shenyang 110042, China
| | - Yonghui Yuan
- Department of Infection, Liaoning Cancer Hospital & Institute, Shenyang 110042, China
| | - Jianchun Cui
- Department of Endocrine Surgery, the People's Hospital of Liaoning Province, Shenyang 110016, China
| | - Tingting Xiao
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Zhipeng Deng
- Institute of Materia Medica, Shandong Academy of Medical Sciences, Jinan 250062, China.
| | - Daqing Jiang
- Breast Surgery, Liaoning Cancer Hospital & Institute, Shenyang 110042, China.
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Zhao L, Wen Q, Yang G, Huang Z, Shen T, Li H, Ren D. Apoptosis induction of dehydrobruceine B on two kinds of human lung cancer cell lines through mitochondrial-dependent pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2016; 23:114-122. [PMID: 26926172 DOI: 10.1016/j.phymed.2015.12.019] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Revised: 12/07/2015] [Accepted: 12/29/2015] [Indexed: 06/05/2023]
Abstract
BACKGROUND Brucea javanica is an effective traditional medicine listed in Chinese Pharmacopoeia. In China, the seed oil of B. javanica has long been used as commercially available drug for the treatment of tumor in clinic. Dehydrobruceine B (DHB) is a quassinoid isolated from B. javanica. PURPOSE The aim of the present study is to investigate the apoptotic effects induced by DHB in human lung cancer A549 and NCI-H292 cells. The involvement of a mitochondria-mediated intrinsic pathway in the pro-apoptotic action of DHB was also investigated. MATERIAL AND METHODS Cell viability was determined by MTT assay. Cell cycle and apoptosis were assessed by flow cytometry analysis. Mitochondrial membrane potential (MMP) was examined through JC-1 staining. The protein translocation in cells was examined by immunostaining. The expression levels of proteins which are closely related to mitochondria-mediated apoptosis pathway were measured by immunoblot analysis. RESULTS Treatment with DHB decreased cell viability, induced apoptosis and blocked cell cycle at S phase. DHB-induced apoptosis was found to be mediated through mitochondrial intrinsic pathway, evidenced by the loss of MMP, the release of cytochrome c into cytosol, and the cleavage of caspase-9, caspase-3 and poly (ADP-ribose) polymerase (PARP). CONCLUSION DHB triggers apoptosis in A549 and NCI-H292 cells via mitochondrial pathway, making it a promising candidate as a therapeutic agent for lung carcinoma.
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Affiliation(s)
- Lijuan Zhao
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 Wenhuaxi Road, Jinan 250012, PR China
| | - Qing Wen
- Department of Pharmacy, Jinan Central Hospital, Shandong University, 105 Jiefang Road, Jinan 250013, PR China
| | - Guotao Yang
- Department of thoracic surgery, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Jinan 250012, PR China
| | - Zhuqing Huang
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 Wenhuaxi Road, Jinan 250012, PR China
| | - Tao Shen
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 Wenhuaxi Road, Jinan 250012, PR China
| | - Haizhen Li
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 Wenhuaxi Road, Jinan 250012, PR China
| | - Dongmei Ren
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 Wenhuaxi Road, Jinan 250012, PR China.
