|
1
|
Li J, Wu J, Chen Q, Yu H, Liu M, Wang Y, Zhang Y, Wang T. 7'-Hydroxyl substituted xanthones from Gentianella acuta revert hepatic steatosis in obese diabetic mice through preserving mitochondrial homeostasis. Biochem Pharmacol 2025; 236:116878. [PMID: 40118286 DOI: 10.1016/j.bcp.2025.116878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 02/24/2025] [Accepted: 03/17/2025] [Indexed: 03/23/2025]
Abstract
Mitochondrial dysfunction is a key contributor to the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Xanthones, bioactive flavonoids derived from various herbal medicines, are renowned for their anti-inflammatory, antioxidant, and anti-tumor properties. This study aimed to investigate the effects of xanthones isolated from Gentianella acuta on hepatic steatosis and the underlying mechanisms regulating mitochondrial function. We report that a xanthone fraction (400 mg/kg/day) effectively prevented obesity and hepatic steatosis in obese diabetic db/db mice in vivo. In vitro, xanthones inhibited lipid accumulation and mitochondrial dysfunction induced by high glucose (20 mM) and high palmitic acid (200 µM) in HepG2 cells. Mechanistically, norathyriol (NTR), a major in vivo metabolite of Gentianella acuta, inhibited the activity of dynamin-related protein 1 (Drp1), a protein associated with mitochondrial fission, and prevented its translocation from the cytoplasm to the mitochondria by inhibiting the orphan nuclear receptor (Nur77). Additionally, NTR increased the expression of the mitochondrial outer membrane protein FUN14 domain containing 1 (FUNDC1), which stimulated mitophagy to clear damaged or dysfunctional mitochondria under overnutrition conditions. We also discovered that reactive oxygen species (ROS) targeted FUNDC1, leading to mitochondrial damage, but this effect could be reversed by 7'-hydroxyl substituted xanthones. Collectively, 7'-hydroxyl substituted xanthones inhibited mitochondrial fission while promoting mitophagy, ultimately improving mitochondrial and liver function in diabetic hepatic steatosis. The modulation of mitochondrial function by 7'-hydroxyl substituted xanthones presents a novel approach for treating hepatic steatosis, particularly in diabetic conditions.
Collapse
Affiliation(s)
- Jian Li
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin 301617, China; Center for Molecular and Translational Medicine, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA.
| | - Jiaqi Wu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin 301617, China
| | - Qian Chen
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin 301617, China
| | - Haiyang Yu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin 301617, China
| | - Mengyang Liu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin 301617, China
| | - Yadong Wang
- Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA
| | - Yi Zhang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin 301617, China.
| | - Tao Wang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin 301617, China.
| |
Collapse
|
|
2
|
Miao K, Wang Y, Hou L, Liu Y, Liu H, Ji Y. Haplotype-resolved genome assembly of the upas tree (Antiaris toxicaria). Sci Data 2024; 11:1011. [PMID: 39294147 PMCID: PMC11410980 DOI: 10.1038/s41597-024-03860-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 09/04/2024] [Indexed: 09/20/2024] Open
Abstract
The upas tree (Antiaris toxicaria Lesch.) is a medically important plant that contains various specialized metabolites with significant bioactivity. The lack of a reference genome hinders the in-depth study as well as rational exploitation and conservation of this plant. Here, we present the first holotype-resolved chromosome-scale genome of the upas tree. The assembled genome consisted of 26 chromosomes that contain 1.34 Gb of sequencing data with a contig N50 length of 60 Mb. Genome annotation identified 43,500 protein-coding genes in the upas tree genome, of which 98.75% were functionally annotated. This high-quality reference genome will lay the foundation for further studies on the evolution and functional genomics of the upas tree.
Collapse
Affiliation(s)
- Ke Miao
- CAS Key Laboratory for Plant Diversity and Biogeography of East Asia, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650201, China
| | - Ya Wang
- CAS Key Laboratory for Plant Diversity and Biogeography of East Asia, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China
| | - Luxiao Hou
- CAS Key Laboratory for Plant Diversity and Biogeography of East Asia, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650201, China
| | - Yan Liu
- CAS Key Laboratory for Plant Diversity and Biogeography of East Asia, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650201, China
| | - Haiyang Liu
- State Key Laboratory of Phytochemistry and Natural Medicine, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
| | - Yunheng Ji
- CAS Key Laboratory for Plant Diversity and Biogeography of East Asia, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
- State Key Laboratory of Phytochemistry and Natural Medicine, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
- Yunnan Key Laboratory for Integrative Conservation of Plant Species with Extremely Small Population, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
| |
Collapse
|
|
3
|
Osman Mohammed RM, Huang Y, Guan X, Huang X, Deng S, Yang R, Li J, Li J. Cytotoxic cardiac glycosides from the root of Streblus asper. PHYTOCHEMISTRY 2022; 200:113239. [PMID: 35623471 DOI: 10.1016/j.phytochem.2022.113239] [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: 12/27/2021] [Revised: 05/07/2022] [Accepted: 05/10/2022] [Indexed: 06/15/2023]
Abstract
Bioassay-guided separation of the root of Streblus asper led to the identification of six undescribed cardiac glycosides, including a rare cardiac glycoside dimer, along with twelve previously reported analogues. Their structures were determined on the basis of analyses of spectroscopic methods (1D and 2D-NMR spectroscopy), high-resolution electrospray ionization mass spectrometry (HRESIMS), circular dichroism (CD), and comparison of their spectroscopic data with previously reported data. Regarding their cytotoxic activities, microculture tetrazolium assays showed that all isolated cardiac glycosides strongly inhibited MCC-803, T24, SKOV-3, HepG2, Wi-38, and A549 cancer cell lines, with IC50 values ranging from 0.075 μM to 0.752 μM. One cardiac glycoside, a rare cardiac glycoside dimer, exhibited the strongest activity against the six cancer cell lines, with IC50 values ranging from 0.075 μM to 0.214 μM. In addition, the structure-activity relationships (SARs) of cardiac glycosides were investigated. In summary, S. asper showed marked cytotoxicity to several cancer cell lines, which could be meaningful for discovering new anticancer agents.
