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Pandey P, Verma M, Sanghvi G, R R, Joshi KK, V K, Ray S, Ramniwas S, Singh A, Lakhanpal S, Khan F. Plant-derived terpenoids modulating cancer cell metabolism and cross-linked signaling pathways: an updated reviews. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-03937-y. [PMID: 40019530 DOI: 10.1007/s00210-025-03937-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Accepted: 02/16/2025] [Indexed: 03/01/2025]
Abstract
Cancer is a critical health issue that remains a predominant cause of mortality globally. It is a complex disease that may effectively regulate many signaling pathways and modify the metabolism of the body to evade the immune system. Understanding neoplastic metabolic reprogramming as a hallmark of cancer has facilitated the creation of innovative metabolism-targeted treatment strategies. Various signaling cascades, such as the PI3K/Akt/mTOR, ERK, JAK/STAT, MAPK/p38, NF-κB/Nrf2, and apoptotic pathways, are commonly involved in this process. It is now widely recognized that an inadequate response and the subsequent development of resistance are frequently caused by the highly selective blockage of these pathways in tumor cells. Consequently, to enhance the overall efficacy of anticancer agents, it is crucial to employ multi-target compounds that can concurrently inhibit multiple vital processes within tumor cells. The utilization of plant-derived bioactive compounds for this purpose is particularly promising, owing to their varied structures and numerous targets. Among these bioactive compounds, terpenoids have exhibited significant anticancer efficacy by targeting various altered signaling pathways. Thus, this review examines the terpenoid class of plant-derived compounds exhibiting potential anticancer activity, including their impact on metabolism and interconnected deregulated signaling pathways in human tumor cells. Accordingly, current research will help in the rational design and critical evaluation of innovative anticancer therapeutics utilizing plant-derived terpenoids for the modulation of cross-linked signaling pathways of cancer metabolism.
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Affiliation(s)
- Pratibha Pandey
- Centre for Research Impact and Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, Punjab, 140401, India
- Chitkara Centre for Research and Development, Chitkara University, Himachal, Pradesh, 174103, India
| | - Meenakshi Verma
- University Centre of Research and Development, Chandigarh University, Gharuan, Punjab, 140413, India
| | - Gaurav Sanghvi
- Department of Microbiology, Faculty of Science, Marwadi University Research Center, Marwadi University, Rajkot, Gujarat, 360003, India
| | - Roopashree R
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Kamal Kant Joshi
- Department of Allied Science, Graphic Era Hill University, Dehradun, Uttarakhand, India
- Graphic Era Deemed to Be University, Dehradun, Uttarakhand, India
| | - Kavitha V
- Department of Chemistry, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Subhashree Ray
- Department of Biochemistry, IMS and SUM Hospital, Siksha 'O' Anusandhan (Deemed to Be University), Bhubaneswar, Odisha, 751003, India
| | - Seema Ramniwas
- University Centre of Research and Development, Chandigarh University, Gharuan, Punjab, 140413, India
| | - Ajay Singh
- School of Applied and Life Sciences, Uttaranchal University, Dehradun, Uttarakhand, 248007, India
| | - Sorabh Lakhanpal
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, 144411, India
| | - Fahad Khan
- Center for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, 602105, India.