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Cragg GM, Pezzuto JM. Natural Products as a Vital Source for the Discovery of Cancer Chemotherapeutic and Chemopreventive Agents. Med Princ Pract 2015; 25 Suppl 2:41-59. [PMID: 26679767 PMCID: PMC5588531 DOI: 10.1159/000443404] [Citation(s) in RCA: 433] [Impact Index Per Article: 43.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Accepted: 12/16/2015] [Indexed: 12/27/2022] Open
Abstract
Throughout history, natural products have played a dominant role in the treatment of human ailments. For example, the legendary discovery of penicillin transformed global existence. Presently, natural products comprise a large portion of current-day pharmaceutical agents, most notably in the area of cancer therapy. Examples include Taxol, vinblastine, and camptothecin. These structurally unique agents function by novel mechanisms of action; isolation from natural sources is the only plausible method that could have led to their discovery. In addition to terrestrial plants as sources for starting materials, the marine environment (e.g., ecteinascidin 743, halichondrin B, and dolastatins), microbes (e.g., bleomycin, doxorubicin, and staurosporin), and slime molds (e.g., epothilone B) have yielded remarkable cancer chemotherapeutic agents. Irrespective of these advances, cancer remains a leading cause of death worldwide. Undoubtedly, the prevention of human cancer is highly preferable to treatment. Cancer chemoprevention, the use of vaccines or pharmaceutical agents to inhibit, retard, or reverse the process of carcinogenesis, is another important approach for easing this formidable public health burden. Similar to cancer chemotherapeutic agents, natural products play an important role in this field. There are many examples, including dietary phytochemicals such as sulforaphane and phenethyl isothiocyanate (cruciferous vegetables) and resveratrol (grapes and grape products). Overall, natural product research is a powerful approach for discovering biologically active compounds with unique structures and mechanisms of action. Given the unfathomable diversity of nature, it is reasonable to suggest that chemical leads can be generated that are capable of interacting with most or possibly all therapeutic targets.
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Affiliation(s)
| | - John M. Pezzuto
- Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, N.Y., USA
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Li Z, Shi K, Guan L, Jiang Q, Yang Y, Xu C. Activation of p53 by sodium selenite switched human leukemia NB4 cells from autophagy to apoptosis. Oncol Res 2015; 21:325-31. [PMID: 25198662 DOI: 10.3727/096504014x14024160459087] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
It was revealed by our previous research that sodium selenite repressed autophagy accompanied by the induction of apoptosis in human leukemia NB4 cells. The inhibition of autophagy exerted a facilitative effect on apoptosis. In the present study, we further explored the mechanisms underlying the switch from autophagy to apoptosis and elucidated p53 played a key role. Selenite induced phosphorylation of p53 at the vital site Ser15 via p38MAPK and ERK. Subsequently p53 dissociated with its inhibitory protein mouse double minute 2 (MDM2). Meanwhile, the nucleolar protein B23 transferred from the nucleolus to the nucleoplasm and associated with MDM2, probably stabilizing p53. The active p53 participated in the decrease of autophagic protein Beclin-1 and LC-3, as well as activation of apoptosis-related caspases. Furthermore, in p53 mutant U937 leukemia cells, selenite could not elicit such a switch from autophagy to apoptosis, laying emphasis on the crucial role p53 played in this process.
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Affiliation(s)
- Zhushi Li
- State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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Turpaev K, Welsh N. Brusatol inhibits the response of cultured beta-cells to pro-inflammatory cytokines in vitro. Biochem Biophys Res Commun 2015; 460:868-72. [PMID: 25824046 DOI: 10.1016/j.bbrc.2015.03.124] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Accepted: 03/21/2015] [Indexed: 01/13/2023]
Abstract
Brusatol is a natural terpenoid that is capable of inducing a variety of biological effects. We presently report that this substance dramatically improves beta-cell survival when exposed to pro-inflammatory cytokines (IL-1β and IFNγ) in vitro. This was observed in insulin producing rat (RIN-5AH), mouse (βTC6) and human (EndoC-βH1) beta-cell lines. Brusatol prevented beta-cell oxidative stress in response to cytokines and counteracted induction of iNOS on the protein level. Brusatol, however, block neither the cytokine-induced increase of iNOS mRNA, nor NF-κB activation, suggesting that inhibition of iNOS protein expression relies on posttranscriptional mechanism. This indicates that brusatol acts via a novel protective pathway, which may represent a more promising way of improving beta-cell function and survival.