Collapse
Affiliation(s)
- Rehab Mobark Osman Mohammed
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Science, Guangxi Normal University, Guilin, 541004, China; Department of Pharmaceutical Cognosy, Faculty of Pharmacy, University of AL-Neelain, Khartoum, Sudan
| | - Yan Huang
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Science, Guangxi Normal University, Guilin, 541004, China
| | - Xinlan Guan
- Peoples' Hospital of Pubei, Pubei, 535300, China
| | - Xishan Huang
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Science, Guangxi Normal University, Guilin, 541004, China
| | - Shengping Deng
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Science, Guangxi Normal University, Guilin, 541004, China
| | - Ruiyun Yang
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Science, Guangxi Normal University, Guilin, 541004, China
| | - Jian Li
- Peoples' Hospital of Pubei, Pubei, 535300, China.
| | - Jun Li
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Science, Guangxi Normal University, Guilin, 541004, China.
| |
Collapse
|
|
4
|
Hu QY, Zhang XK, Wang JN, Chen HX, He LP, Tang JS, Yao XS, Liu J. Malayoside, a cardenolide glycoside extracted from Antiaris toxicaria Lesch, induces apoptosis in human non-small lung cancer cells via MAPK-Nur77 signaling pathway. Biochem Pharmacol 2021; 190:114622. [PMID: 34043967 DOI: 10.1016/j.bcp.2021.114622] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 05/01/2021] [Accepted: 05/20/2021] [Indexed: 12/25/2022]
Abstract
Lung cancer is the leading cause of cancer deaths in the world. Non-small cell lung cancer (NSCLC), with poor prognosis and resistance to chemoradiotherapy, is the most common histological type of lung cancer. Therefore, it is necessary to develop new and more effective treatment strategy for NSCLC. Nur77, an orphan member of the nuclear receptor superfamily, induces apoptosis in cancer cells including NSCLC cells, by high expression and translocation to mitochondria. Small molecules trigger expression and mitochondrial localization of Nur77 may be an ideal anti-cancer drug candidate. Here, we report malayoside, a cardiac glycoside in the extract of Antiaris toxicaria Lesch., had different sensitivities to NSCLC cells. Malayoside induced apoptosis in NCI-H460 cells. Meanwhile, malayoside induced Nur77 expression and mitochondrial localization, and its induction of apoptosis was Nur77-dependent. To investigate the molecular mechanism of malayoside inducing Nur77 and apoptosis, we found that malayoside activated MAPK signaling pathway, including both ERK and p38 phosphorylation. The suppression of MAPK signaling activation inhibited the expression of Nur77 and apoptosis induced by malayoside. Our studies in nude mice showed that malayside potently inhibited the growth of tumor cells in vivo. Furthermore, the anti-cancer effect of malayosidwas in vivo was also related to the elevated expression of Nur77, p-ERK, and p-p38 proteins. Our results suggest that malayoside possesses an anti-NSCLC activity in vitro and in vivo mainly via activation of MAPK-Nur77 signaling pathway, indicating that malayoside is a promising chemotherapeutic candidate for NSCLC.
Collapse
Affiliation(s)
- Qiong-Ying Hu
- School of Medicine, Taizhou University, Taizhou 318000, Zhejiang, China.
| | - Xiao-Kun Zhang
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China
| | - Jia-Nan Wang
- School of Medicine, Taizhou University, Taizhou 318000, Zhejiang, China
| | - Hao-Xuan Chen
- School of Medicine, Taizhou University, Taizhou 318000, Zhejiang, China
| | - Lian-Ping He
- School of Medicine, Taizhou University, Taizhou 318000, Zhejiang, China
| | - Jin-Shan Tang
- Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Xin-Sheng Yao
- Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Jie Liu
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
| |
Collapse
|
|
5
|
Zhang BD, Zhu WF, Akihisa T, Kikuchi T, Ukiya M, Maya F, Xu J, Liu WY, Feng F, Zhang J. Cardiac glycosides from the roots of Streblus asper Lour. and their apoptosis-inducing activities in A549 cells. PHYTOCHEMISTRY 2021; 181:112544. [PMID: 33130375 DOI: 10.1016/j.phytochem.2020.112544] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 10/07/2020] [Accepted: 10/13/2020] [Indexed: 06/11/2023]
Abstract
Phytochemical investigation of the roots of Streblus asper Lour. resulted in the isolation of six previously undescribed cardiac glycosides, designated 2'-de-O-methylstrebloside (1), cannogenol-3α-O-β-D-gluopyranosyl-(1 → 4)-6-deoxy -2,3-dimethoxyl-β-D-fucopyranoside (2), periplogenin-3-O-α-L-rhamnopyranosyl -(1 → 4)-6-deoxy-β-D-allopyranoside (3), 5-de-O-hydroxylstrebloside (4), 5βH-16β-hydroxylkamaloside (5), and 17S, 21R-21-hydroxylstrebloside (6), and three known analogues (7-9). The structures were elucidated using NMR spectroscopic techniques, mass spectrometry, and comparison of the spectroscopic data with previously reported data. Compound 6 is a novel C-21 hydroxyl cardiac glycoside, its absolute configuration was established from the analysis of computational ECD calculations and NMR spectroscopic data. The effects of the cardiac glycosides on apoptosis and cytotoxicity were examined in human A549 lung cancer cells. All the compounds showed remarkable inhibitory activities, with IC50 values in the range of 0.01-6.08 μM. Furthermore, compound 3 was able to significantly inhibit A549 cell growth proliferation via the induction of apoptosis, due to the activation of caspases-3, -8 and -9 in A549 cells, as revealed by Western blot analysis.