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Rostro-Alonso GO, Castillo-Montoya AI, García-Acosta JC, Aguilar-Llanos EF, Quintas-Granados LI, Villegas-Vazquez EY, García-Aguilar R, Porras-Vázquez SA, Bustamante-Montes LP, Alvarado-Sansininea JJ, Jiménez-Estrada M, Cariño-Calvo L, Carmen MGD, Cortés H, Leyva-Gómez G, Figueroa-González G, Reyes-Hernández OD. Cacalol Acetate as Anticancer Agent: Antiproliferative, Pro-Apoptotic, Cytostatic, and Anti-Migratory Effects. Curr Issues Mol Biol 2024; 46:9298-9311. [PMID: 39329902 PMCID: PMC11430360 DOI: 10.3390/cimb46090550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 08/19/2024] [Accepted: 08/21/2024] [Indexed: 09/28/2024] Open
Abstract
Cacalol (C), a sesquiterpene isolated from Psacalium decompositum, has demonstrated anti-inflammatory and antioxidant activities. Its cytotoxic, antiproliferative, and pro-apoptotic effects have been previously shown in an in vitro breast cancer model. A derivative, cacalol acetate (CA), shows potential in regulating these processes, which has not been previously reported. This study focused on an in vitro cervical cancer model, assessing CA's antiproliferative, pro-apoptotic, cytostatic, and anti-migratory activities using the HeLa cell line. The natural anticancer agent indole-3-carbinol (I3C) was used as a control for comparison. CA demonstrated significant antitumor activities, including inhibiting cell growth, inducing apoptosis, arresting cells in the G2 phase of the cell cycle, and inhibiting cell migration. These effects were notably greater compared to I3C. I3C, while following a similar trend, did not induce Cas-3 expression, suggesting a different apoptotic pathway. Neither CA nor I3C increased p62 and LC3B levels, indicating they do not stimulate autophagy marker expression. Both compounds inhibited HeLa cell migration and induced cell cycle arrest. Despite both holding promise as anticancer agents for cervical cancer, CA's lower cytotoxicity and stronger regulation of tumor phenotypes make it a more promising agent compared to I3C.
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Affiliation(s)
- Gareth Omar Rostro-Alonso
- Laboratorio de Farmacogenética, Unidad Multidisciplinaria de Investigación Experimental Zaragoza, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Batalla 5 de Mayo s/n Esquina Fuerte de Loreto, Iztapalapa, Mexico City 09230, Mexico
| | - Alejandro Israel Castillo-Montoya
- Laboratorio de Farmacogenética, Unidad Multidisciplinaria de Investigación Experimental Zaragoza, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Batalla 5 de Mayo s/n Esquina Fuerte de Loreto, Iztapalapa, Mexico City 09230, Mexico
| | - Juan Carlos García-Acosta
- Laboratorio de Farmacogenética, Unidad Multidisciplinaria de Investigación Experimental Zaragoza, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Batalla 5 de Mayo s/n Esquina Fuerte de Loreto, Iztapalapa, Mexico City 09230, Mexico
| | - Erick Fernando Aguilar-Llanos
- Laboratorio de Biología Molecular del Cáncer, Unidad Multidisciplinaria de Investigación Experimental Zaragoza, Facultad de Estudios Superiores-Zaragoza, Universidad Nacional Autónoma de México, Iztapalapa, Mexico City 09230, Mexico
| | - Laura Itzel Quintas-Granados
- Colegio de Ciencias y Humanidades, Plantel Cuautepec, Universidad Autónoma de la Ciudad de México, Calle Dr. García Diego 168, Doctores, Cuauhtémoc, Mexico City 06720, Mexico
| | - Edgar Yebrán Villegas-Vazquez
- Laboratorio de Farmacogenética, Unidad Multidisciplinaria de Investigación Experimental Zaragoza, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Batalla 5 de Mayo s/n Esquina Fuerte de Loreto, Iztapalapa, Mexico City 09230, Mexico
| | - Rosario García-Aguilar
- Laboratorio de Citometría de Flujo y Hematología, Diagnóstico Molecular de Leucemias y Terapia Celular (DILETEC), Gustavo A. Madero, Mexico City 06350, Mexico
| | - Samantha Andrea Porras-Vázquez
- Laboratorio de Farmacogenética, Unidad Multidisciplinaria de Investigación Experimental Zaragoza, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Batalla 5 de Mayo s/n Esquina Fuerte de Loreto, Iztapalapa, Mexico City 09230, Mexico
| | | | - Jesús J Alvarado-Sansininea
- Laboratorio 2-10, Departamento de Productos Naturales, Instituto de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Manuel Jiménez-Estrada
- Laboratorio 2-10, Departamento de Productos Naturales, Instituto de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | | | | | - Hernán Cortés
- Laboratorio de Medicina Genómica, Departamento de Genómica, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico
| | - Gerardo Leyva-Gómez
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Gabriela Figueroa-González
- Laboratorio de Farmacogenética, Unidad Multidisciplinaria de Investigación Experimental Zaragoza, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Batalla 5 de Mayo s/n Esquina Fuerte de Loreto, Iztapalapa, Mexico City 09230, Mexico