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Affiliation(s)
- Kyril Turpaev
- Department of Medical Cell Biology, Uppsala University, Biomedicum, SE-751 23 Uppsala, Sweden; Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, 119991 Moscow, Russia.
| | - Nils Welsh
- Department of Medical Cell Biology, Uppsala University, Biomedicum, SE-751 23 Uppsala, Sweden
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Yan Z, Zhang B, Huang Y, Qiu H, Chen P, Guo GF. Involvement of autophagy inhibition in Brucea javanica oil emulsion-induced colon cancer cell death. Oncol Lett 2015; 9:1425-1431. [PMID: 25663926 PMCID: PMC4315055 DOI: 10.3892/ol.2015.2875] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2014] [Accepted: 11/28/2014] [Indexed: 02/06/2023] Open
Abstract
Brucea javanica oil emulsion (BJOE), the petroleum ether extract of B. javanica emulsified by phospholipid, is widely used in China as an anticancer agent. The extracts from B. javanica induce cancer cell death by various mechanisms; however, it is not known whether these mechanisms involve autophagy, which is an important process in cancer development and treatment. Thus, the current study aimed to investigate whether BJOE modulates autophagy in HCT116 human colon cancer cells and whether modulation of autophagy is an anticancer mechanism of BJOE. Immunoblotting was employed to analyze the protein expression levels of microtubule-associated protein light-chain 3 (LC3), a specific protein marker of autophagy, in HCT116 cancer cells following exposure to BJOE. The apoptosis rate of the HCT116 cancer cells was detected by performing an Annexin V-fluorescein isothiocyanate/propidium iodide assay. According to the effect of BJOE administration on autophagy in the HCT116 cancer cells (induction or suppression), a functionally opposite agent (autophagy suppressor or inducer) was applied to counteract this effect, and the apoptosis rate of the cancer cells was detected again. The role of autophagy (pro-survival or pro-death) was demonstrated by comparing the rates of apoptotic cancer cells prior to and following the counteraction. The results revealed that BJOE suppressed the protein expression levels of LC3, including the LC3-I and LC3-II forms, and induced apoptosis in the HCT116 cancer cells with a high level of basal LC3. The apoptosis-inducing activity of BJOE was significantly attenuated when autophagy was induced by the administration of trehalose, an autophagy inducer. The data indicates that autophagy inhibition is involved in BJOE-induced cancer cell death, and that this inhibition may be a potential anticancer mechanism of BJOE.
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Affiliation(s)
- Zheng Yan
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China ; Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Bei Zhang
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China ; VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Yuanyuan Huang
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China ; VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Huijuan Qiu
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China ; VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Ping Chen
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China ; VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Gui-Fang Guo
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China ; VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
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Zhang L, Feng X, Ma D, Yang J, Jiang H, Zhang Y, He W. Brusatol isolated from Brucea javanica (L.) Merr. induces apoptotic death of insect cell lines. PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY 2013; 107:18-24. [PMID: 25149230 DOI: 10.1016/j.pestbp.2013.04.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2012] [Revised: 04/19/2013] [Accepted: 04/20/2013] [Indexed: 06/03/2023]
Abstract
Brucea javanica (L.) Merr. is a medicine plant distributed widely throughout Asia where its bitter fruits have been used traditionally in medicine for treating various ailments and controlling some pests. In recent years, concerns over the potential impact of synthetic pesticides on human health and environment have now become more pressing to develop environmentally friendly pesticides. In this paper, brusatol, a quassinoid, was isolated from the fruit of B. javanica, and identified using X-ray crystallographic analysis. Results showed that brusatol has potent contact toxicity (LD50, 2.91 μg/larva, 72 h) and anfieedant activity (AFC50, 17.4 mg/L, 48 h) against the third-instar larvae of Spodoptera exigua. Brusatol demonstrated cytotoxic effects to the tested insect cell lines, IOZCAS-Spex-II and Sf21, in a time- and dose-dependent manner. After brusatol treatment, apoptotic cell death with the DNA fragmentation, activation of caspase-3 and release of cytochrome c was preliminarily observed in both IOZCAS-Spex-II and Sf21. These results indicated the existence of apoptotic death with the mitochondrial-dependent pathway induced by brusatol in Sf21 and IOZCAS-Spex-II cell lines. Our studies will provide important knowledge to understand mechanisms of action of brusatol and to develop brusatol and its derivatives as insecticides.