Collapse
Affiliation(s)
- Bo-Dou Zhang
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China
| | - Wan-Fang Zhu
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Toshihiro Akihisa
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; Research Institute for Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
| | - Takashi Kikuchi
- Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan
| | - Motohiko Ukiya
- College of Science and Technology, Nihon University, 1-8-14 Kanda Surugadai, Chiyoda-ku, Tokyo 101-8308, Japan
| | - Fukuda Maya
- College of Science and Technology, Nihon University, 1-8-14 Kanda Surugadai, Chiyoda-ku, Tokyo 101-8308, Japan
| | - Jian Xu
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China
| | - Wen-Yuan Liu
- School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Feng Feng
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; Jiangsu Food and Pharmaceutical Science College, Huaian, Jiangsu, 223003, China.
| | - Jie Zhang
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; Jiangsu Food and Pharmaceutical Science College, Huaian, Jiangsu, 223003, China.
| |
Collapse
|
|
6
|
Cardiac glycosides with target at direct and indirect interactions with nuclear receptors. Biomed Pharmacother 2020; 127:110106. [PMID: 32248001 DOI: 10.1016/j.biopha.2020.110106] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 03/13/2020] [Accepted: 03/17/2020] [Indexed: 12/15/2022] Open
Abstract
Cardiac glycosides are compounds isolated from plants and animals and have been known since ancient times. These compounds inhibit the activity of the sodium potassium pump in eukaryotic cells. Cardiac glycosides were used as drugs in heart ailments to increase myocardial contraction force and, at the same time, to lower frequency of this contraction. An increasing number of studies have indicated that the biological effects of these compounds are not limited to inhibition of sodium-potassium pump activity. Furthermore, an increasing number of data have shown that they are synthesized in tissues of mammals, where they may act as a new class of steroid hormones or other hormones by mimicry to modulate various signaling pathways and influence whole organisms. Thus, we discuss the interactions of cardiac glycosides with the nuclear receptor superfamily of transcription factors activated by low-weight molecular ligands (including hormones) that regulate many functions of cells and organisms. Cardiac glycosides of endogenous and exogenous origin by interacting with nuclear receptors can affect the processes regulated by these transcription factors, including hormonal management, immune system, body defense, and carcinogenesis. They can also be treated as initial structures for combinatorial chemistry to produce new compounds (including drugs) with the desired properties.
Collapse
|
|
7
|
Regioselective single pot C3-glycosylation of strophanthidol using methylboronic acid as a transient protecting group. J Antibiot (Tokyo) 2019; 72:437-448. [PMID: 30948784 DOI: 10.1038/s41429-019-0172-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 02/09/2019] [Accepted: 02/18/2019] [Indexed: 12/15/2022]
Abstract
This manuscript describes a single pot protocol for the selective introduction of unprotected sugars to the C3 position of the cardiotonic steroid strophanthidol. These reactions proceed with high levels of regiocontrol (>20:1 rr) in the presence of three other hydroxyl functionalities including the C19 primary hydroxyl group and could be applied to different sugars to provide the deprotected cardiac glycosides upon work up (5 examples, 77-69% yield per single operation). The selective glycosylation of the less reactive C3 position is accomplished by the use of traceless protection with methylboronic acid that blocks the C5 and C19 hydroxyls by forming a cyclic boronic ester, followed by in situ glycosylation and a work up with ammonia in methanol to remove the boronic ester and the carbohydrate ester protecting groups.
Collapse
|
|
8
|
Wen SY, Chen YY, Deng CM, Zhang CQ, Jiang MM. Nerigoside suppresses colorectal cancer cell growth and metastatic potential through inhibition of ERK/GSK3β/β-catenin signaling pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 57:352-363. [PMID: 30831484 DOI: 10.1016/j.phymed.2018.12.033] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 12/27/2018] [Accepted: 12/29/2018] [Indexed: 06/09/2023]
Abstract
BACKGROUND Nerigoside (NG), a cardenolide isolated from a commonfolk medicine, Nerium oleander Linn. (Apocynaceae), has not been explored for its biological effects. To date, cardenolides have received considerable attention in pharmacology studies due to their direct effects of apoptosis-induction or growth-inhibitory against tumor in vitro and in vivo. Whether and how NG exerts anticancer effects against colorectal cancer remains to be elucidated. PURPOSE The aim of this study was to investigate the anticancer effect of NG in human colorectal cancer cells. METHODS To test anticancer effect, we compared potency of NG in two colorectal cancer cell lines, HT29 and SW620 by WST-1 and colony proliferation assays. And we investigated mechanism of anticancer activities by analyzing players in apoptotic and ERK/GSK3β/β-catenin signaling pathways in HT29 and SW620 cells treated with NG. RESULTS In this study, we showed that NG markedly suppressed the cell viability and colony formation of colorectal cancer cells HT29 and SW620, with no significant toxic effect on non-cancer cells NCM460. Annexin V-FITC/PI and CFSE labeling results revealed that NG suppressed cell proliferation in low concentration, along with reducing expression of PCNA, while NG induced apoptosis in high concentration,. Meanwhile, NG significantly arrested cell migration by reversal of EMT and cell cycle on G2/M. Then, we found that the ERK and GSK3β/β-catenin signaling pathway were noticeably blocked in CRC cells after treatment with NG. According to western blot, NG upregulated the expression of p-GSK3β/GSK3β and decreased especially the expression of β-catenin in nuclear. In addition, Wnt signaling and its target genes were suppressed in response to NG. Then, the Ser9 phosphorylation of GSK3β can be reduced / raised by GÖ 6983 / LiCl, respectively. Thus, we further confirmed that the GSK3β/β-catenin axis is involved in NG-prevented cell proliferation. CONCLUSION NG inhibited the growth of colorectal cancer cells by suppressing ERK/GSK3β/β-catenin signaling pathway. And the GSK3β/β-catenin axis is involved in preventing cell proliferation and migration by NG-treatment. These results suggest that NG may be used to treat colorectal cancer, with better outcome by combining with GSK3β inhibitor to block Wnt pathway.