| | - Octavio Daniel Reyes-Hernández
- Laboratorio de Farmacogenética, Unidad Multidisciplinaria de Investigación Experimental Zaragoza, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Batalla 5 de Mayo s/n Esquina Fuerte de Loreto, Iztapalapa, Mexico City 09230, Mexico
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Ebrahimi SM, Asadi J, Fattahian M, Jafari SM, Ghanadian M. Persianolide-A, an eudesmanolide-type sesquiterpene lactone from Artemisia kopetdaghensis, induces apoptosis by regulating ERK signaling pathways. Res Pharm Sci 2024; 19:328-337. [PMID: 39035813 PMCID: PMC11257198 DOI: 10.4103/rps.rps_175_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 10/18/2023] [Accepted: 11/13/2023] [Indexed: 07/23/2024] Open
Abstract
Background and purpose Herbal components, particularly sesquiterpenes, are progressively recognized as a crucial resource for developing effective therapeutic agents for breast cancer. In this study, the effect of a sesquiterpene lactone known as 8-O-dihydroxy-11a,13-dihydroeudesma-4(15)-en-12,6a-olide (persianolide- A) was examined in breast cancer cell lines. Experimental approach MDA-MB-231 and MCF-7 cancer cells were grown in DMEM solution with 10% FBS. Then, an MTT assay was performed to evaluate cell viability. Apoptosis was detected by annexin-PI staining. A caspase 3/7 activity assay kit was used to assess the activity of caspase-3 and caspase-7. Protein expression of Bcl-2, Bax, and p-ERK1/2 was determined by western blotting. Findings/Results This study showed that the IC50 values of the persianolide-A for MCF-7 and MDA-MB- 468 cells are 34.76 and 54.48 μM, respectively. In addition, persianolide-A showed a significant increase in apoptosis in both MDAMB-231 and MCF-7 breast cancer cell lines. Persianolide-A significantly increased the expression of the pro-apoptotic protein Bax and decreased the expression of the anti-apoptotic protein Bcl-2. Also, presinolide-A treatment led to a substantial increase in caspase activity with a ratio of 3/7 in both MCF- 7 and MDA-MB-231 cancer cells. In addition, the study showed that persianolide-A decreased the expression of p-ERK1/2 protein. Conclusion and implications The results of this study suggest that persianolide-A, sourced from Artemisia kopetdaghensis, induces cell apoptosis in breast cancer cell types. The molecular mechanisms could be implicated in the modulation of the ERK1/2 signaling pathway.
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Affiliation(s)
- Seyyed Moein Ebrahimi
- Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
- Department of Biochemistry and Biophysics, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, I.R. Iran
| | - Jahanbakhsh Asadi
- Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
- Department of Biochemistry and Biophysics, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, I.R. Iran
| | - Maryam Fattahian
- Department of Pharmacognosy, Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Seyyed Mehdi Jafari
- Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
- Department of Biochemistry and Biophysics, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, I.R. Iran
| | - Mustafa Ghanadian
- Department of Pharmacognosy, Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
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Mallick R, Bhowmik P, Duttaroy AK. Targeting fatty acid uptake and metabolism in cancer cells: A promising strategy for cancer treatment. Biomed Pharmacother 2023; 167:115591. [PMID: 37774669 DOI: 10.1016/j.biopha.2023.115591] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 09/21/2023] [Accepted: 09/25/2023] [Indexed: 10/01/2023] Open
Abstract
Despite scientific development, cancer is still a fatal disease. The development of cancer is thought to be significantly influenced by fatty acids. Several mechanisms that control fatty acid absorption and metabolism are reported to be altered in cancer cells to support their survival. Cancer cells can use de novo synthesis or uptake of extracellular fatty acid if one method is restricted. This factor makes it more difficult to target one pathway while failing to treat the disease properly. Side effects may also arise if several inhibitors simultaneously target many targets. If a viable inhibitor could work on several routes, the number of negative effects might be reduced. Comparative investigations against cell viability have found several potent natural and manmade substances. In this review, we discuss the complex roles that fatty acids play in the development of tumors and the progression of cancer, newly discovered and potentially effective natural and synthetic compounds that block the uptake and metabolism of fatty acids, the adverse side effects that can occur when multiple inhibitors are used to treat cancer, and emerging therapeutic approaches.