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Affiliation(s)
- Lan Zhang
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China
| | - Xuehuan Feng
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China
| | - Dejun Ma
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China
| | - Jingjing Yang
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China
| | - Hongyun Jiang
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China.
| | - Yanning Zhang
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China
| | - Weizhi He
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China
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Al-Salahi OSA, Kit-Lam C, Majid AMSA, Al-Suede FSR, Mohammed Saghir SA, Abdullah WZ, Ahamed MBK, Yusoff NM. Anti-angiogenic quassinoid-rich fraction from Eurycoma longifolia modulates endothelial cell function. Microvasc Res 2013; 90:30-9. [PMID: 23899415 DOI: 10.1016/j.mvr.2013.07.007] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2013] [Revised: 07/22/2013] [Accepted: 07/22/2013] [Indexed: 01/12/2023]
Abstract
Targeting angiogenesis could be an excellent strategy to combat angiogenesis-dependent pathophysiological conditions such as cancer, rheumatoid arthritis, obesity, systemic lupus erythematosus, psoriasis, proliferative retinopathy and atherosclerosis. Recently a number of clinical investigations are being undertaken to assess the potential therapeutic application of various anti-angiogenic agents. Many of these angiogenesis inhibitors are directed against the functions of endothelial cells, which are considered as the building blocks of blood vessels. Similarly, roots of a traditional medicinal plant, Eurycoma longifolia, can be used as an alternative treatment to prevent and treat the angiogenesis-related diseases. In the present study, antiangiogenic potential of partially purified quassinoid-rich fraction (TAF273) of E. longifolia root extract was evaluated using ex vivo and in vivo angiogenesis models and the anti-angiogenic efficacy of TAF273 was investigated in human umbilical vein endothelial cells (HUVEC). TAF273 caused significant suppression in sprouting of microvessels in rat aorta with IC50 11.5μg/ml. TAF273 (50μg/ml) showed remarkable inhibition (63.13%) of neovascularization in chorioallantoic membrane of chick embryo. Tumor histology also revealed marked reduction in extent of vascularization. In vitro, TAF273 significantly inhibited the major angiogenesis steps such as proliferation, migration and differentiation of HUVECs. Phytochemical analysis revealed high content of quassinoids in TAF273. Specially, HPLC characterization showed that TAF273 is enriched with eurycomanone, 13α(21)-epoxyeurycomanone and eurycomanol. These results demonstrated that the antiangiogenic activity of TAF273 may be due to its inhibitory effect on endothelial cell proliferation, differentiation and migration which could be attributed to the high content of quassinoids in E. longifolia.
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Affiliation(s)
- Omar Saeed Ali Al-Salahi
- Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia (USM), 13200 Kepala Batas, Pulau Pinang, Malaysia
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Cavalcanti BC, da Costa PM, Carvalho AA, Rodrigues FAR, Amorim RCN, Silva ECC, Pohlit AM, Costa-Lotufo LV, Moraes MO, Pessoa C. Involvement of intrinsic mitochondrial pathway in neosergeolide-induced apoptosis of human HL-60 leukemia cells: the role of mitochondrial permeability transition pore and DNA damage. PHARMACEUTICAL BIOLOGY 2012; 50:980-993. [PMID: 22775415 DOI: 10.3109/13880209.2012.654921] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