Collapse
Affiliation(s)
- Shi-Yuan Wen
- Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Yan-Yan Chen
- Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Chun-Miao Deng
- Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Cui-Qiong Zhang
- Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Miao-Miao Jiang
- Tianjin State Key Laboratory of Modern Chinese Medicine, Pharmacology of Traditional Chinese Medicine Formulae, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
| |
Collapse
|
|
9
|
Khatri HR, Bhattarai B, Kaplan W, Li Z, Curtis Long MJ, Aye Y, Nagorny P. Modular Total Synthesis and Cell-Based Anticancer Activity Evaluation of Ouabagenin and Other Cardiotonic Steroids with Varying Degrees of Oxygenation. J Am Chem Soc 2019; 141:4849-4860. [PMID: 30802047 PMCID: PMC6516474 DOI: 10.1021/jacs.8b12870] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
A Cu(II)-catalyzed diastereoselective Michael/aldol cascade approach is used to accomplish concise total syntheses of cardiotonic steroids with varying degrees of oxygenation including cardenolides ouabagenin, sarmentologenin, 19-hydroxysarmentogenin, and 5- epi-panogenin. These syntheses enabled the subsequent structure activity relationship (SAR) studies on 37 synthetic and natural steroids to elucidate the effect of oxygenation, stereochemistry, C3-glycosylation, and C17-heterocyclic ring. Based on this parallel evaluation of synthetic and natural steroids and their derivatives, glycosylated steroids cannogenol-l-α-rhamnoside (79a), strophanthidol-l-α-rhamnoside (92), and digitoxigenin-l-α-rhamnoside (97) were identified as the most potent steroids demonstrating broad anticancer activity at 10-100 nM concentrations and selectivity (nontoxic at 3 μM against NIH-3T3, MEF, and developing fish embryos). Further analyses indicate that these molecules show a general mode of anticancer activity involving DNA-damage upregulation that subsequently induces apoptosis.
Collapse
Affiliation(s)
- Hem Raj Khatri
- Chemistry Department, University of Michigan, Ann Arbor, MI 48109 USA
| | - Bijay Bhattarai
- Chemistry Department, University of Michigan, Ann Arbor, MI 48109 USA
| | - Will Kaplan
- Chemistry Department, University of Michigan, Ann Arbor, MI 48109 USA
| | - Zhongzheng Li
- Department of Chemistry, Nankai University, Nankai, People Republic of China
| | | | - Yimon Aye
- École Polytechnique Fédérale de Lausanne, Institute of Chemical Sciences and Engineering, 1015, Lausanne, Switzerland
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853 USA
| | - Pavel Nagorny
- Chemistry Department, University of Michigan, Ann Arbor, MI 48109 USA
| |
Collapse
|
|
10
|
El-Seedi HR, Khalifa SAM, Taher EA, Farag MA, Saeed A, Gamal M, Hegazy MEF, Youssef D, Musharraf SG, Alajlani MM, Xiao J, Efferth T. Cardenolides: Insights from chemical structure and pharmacological utility. Pharmacol Res 2019; 141:123-175. [PMID: 30579976 DOI: 10.1016/j.phrs.2018.12.015] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 12/07/2018] [Accepted: 12/18/2018] [Indexed: 02/08/2023]
Abstract
Cardiac glycosides (CGs) are a class of naturally occurring steroid-like compounds, and members of this class have been in clinical use for more than 1500 years. They have been used in folk medicine as arrow poisons, abortifacients, heart tonics, emetics, and diuretics as well as in other applications. The major use of CGs today is based on their ability to inhibit the membrane-bound Na+/K+-ATPase enzyme, and they are regarded as an effective treatment for congestive heart failure (CHF), cardiac arrhythmia and atrial fibrillation. Furthermore, increasing evidence has indicated the potential cytotoxic effects of CGs against various types of cancer. In this review, we highlight some of the structural features of this class of natural products that are crucial for their efficacy, some methods of isolating these compounds from natural resources, and the structural elucidation tools that have been used. We also describe their physicochemical properties and several modern biotechnological approaches for preparing CGs that do not require plant sources.
Collapse
Affiliation(s)
- Hesham R El-Seedi
- Division of Pharmacognosy, Department of Medicinal Chemistry, Uppsala University, Biomedical Centre, Box 574, SE-75123, Uppsala, Sweden; Chemistry Department, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia; H. E. J. Research Institute of Chemistry, International Center for Chemical Sciences, University of Karachi, Karachi 75270, Pakistan; Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Kom, Egypt.
| | - Shaden A M Khalifa
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, S-106 91, Stockholm, Sweden
| | - Eman A Taher
- National Organization for Drug Control and Research (NODCAR), P.O. Box 29, Cairo, Egypt; Department of Chemistry, Royal Institute of Technology, KTH, Sweden
| | - Mohamed A Farag
- Pharmacognosy Department, College of Pharmacy, Cairo University, Kasr el Aini St., 11562 Cairo, Egypt; Department of Chemistry, School of Sciences & Engineering, The American University in Cairo, New Cairo, Egypt
| | - Aamer Saeed
- Chemistry Department, Quaid-i-Azam University, Islamabad, 45320, Pakistan
| | - Mohamed Gamal
- Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Kom, Egypt
| | - Mohamed-Elamir F Hegazy
- Chemistry of Medicinal Plants Department, National Research Centre, 33 El-Bohouth St., Dokki, Giza 12622, Egypt; Department of Pharmaceutical Biology, Institute of Pharmacy, Johannes Gutenberg University, 55128 Mainz, Germany
| | - Diaa Youssef
- Faculty of Pharmacy, King Abdulaziz University, P.O. Box 80260, Jeddah 21589, Saudi Arabia
| | - Syed G Musharraf
- H. E. J. Research Institute of Chemistry, International Center for Chemical Sciences, University of Karachi, Karachi 75270, Pakistan
| | - Muaaz M Alajlani
- Division of Pharmacognosy, Department of Medicinal Chemistry, Uppsala University, Biomedical Centre, Box 574, SE-75123, Uppsala, Sweden
| | - Jianbo Xiao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Control in Chinese Medicine, University of Macau, Macau, China
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmacy, Johannes Gutenberg University, 55128 Mainz, Germany
| |
Collapse
|
|
11
|
Abstract
Six new cardenolides (1-6), including three 14-hydroxylated cardenolides and three 14-carbonylated cardenolides were isolated from the dried aerial parts of Nerium oleander Linn in addition to twenty-seven known compounds (7-33). Their structures were elucidated on the basis of extensive spectroscopic evidences and single-crystal X-ray diffraction analysis. Compounds 1, 4, 7-10 and 13 exhibited significant cytotoxicity against four colon cancer cell lines (HCT116, HT29, SW620, RKO), one gastric cancer cell line (GT) and one cervical cancer cell line (HeLa) in vitro.