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Affiliation(s)
- Rahul Mallick
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Finland
| | - Prasenjit Bhowmik
- Department of Chemistry, Uppsala Biomedical Centre, Uppsala University, Sweden
| | - Asim K Duttaroy
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Norway.
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Comment on Pyrrolizidine Alkaloids and Terpenes from Senecio (Asteraceae): Chemistry and Research Gaps in Africa. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27248868. [PMID: 36558004 PMCID: PMC9781224 DOI: 10.3390/molecules27248868] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/09/2022] [Accepted: 12/12/2022] [Indexed: 12/15/2022]
Abstract
The genus Senecio is one of the largest in Asteraceae. There are thousands of species across the globe, either confirmed or awaiting taxonomic delimitation. While the species are best known for the toxic pyrrolizidine alkaloids that contaminate honeys (as bees select pollen from the species) and teas via lateral transfer and accumulation from adjacent roots of Senecio in the rhizosphere, they are also associated with more serious cases leading to fatality of grazing ruminants or people by contamination or accidental harvesting for medicine. Surprisingly, there are significantly more sesquiterpenoid than pyrrolizidine alkaloid-containing species. The main chemical classes, aside from alkaloids, are flavonoids, cacalols, eremophilanes, and bisabolols, often in the form of furan derivatives or free acids. The chemistry of the species across the globe generally overlaps with the 469 confirmed species of Africa. A small number of species express multiple classes of compounds, meaning the presence of sesquiterpenes does not exclude alkaloids. It is possible that there are many species that express the pyrrolizidine alkaloids, in addition to the cacalols, eremophilanes, and bisabolols. The aim of the current communication is, thus, to identify the research gaps related to the chemistry of African species of Senecio and reveal the possible chemical groups in unexplored taxa by way of example, thereby creating a summary of references that could be used to guide chemical assignment in future studies.
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Uesugi S, Hakozaki M, Kanno Y, Takahashi Y, Shindo K, Kimura KI, Yano A. Anti-melanogenic effect of furanoeremophilanes identified from edible wild plants belonging to the genus Cacalia. Biosci Biotechnol Biochem 2022; 86:1462-1466. [PMID: 35867866 DOI: 10.1093/bbb/zbac124] [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: 06/08/2022] [Accepted: 07/09/2022] [Indexed: 11/14/2022]
Abstract
Cacalia delphiniifolia and C. hastata are edible wild plants in Japan. We found that these plants have anti-melanogenic activity in B16F10 mouse melanoma cells. Three furanoeremophilanes, cacalol (from C. delphiniifolia), dehydrocacalohastin, and cacalohastin (from C. hastata), were identified as the main active components. The genus Cacalia may be a good source of beneficial materials with anti-melanogenic effects.