CONTEXT Quassinoids are biologically active secondary metabolites found exclusively in the Simaroubaceae family of plants. These compounds generally present important biological properties, including cytotoxic and antitumor properties. OBJECTIVE In the present study, the cytotoxic effects of neosergeolide, a quassinoid isolated from Picrolemma sprucei Hook. f., were evaluated in human promyelocytic leukemia cells (HL-60). MATERIALS AND METHODS Cytotoxicity and antiproliferative effects were evaluated by the MTT assay, May-Grünwald-Giemsa's staining, BrdU incorporation test, and flow cytometry procedures. The comet assay and micronuclei analysis were applied to determine the genotoxic and mutagenic potential of neosergeolide. RESULTS After 24 h exposure, neosergeolide strongly inhibited cancer cell proliferation (IC₅₀ 0.1 µM), and its activity seemed to be selective to tumor cells because it had no antiproliferative effect on human peripheral blood mononuclear cells (PBMC) at tested concentrations. Apoptosis was induced at submicromolar concentrations (0.05, 0.1, and 0.2 µM) as evidenced by morphological changes, mitochondrial depolarization, phosphatidylserine externalization, caspases activation, and internucleosomal DNA fragmentation. Additionally, neosergeolide effects were prevented by cyclosporine A (CsA), an inhibitor of the mitochondrial permeability transition (MPT) pore, which reinforced the participation of intrinsic pathways in the apoptotic process induced by this natural quassinoid. Direct DNA damage was further confirmed by comet assay and cytokinesis-block micronucleus test. DISCUSSION AND CONCLUSION The present study provided experimental evidence to support the underlying mechanism of action involved in the neosergeolide-mediated apoptosis. In addition, no antiproliferative effect or DNA damage effect of neosergeolide was evident in PBMC, highlighting its therapeutic potential.
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MESH Headings
- Antineoplastic Agents, Phytogenic/adverse effects
- Antineoplastic Agents, Phytogenic/antagonists & inhibitors
- Antineoplastic Agents, Phytogenic/pharmacology
- Apoptosis/drug effects
- Cell Proliferation/drug effects
- Cells, Cultured
- Comet Assay
- Cyclosporine/pharmacology
- Cytokinesis/drug effects
- DNA Fragmentation/drug effects
- HL-60 Cells
- Humans
- Inhibitory Concentration 50
- Leukemia, Promyelocytic, Acute/drug therapy
- Leukemia, Promyelocytic, Acute/metabolism
- Leukemia, Promyelocytic, Acute/pathology
- Leukocytes, Mononuclear/drug effects
- Membrane Potential, Mitochondrial/drug effects
- Micronucleus Tests
- Mitochondria/drug effects
- Mitochondria/metabolism
- Mitochondrial Membrane Transport Proteins/antagonists & inhibitors
- Mitochondrial Membrane Transport Proteins/metabolism
- Mitochondrial Permeability Transition Pore
- Neoplasm Proteins/antagonists & inhibitors
- Neoplasm Proteins/metabolism
- Quassins/adverse effects
- Quassins/antagonists & inhibitors
- Quassins/pharmacology
- Simaroubaceae/chemistry
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Affiliation(s)
- Bruno C Cavalcanti
- National Laboratory of Experimental Oncology, Federal University of Ceará, CEP 60430-270, Fortaleza, CE, Brazil.
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Zhao M, Lau ST, Leung PS, Che CT, Lin ZX. Seven Quassinoids from Fructus Bruceae with Cytotoxic Effects on Pancreatic Adenocarcinoma Cell Lines. Phytother Res 2011; 25:1796-800. [DOI: 10.1002/ptr.3477] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2010] [Revised: 02/14/2011] [Accepted: 02/16/2011] [Indexed: 11/12/2022]
Affiliation(s)
- M. Zhao
- School of Chinese Medicine; The Chinese University of Hong Kong; Hong Kong SAR China
| | - S. T. Lau
- School of Chinese Medicine; The Chinese University of Hong Kong; Hong Kong SAR China
- School of Biomedical Science; The Chinese University of Hong Kong; Hong Kong SAR China
| | - P. S. Leung
- School of Biomedical Science; The Chinese University of Hong Kong; Hong Kong SAR China
| | - C. T. Che
- School of Chinese Medicine; The Chinese University of Hong Kong; Hong Kong SAR China
| | - Z. X. Lin
- School of Chinese Medicine; The Chinese University of Hong Kong; Hong Kong SAR China
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