Collapse
Affiliation(s)
- Yuan-Lin Cao
- Tianjin State Key Laboratory of Modern Chinese Medicine, Pharmacology of Traditional Chinese Medicine Formulae, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Meng-Han Zhang
- Tianjin State Key Laboratory of Modern Chinese Medicine, Pharmacology of Traditional Chinese Medicine Formulae, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Yun-Fang Lu
- Tianjin State Key Laboratory of Modern Chinese Medicine, Pharmacology of Traditional Chinese Medicine Formulae, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Chen-Yang Li
- Department of Pharmacy, School of Medicine, Shenzhen University, Shenzhen 518060, China.
| | - Jin-Shan Tang
- Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Miao-Miao Jiang
- Tianjin State Key Laboratory of Modern Chinese Medicine, Pharmacology of Traditional Chinese Medicine Formulae, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
| |
Collapse
|
|
12
|
Jones KD, Stewart SG. Recent Advances in Steroid Synthesis: A Tribute to Sir Derek Barton. Aust J Chem 2018. [DOI: 10.1071/ch18256] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
The synthesis of steroids and gaining an ultimate understanding of their reactivity was one of Sir Derek Barton’s most notable research areas. This highlight will focus on the construction of the steroid ring system from 2016 to 2018, and will include pathways that eventually led to natural product synthesis. For example, efficient syntheses of ent-pregnanolone sulfate and oestradiol methyl ether will be explained along with the total synthesis of cannogenol-3-O-α-l-rhamnoside.
Collapse
|
|
13
|
Bhattarai B, Nagorny P. Enantioselective Total Synthesis of Cannogenol-3-O-α-l-rhamnoside via Sequential Cu(II)-Catalyzed Michael Addition/Intramolecular Aldol Cyclization Reactions. Org Lett 2017; 20:154-157. [PMID: 29244520 DOI: 10.1021/acs.orglett.7b03513] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
A concise and scalable enantioselective total synthesis of the natural cardenolides cannogenol and cannogenol-3-O-α-l-rhamnoside has been achieved in 18 linear steps. The synthesis features a Cu(II)-catalyzed enantioselective and diastereoselective Michael reaction/tandem aldol cyclization and a one-pot reduction/transposition, which resulted in a rapid (6 linear steps) assembly of a functionalized intermediate containing C19 oxygenation that could be elaborated to cardenolide cannogenol. In addition, a strategy for achieving regio- and stereoselective glycosylation at the C3 position of synthetic cannogenol was developed and applied to the preparation of cannogenol-3-O-α-l-rhamnoside.
Collapse
Affiliation(s)
- Bijay Bhattarai
- Chemistry Department, University of Michigan , 930 North University Avenue, Ann Arbor, Michigan 48109, United States
| | - Pavel Nagorny
- Chemistry Department, University of Michigan , 930 North University Avenue, Ann Arbor, Michigan 48109, United States
| |
Collapse
|
|
14
|
Li L, Bonneton F, Chen XY, Laudet V. Botanical compounds and their regulation of nuclear receptor action: the case of traditional Chinese medicine. Mol Cell Endocrinol 2015; 401:221-37. [PMID: 25449417 DOI: 10.1016/j.mce.2014.10.028] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Revised: 10/23/2014] [Accepted: 10/31/2014] [Indexed: 02/06/2023]
Abstract
Nuclear receptors (NRs) are major pharmacological targets that allow an access to the mechanisms controlling gene regulation. As such, some NRs were identified as biological targets of active compounds contained in herbal remedies found in traditional medicines. We aim here to review this expanding literature by focusing on the informative articles regarding the mechanisms of action of traditional Chinese medicines (TCMs). We exemplified well-characterized TCM action mediated by NR such as steroid receptors (ER, GR, AR), metabolic receptors (PPAR, LXR, FXR, PXR, CAR) and RXR. We also provided, when possible, examples from other traditional medicines. From these, we draw a parallel between TCMs and phytoestrogens or endocrine disrupting chemicals also acting via NR. We define common principle of action and highlight the potential and limits of those compounds. TCMs, by finely tuning physiological reactions in positive and negative manners, could act, in a subtle but efficient way, on NR sensors and their transcriptional network.
Collapse
Affiliation(s)
- Ling Li
- Institut de Génomique Fonctionnelle de Lyon; Université de Lyon; Université Lyon 1; CNRS UMR 5242; Ecole Normale Supérieure de Lyon, France.; School of Ecological and Environmental Science, East China Normal University, Shanghai, China
| | - François Bonneton
- Institut de Génomique Fonctionnelle de Lyon; Université de Lyon; Université Lyon 1; CNRS UMR 5242; Ecole Normale Supérieure de Lyon, France
| | - Xiao Yong Chen
- School of Ecological and Environmental Science, East China Normal University, Shanghai, China
| | - Vincent Laudet
- Institut de Génomique Fonctionnelle de Lyon; Université de Lyon; Université Lyon 1; CNRS UMR 5242; Ecole Normale Supérieure de Lyon, France..
| |
Collapse
|
|
15
|
Li XS, Hu MJ, Liu J, Liu Q, Huang ZX, Li SL, Hao XJ, Zhang XK, Yao XS, Tang JS. Cardiac glycosides from the bark of Antiaris toxicaria. Fitoterapia 2014; 97:71-7. [DOI: 10.1016/j.fitote.2014.05.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Revised: 05/20/2014] [Accepted: 05/21/2014] [Indexed: 10/25/2022]
|
|
16
|
Wu XL, Wu YL, Li HG, Liu HT, Fu XY, Cui RQ, Wang JH, Liu C, Chen J. A new periplogenin cardenolide from the seeds of Antiaris toxicaria. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2014; 16:418-421. [PMID: 24597720 DOI: 10.1080/10286020.2014.885506] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Accepted: 01/16/2014] [Indexed: 06/03/2023]
Abstract
A new periplogenin cardenolide, periplogulcoside (1), together with three known cardenolides, was isolated from the seeds of Antiaris toxicaria. The structure of the new compound was characterized as periplogenin-3-O-β-D-glucopyranosyl-(1 → 4)-β-D-glucopyranoside (1) by spectroscopic methods including 1D and 2D NMR, HR-TOF-MS, and CD spectrometry, and the known compounds were identified by comparison of their NMR and HR-TOF-MS data with those reported in the literature. Compound 1 showed significant cytotoxicity against Hela and HepG-2 cell lines.