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Affiliation(s)
- Shota Uesugi
- Iwate Biotechnology Research Center, Kitakami, Iwate, Japan
| | | | - Yuko Kanno
- Iwate Biotechnology Research Center, Kitakami, Iwate, Japan
| | - Yuta Takahashi
- Graduate School of Agriculture, Iwate University, Morioka, Iwate, Japan
| | - Kazutoshi Shindo
- Department of Food and Nutrition, Japan Women's University, Bunkyo-ku, Tokyo, Japan
| | - Ken-Ichi Kimura
- Graduate School of Agriculture, Iwate University, Morioka, Iwate, Japan
| | - Akira Yano
- Iwate Biotechnology Research Center, Kitakami, Iwate, Japan
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Pulla LSS, Begum Ahil S. Review on target domains and natural compound-based inhibitors of fatty acid synthase for anticancer drug discovery. Chem Biol Drug Des 2021; 98:869-884. [PMID: 34459114 DOI: 10.1111/cbdd.13942] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 08/20/2021] [Accepted: 08/24/2021] [Indexed: 12/20/2022]
Abstract
Cancer cells require a higher amount of energy in the form of fatty acids for their uncontrolled proliferation and growth. Fatty acid synthase (FASN) plays a crucial role in the synthesis of palmitate, which is involved in most of the critical malignant pathways. Hence, by targeting FASN, tumour growth can be controlled. By designing and developing FASN inhibitors with catalytic domain specificity, safe and potential anticancer drugs can be achieved. The article draws light towards the catalytic domains of FASN, their active site residues and interaction of some of the reported natural FASN inhibitors (resveratrol, lavandulyl flavonoids, catechins, stilbene derivatives, etc). The rationality (structure-activity relationship) behind the variation in the activity of the reported natural FASN inhibitors (butyrolactones, polyphenolics, galloyl esters and thiolactomycins) has also been covered. Selective, safe and potentially active FASN inhibitors could be developed by: (i) having proper understanding of the function of all catalytic domains of FASN (ii) studying the upstream and downstream FASN regulators (iii) identifying cancer-specific FASN biomarkers (that are non-essential/absent in the normal healthy cells) (iv) exploring the complete protein structure of FASN, e-screening of the compounds prior to synthesis and study their ADME properties (v) predicting the selectivity based on their strong affinity at the catalytic site of FASN.
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Affiliation(s)
- Lakshmi Soukya Sai Pulla
- Department of Pharmacy, Birla Institute of Technology and Science (BITS)-Pilani, Hyderabad, India
| | - Sajeli Begum Ahil
- Department of Pharmacy, Birla Institute of Technology and Science (BITS)-Pilani, Hyderabad, India
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Khan A, Siddiqui S, Husain SA, Mazurek S, Iqbal MA. Phytocompounds Targeting Metabolic Reprogramming in Cancer: An Assessment of Role, Mechanisms, Pathways, and Therapeutic Relevance. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:6897-6928. [PMID: 34133161 DOI: 10.1021/acs.jafc.1c01173] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
The metabolism of cancer is remarkably different from that of normal cells and confers a variety of benefits, including the promotion of other cancer hallmarks. As the rewired metabolism is a near-universal property of cancer cells, efforts are underway to exploit metabolic vulnerabilities for therapeutic benefits. In the continued search for safer and effective ways of cancer treatment, structurally diverse plant-based compounds have gained substantial attention. Here, we present an extensive assessment of the role of phytocompounds in modulating cancer metabolism and attempt to make a case for the use of plant-based compounds in targeting metabolic vulnerabilities of cancer. We discuss the pharmacological interactions of phytocompounds with major metabolic pathways and evaluate the role of phytocompounds in the regulation of growth signaling and transcriptional programs involved in the metabolic transformation of cancer. Lastly, we examine the potential of these compounds in the clinical management of cancer along with limitations and challenges.