Collapse
Affiliation(s)
- Xiu-Li Wu
- a College of Pharmacy, Ningxia Medical University , Yinchuan 750004 , China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
17
|
Liu Q, Tang JS, Hu MJ, Liu J, Chen HF, Gao H, Wang GH, Li SL, Hao XJ, Zhang XK, Yao XS. Antiproliferative cardiac glycosides from the latex of Antiaris toxicaria. JOURNAL OF NATURAL PRODUCTS 2013; 76:1771-1780. [PMID: 24033101 DOI: 10.1021/np4005147] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Phytochemical investigation of the latex of Antiaris toxicaria resulted in the isolation of 15 new [antiarosides J-X (1-15)] and 17 known cardiac glycosides. The effects of the cardiac glycosides on apoptosis and the expression of orphan nuclear receptor Nur77 were examined in human NIH-H460 lung cancer cells. Several of the cardiac glycosides induced apoptosis in lung cancer cells, which was accompanied by induction of Nur77 protein expression. Treatment of cancer cells with the cardiac glycosides resulted in translocation of the Nur77 protein from the nucleus to the cytoplasm and subsequent targeting to mitochondria. The results show that the cardiac glycosides exert their apoptotic effect through the Nur77-dependent apoptotic pathway.
Collapse
MESH Headings
- Antiaris/chemistry
- Antineoplastic Agents, Phytogenic/chemistry
- Antineoplastic Agents, Phytogenic/isolation & purification
- Antineoplastic Agents, Phytogenic/pharmacology
- Apoptosis/drug effects
- Cardiac Glycosides/chemistry
- Cardiac Glycosides/isolation & purification
- Cardiac Glycosides/pharmacology
- Drug Screening Assays, Antitumor
- Drugs, Chinese Herbal/chemistry
- Drugs, Chinese Herbal/isolation & purification
- Drugs, Chinese Herbal/pharmacology
- Humans
- Latex/chemistry
- Mitochondria/metabolism
- Nuclear Magnetic Resonance, Biomolecular
- Nuclear Receptor Subfamily 4, Group A, Member 1/drug effects
Collapse
Affiliation(s)
- Qian Liu
- Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University , Guangzhou 510632, People's Republic of China
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
18
|
Salvador JAR, Carvalho JFS, Neves MAC, Silvestre SM, Leitão AJ, Silva MMC, Sá e Melo ML. Anticancer steroids: linking natural and semi-synthetic compounds. Nat Prod Rep 2013; 30:324-74. [PMID: 23151898 DOI: 10.1039/c2np20082a] [Citation(s) in RCA: 209] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Steroids, a widespread class of natural organic compounds occurring in animals, plants and fungi, have shown great therapeutic value for a broad array of pathologies. The present overview is focused on the anticancer activity of steroids, which is very representative of a rich structural molecular diversity and ability to interact with various biological targets and pathways. This review encompasses the most relevant discoveries on steroid anticancer drugs and leads through the last decade and comprises 668 references.
Collapse
Affiliation(s)
- Jorge A R Salvador
- Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, Polo das Ciências da Saúde, 3000-508, Coimbra, Portugal.
| | | | | | | | | | | | | |
Collapse
|
|
19
|
|
|
20
|
Huang FY, Mei WL, Li YN, Tan GH, Dai HF, Guo JL, Wang H, Huang YH, Zhao HG, Zhou SL, Lin YY. Toxicarioside A inhibits tumor growth and angiogenesis: involvement of TGF-β/endoglin signaling. PLoS One 2012; 7:e50351. [PMID: 23209720 PMCID: PMC3508932 DOI: 10.1371/journal.pone.0050351] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2012] [Accepted: 10/19/2012] [Indexed: 11/28/2022] Open
Abstract
Toxicarioside A is a cardenolide isolated mainly from plants and animals. Emerging evidence demonstrate that cardenolides not only have cardiac effects but also anticancer effects. In this study, we used in vivo models to investigate the antitumor activities of toxicarioside A and the potential mechanisms behind them. Murine colorectal carcinoma (CT26) and Lewis lung carcinoma (LL/2) models were established in syngeneic BALB/c and C57BL/6 mice, respectively. We found that the optimum effective dose of toxicarioside A treatment significantly suppressed tumor growth and angiogenesis in CT and LL/2 tumor models in vivo. Northern and Western blot analysis showed significant inhibition of endoglin expression in toxicarioside A-treated human umbilical vein endothelial cells (HUVECs) in vitro and tumor tissues in vivo. Toxicarioside A treatment significantly inhibited cell proliferation, migration and invasion, but did not cause significant cell apoptosis and affected other membrane protein (such as CD31 and MHC I) expression. In addition, TGF-β expression was also significantly inhibited in CT26 and LL/2 tumor cells treated with toxicarioside A. Western blot analysis indicated that Smad1 and phosphorylated Smad1 but not Smad2/3 and phosphorylated Smad2/3 were attenuated in HUVECs treated with toxicarioside A. Smad1 and Smad2/3 signaling remained unchanged in CT26 and LL/2 tumor cells treated with toxicarioside A. Endoglin knockout by small interfering RNA against endoglin induced alternations in Smad1 and Smad2/3 signaling in HUVECs. Our results indicate that toxicarioside A suppresses tumor growth through inhibition of endoglin-related tumor angiogenesis, which involves in the endoglin/TGF-β signal pathway.