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Affiliation(s)
- Asifa Khan
- Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi 110025, India
- Department of Biosciences, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi 110025, India
| | - Shumaila Siddiqui
- Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi 110025, India
| | - Syed Akhtar Husain
- Department of Biosciences, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi 110025, India
| | - Sybille Mazurek
- Institute of Veterinary-Physiology and Biochemistry, University of Giessen, Giessen 35392, Germany
| | - Mohammad Askandar Iqbal
- Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi 110025, India
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9
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Wang Y, Yang H, Chen L, Jafari M, Tang J. Network-based modeling of herb combinations in traditional Chinese medicine. Brief Bioinform 2021; 22:6217717. [PMID: 33834186 PMCID: PMC8425426 DOI: 10.1093/bib/bbab106] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 03/10/2021] [Accepted: 03/11/2021] [Indexed: 12/12/2022] Open
Abstract
Traditional Chinese medicine (TCM) has been practiced for thousands of years for treating human diseases. In comparison to modern medicine, one of the advantages of TCM is the principle of herb compatibility, known as TCM formulae. A TCM formula usually consists of multiple herbs to achieve the maximum treatment effects, where their interactions are believed to elicit the therapeutic effects. Despite being a fundamental component of TCM, the rationale of combining specific herb combinations remains unclear. In this study, we proposed a network-based method to quantify the interactions in herb pairs. We constructed a protein–protein interaction network for a given herb pair by retrieving the associated ingredients and protein targets, and determined multiple network-based distances including the closest, shortest, center, kernel, and separation, both at the ingredient and at the target levels. We found that the frequently used herb pairs tend to have shorter distances compared to random herb pairs, suggesting that a therapeutic herb pair is more likely to affect neighboring proteins in the human interactome. Furthermore, we found that the center distance determined at the ingredient level improves the discrimination of top-frequent herb pairs from random herb pairs, suggesting the rationale of considering the topologically important ingredients for inferring the mechanisms of action of TCM. Taken together, we have provided a network pharmacology framework to quantify the degree of herb interactions, which shall help explore the space of herb combinations more effectively to identify the synergistic compound interactions based on network topology.
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Affiliation(s)
| | - Hongbin Yang
- Department of Chemistry, University of Cambridge, Cambridge, UK
| | - Linxiao Chen
- Department of Mathematics and Statistics, University of Helsinki, Finland
| | | | - Jing Tang
- Faculty of Medicine of the University of Helsinki and Group Leader of Network Pharmacology for Precision Medicine group, Finland
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10
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Chan D, Meister ML, Madhani CR, Elfakhani M, Yount ST, Ji X, Feresin RG, Wanders D, Mo H. Synergistic Impact of Xanthorrhizol and d-δ-Tocotrienol on the Proliferation of Murine B16 Melanoma Cells and Human DU145 Prostate Carcinoma Cells. Nutr Cancer 2020; 73:1746-1757. [PMID: 32811212 DOI: 10.1080/01635581.2020.1807573] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Isoprenoids suppress the mevalonate pathway that provides prenyl groups for the posttranslational modification of growth-regulating proteins. We hypothesize that xanthorrhizol and d-δ-tocotrienol synergistically suppress the growth of murine B16 melanoma and human DU145 prostate carcinoma cells. Xanthorrhizol (0-200 µmol/L; half maximal inhibitory concentration [IC50] = 65 µmol/L) and d-δ-tocotrienol (0-40 µmol/L; IC50 = 20 µmol/L) each induced a concentration-dependent suppression of the proliferation of B16 cells and concurrent cell cycle arrest at the G1 phase. A blend of 16.25 µmol/L xanthorrhizol and 10 µmol/L d-δ-tocotrienol suppressed B16 cell proliferation by 69%, an impact greater than the sum of those induced by xanthorrhizol (15%) and d-δ-tocotrienol (12%) individually. The blend cumulatively reduced the levels of cyclin-dependent kinase four and cyclin D1, key regulators of cell cycle progression at the G1 phase. The expression of RAS and extracellular signal-regulated kinase (ERK1/2) in the proliferation-stimulating RAS-RAF-MEK-ERK pathway was downregulated by the blend. Xanthorrhizol also induced a concentration-dependent suppression of the proliferation of DU145 cells with concomitant morphological changes. Isobologram confirmed the synergistic effect of xanthorrhizol and d-δ-tocotrienol on DU145 cell proliferation with combination index values ranging 0.61-0.94. Novel combinations of isoprenoids with synergistic actions may offer effective approaches in cancer prevention and therapy.