Collapse
Affiliation(s)
- Feng-ying Huang
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, People's Republic of China
| | - Wen-li Mei
- Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences, Haikou, People's Republic of China
| | - Yue-nan Li
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, People's Republic of China
| | - Guang-hong Tan
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, People's Republic of China
| | - Hao-fu Dai
- Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences, Haikou, People's Republic of China
| | - Jun-li Guo
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, People's Republic of China
| | - Hua Wang
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, People's Republic of China
| | - Yong-hao Huang
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, People's Republic of China
| | - Huan-ge Zhao
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, People's Republic of China
| | - Song-lin Zhou
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, People's Republic of China
| | - Ying-ying Lin
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, People's Republic of China
| |
Collapse
|
|
21
|
Guo JL, Zheng SJ, Li YN, Jie W, Hao XB, Li TF, Xia LP, Mei WL, Huang FY, Kong YQ, He QY, Yang K, Tan GH, Dai HF. Toxicarioside A inhibits SGC-7901 proliferation, migration and invasion via NF-κB/bFGF signaling. World J Gastroenterol 2012; 18:1602-9. [PMID: 22529688 PMCID: PMC3325525 DOI: 10.3748/wjg.v18.i14.1602] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2011] [Revised: 01/17/2012] [Accepted: 02/08/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the inhibitory role of toxicarioside A on the gastric cancer cell line human gastric cancer cell line (SGC-7901) and determine the underlying molecular mechanism.
METHODS: After SGC-7901 cells were treated with toxicarioside A at various concentrations (0.5, 1.5, 4.5, 9.0 μg/mL) for 24 h or 48 h, cell viability was determined by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay, and the motility and invasion of tumor cells were assessed by the Transwell chamber assay. Immunofluorescence staining, reverse transcription polymerase chain reaction and Western blotting were performed to detect the expression of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor-1 (FGFR1), and nuclear factor-kappa B (NF-κB) activation was examined by electrophoretic mobility shift assay.
RESULTS: The results showed that toxicarioside A was capable of reducing cell viability, inhibiting cell growth, and suppressing cell migration and invasion activities in a time- and dose-dependent manner in SGC-7901 cells. Further analysis revealed that not only the expression of bFGF and its high-affinity receptor FGFR1 but also the NF-κB-DNA binding activity were effectively blocked by toxicarioside A in a dose-dependent manner compared with the control group (P < 0.05 or P < 0.01). Interestingly, application of the NF-κB specific inhibitor, pyrrolidinedithiocarbamate (PDTC), to SGC-7901 cells significantly potentized the toxicarioside A-induced down-regulation of bFGF compared with the control group (P < 0.05).
CONCLUSION: These findings suggest that toxicarioside A has an anti-gastric cancer activity and this effect may be achieved partly through down-regulation of NF-κB and bFGF/FGFR1 signaling.
Collapse
|
|
22
|
Li YN, Huang FY, Mei WL, Dai HF, Guo JL, Tan GH, Zhou P. Toxicarioside A, isolated from tropical Antiaris toxicaria, blocks endoglin/TGF-β signaling in a bone marrow stromal cell line. ASIAN PAC J TROP MED 2012; 5:91-7. [PMID: 22221748 DOI: 10.1016/s1995-7645(12)60002-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2011] [Revised: 12/15/2011] [Accepted: 01/15/2012] [Indexed: 10/14/2022] Open
Abstract
OBJECTIVE To investigate possible mechanism of toxicarioside A in HS-5 bone stromal cells. METHODS HS-5 bone stromal cells were cultured in media supplemented with various concentrations of toxicarioside A or control DMSO (not treatment). Endoglin and TGF-β were detected by Northern and Western blot analysis and quantified in a standard method. Downstream molecules of endoglin and TGF-β (Smad1, Smad2 and their active phosphorylated counterparts, pSmad1 and pSmad2) were also detected and quantified by Western blot analysis. In addition, cell proliferation assay and small interfering RNA (siRNA) against endoglin were used to certificate the function of endolgin in the HS-5 cells. RESULTS Compared with the not treated (0 μg/mL) or DMSO treated control HS-5 cells, HS-5 cells treated with toxicarioside A were found significant attenuation of endolgin and TGF-β expression. Significant inhibition of cell proliferation was also found in the HS-5 cells treated with toxicarioside A. ALK1-related Smad1 and ALK5-related Smad2 were decreased in HS-5 cells treated with toxicarioside A. In addition, phosphorylated Smad1 (pSmad1) and Smad2 (pSmad2) were also found attenuation in toxicarioside A-treated HS-5 cells. RNA interference showed that blockage of endoglin by siRNA also decreased Smad1 and Smad2 expression in HS-5 cells. CONCLUSIONS Our results indicate that toxicarioside A can influence bone marrow stromal HS-5's function and inhibit HS-5 cell proliferation by alteration of endoglin-related ALK1 (Smad1) and ALK5 (Smad2) signaling.
Collapse
Affiliation(s)
- Yue-Nan Li
- Agriculture College, and Hainan Provincial Key Laboratory of Tropical Medicine, Hainan University, Haikou, China
| | | | | | | | | | | | | |
Collapse
|
|
23
|
Sun Z, Cao X, Jiang MM, Qiu Y, Zhou H, Chen L, Qin B, Wu H, Jiang F, Chen J, Liu J, Dai Y, Chen HF, Hu QY, Wu Z, Zeng JZ, Yao XS, Zhang XK. Inhibition of β-catenin signaling by nongenomic action of orphan nuclear receptor Nur77. Oncogene 2011; 31:2653-67. [PMID: 21986938 PMCID: PMC3257393 DOI: 10.1038/onc.2011.448] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Dysregulation of β-catenin turnover due to mutations of its regulatory proteins including adenomatous polyposis coli (APC) and p53 is implicated in the pathogenesis of cancer. Thus, intensive effort is being made to search for alternative approaches to reduce abnormally activated β-catenin in cancer cells. Nur77, an orphan member of the nuclear receptor superfamily, has a role in the growth and apoptosis of cancer cells. Here, we reported that Nur77 could inhibit transcriptional activity of β-catenin by inducing β-catenin degradation via proteasomal degradation pathway that is glycogen synthase kinase 3β and Siah-1 independent. Nur77 induction of β-catenin degradation required both the N-terminal region of Nur77, which was involved in Nur77 ubiquitination, and the C-terminal region, which was responsible for β-catenin binding. Nur77/ΔDBD, a Nur77 mutant lacking its DNA-binding domain, resided in the cytoplasm, interacted with β-catenin, and induced β-catenin degradation, demonstrating that Nur77-mediated β-catenin degradation was independent of its DNA binding and transactivation, and might occur in the cytoplasm. In addition, we reported our identification of two digitalis-like compounds (DLCs), H-9 and ATE-i2-b4, which potently induced Nur77 expression and β-catenin degradation in SW620 colon cancer cells expressing mutant APC protein in vitro and in animals. DLC-induced Nur77 protein was mainly found in the cytoplasm, and inhibition of Nur77 nuclear export by the CRM1-dependent nuclear export inhibitor leptomycin B or Jun N-terminal kinase inhibitor prevented the effect of DLC on inducing β-catenin degradation. Together, our results demonstrate that β-catenin can be degraded by cytoplasmic Nur77 through their interaction and identify H-9 and ATE-i2-b4 as potent activators of the Nur77-mediated pathway for β-catenin degradation.
Collapse
Affiliation(s)
- Z Sun
- School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
24
|
Dong WH, Mei WL, Zhao YX, Zeng YB, Wang H, Dai HF. A new drimane sesquiterpenoid glycoside from the seeds of Antiaris toxicaria. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2011; 13:561-565. [PMID: 21623521 DOI: 10.1080/10286020.2011.573479] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
A new drimane sesquiterpenoid glycoside, named 7-drimen-3β,11-diol 3-O-β-d-glucopyranoside, was isolated from the 95% EtOH extract of the seeds of Antiaris toxicaria (Pers.) Lesch. The chemical structure was completely elucidated using a combination of 1D and 2D NMR techniques (COSY, HMQC, HMBC, and ROESY) and HR-ESI-MS analysis. The compound showed inhibitory activities toward methicillin-resistant Staphylococcus aureus (MRSA), chronic myelogenous leukemia (K562), and human hepatoma (SMMC-7721) cell lines.
Collapse
Affiliation(s)
- Wen-Hua Dong
- Key Laboratory of Tropical Crop Biotechnology, Ministry of Agriculture, Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences, Haikou, China
| | | | | | | | | | | |
Collapse
|
|
25
|
Dai HF, Gan YJ, Que DM, Wu J, Wen ZC, Mei WL. A new cytotoxic 19-nor-cardenolide from the latex of Antiaris toxicaria. Molecules 2009; 14:3694-9. [PMID: 19783952 PMCID: PMC6255088 DOI: 10.3390/molecules14093694] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2009] [Revised: 09/08/2009] [Accepted: 09/15/2009] [Indexed: 11/23/2022] Open
Abstract
A new nor-cardenolide, named toxicarioside H (1), was isolated from the latex of Antiaris toxicaria (Pers.) Lesch (Moraceae). Its structure was elucidated on the basis of HRFAB-MS and spectroscopic techniques (IR, UV, 1D and 2D NMR). Compound 1 showed significant cytotoxicity against K562, SGC-7901, SMMC-7721, and HeLa cell lines in vitro by MTT method.
Collapse
Affiliation(s)
- Hao-Fu Dai
- Key Laboratory of Tropical Crop Biotechnology, Ministry of Agriculture, Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China; E-Mails: (H.-F.D.); (Y.-J.G.); (D.-M.Q.); (J.W.)
| | - Yu-Juan Gan
- Key Laboratory of Tropical Crop Biotechnology, Ministry of Agriculture, Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China; E-Mails: (H.-F.D.); (Y.-J.G.); (D.-M.Q.); (J.W.)
| | - Dong-Mei Que
- Key Laboratory of Tropical Crop Biotechnology, Ministry of Agriculture, Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China; E-Mails: (H.-F.D.); (Y.-J.G.); (D.-M.Q.); (J.W.)
| | - Jiao Wu
- Key Laboratory of Tropical Crop Biotechnology, Ministry of Agriculture, Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China; E-Mails: (H.-F.D.); (Y.-J.G.); (D.-M.Q.); (J.W.)
| | - Zhen-Chang Wen
- Key Laboratory of Tropic Biological Resources of Ministry of Education, Hainan University, Haikou 570228, China; E-Mail: (Z.-C.W.)
| | - Wen-Li Mei
- Key Laboratory of Tropical Crop Biotechnology, Ministry of Agriculture, Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China; E-Mails: (H.-F.D.); (Y.-J.G.); (D.-M.Q.); (J.W.)
- Author to whom correspondence should be addressed; E-Mail:
| |
Collapse
|
|
26
|
Dai HF, Gan YJ, Que DM, Wu J, Wen ZC, Mei WL. A new cytotoxic 19-nor-cardenolide from the latex of Antiaris toxicaria. CHINESE CHEM LETT 2009. [PMID: 19783952 DOI: 10.1016/j.cclet.2008.12.043] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
A new nor-cardenolide, named toxicarioside H (1), was isolated from the latex of Antiaris toxicaria (Pers.) Lesch (Moraceae). Its structure was elucidated on the basis of HRFAB-MS and spectroscopic techniques (IR, UV, 1D and 2D NMR). Compound 1 showed significant cytotoxicity against K562, SGC-7901, SMMC-7721, and HeLa cell lines in vitro by MTT method.
Collapse
Affiliation(s)
- Hao-Fu Dai
- Key Laboratory of Tropical Crop Biotechnology, Ministry of Agriculture, Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China.
| | | | | | | | | | | |
Collapse
|
|
27
|
Dai HF, Gan YJ, Que DM, Wu J, Wen ZC, Mei WL. Two new cytotoxic cardenolides from the latex of Antiaris toxicaria. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2009; 11:832-837. [PMID: 20183332 DOI: 10.1080/10286020903164285] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Two new cardenolides, toxicarioside F (1) and toxicarioside G (2), were isolated from the latex of Antiaris toxicaria (Pers.) Lesch (Moraceae). Their structures were elucidated on the basis of spectral data and chemical evidence. Compounds 1 and 2 showed significant cytotoxicity against K562, SGC-7901, SMMC-7721, and HeLa cell lines in vitro by the MTT method.
Collapse
Affiliation(s)
- Hao-Fu Dai
- Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences, Haikou, China
| | | | | | | | | | | |
Collapse
|
|
28
|
Juncker T, Schumacher M, Dicato M, Diederich M. UNBS1450 from Calotropis procera as a regulator of signaling pathways involved in proliferation and cell death. Biochem Pharmacol 2009; 78:1-10. [DOI: 10.1016/j.bcp.2009.01.018] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2008] [Revised: 01/21/2009] [Accepted: 01/29/2009] [Indexed: 10/21/2022]
|