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Affiliation(s)
- Darren Chan
- Department of Nutrition, Byrdine F. Lewis College of Nursing and Health Professions, Georgia State University, Atlanta, Georgia, USA
| | - Maureen L Meister
- Department of Nutrition, Byrdine F. Lewis College of Nursing and Health Professions, Georgia State University, Atlanta, Georgia, USA
| | - Chappell R Madhani
- Department of Nutrition, Byrdine F. Lewis College of Nursing and Health Professions, Georgia State University, Atlanta, Georgia, USA
| | - Manal Elfakhani
- Department of Nutrition, Byrdine F. Lewis College of Nursing and Health Professions, Georgia State University, Atlanta, Georgia, USA
| | - Sophie T Yount
- Department of Chemistry, Georgia State University, Atlanta, Georgia, USA
| | - Xiangming Ji
- Department of Nutrition, Byrdine F. Lewis College of Nursing and Health Professions, Georgia State University, Atlanta, Georgia, USA
| | - Rafaela G Feresin
- Department of Nutrition, Byrdine F. Lewis College of Nursing and Health Professions, Georgia State University, Atlanta, Georgia, USA
| | - Desiree Wanders
- Department of Nutrition, Byrdine F. Lewis College of Nursing and Health Professions, Georgia State University, Atlanta, Georgia, USA
| | - Huanbiao Mo
- Department of Nutrition, Byrdine F. Lewis College of Nursing and Health Professions, Georgia State University, Atlanta, Georgia, USA
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Stable Isotope Tracing Metabolomics to Investigate the Metabolic Activity of Bioactive Compounds for Cancer Prevention and Treatment. Cancers (Basel) 2020; 12:cancers12082147. [PMID: 32756373 PMCID: PMC7463803 DOI: 10.3390/cancers12082147] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/29/2020] [Accepted: 07/30/2020] [Indexed: 12/11/2022] Open
Abstract
A major hallmark of cancer is the metabolic reprogramming of cancer cells to fuel tumor growth and proliferation. Various plant-derived bioactive compounds efficiently target the metabolic vulnerabilities of cancer cells and exhibit potential as emerging therapeutic agents. Due to their safety and common use as dietary components, they are also ideal for cancer prevention. However, to render their use as efficient as possible, the mechanism of action of these phytochemicals needs to be well characterized. Stable isotope tracing is an essential technology to study the molecular mechanisms by which nutraceuticals modulate and target cancer metabolism. The use of positionally labeled tracers as exogenous nutrients and the monitoring of their downstream metabolites labeling patterns enable the analysis of the specific metabolic pathway activity, via the relative production and consumption of the labeled metabolites. Although stable isotope tracing metabolomics is a powerful tool to investigate the molecular activity of bioactive compounds as well as to design synergistic nutraceutical combinations, this methodology is still underutilized. This review aims to investigate the research efforts and potentials surrounding the use of stable isotope tracing metabolomics to examine the metabolic alterations mediated by bioactive compounds in cancer.
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Fakhri S, Moradi SZ, Farzaei MH, Bishayee A. Modulation of dysregulated cancer metabolism by plant secondary metabolites: A mechanistic review. Semin Cancer Biol 2020; 80:276-305. [PMID: 32081639 DOI: 10.1016/j.semcancer.2020.02.007] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 02/08/2020] [Accepted: 02/10/2020] [Indexed: 12/12/2022]
Abstract
Several signaling pathways and basic metabolites are responsible for the control of metabolism in both normal and cancer cells. As emerging hallmarks of cancer metabolism, the abnormal activities of these pathways are of the most noticeable events in cancer. This altered metabolism expedites the survival and proliferation of cancer cells, which have attracted a substantial amount of interest in cancer metabolism. Nowadays, targeting metabolism and cross-linked signaling pathways in cancer has been a hot topic to investigate novel drugs against cancer. Despite the efficiency of conventional drugs in cancer therapy, their associated toxicity, resistance, and high-cost cause limitations in their application. Besides, considering the numerous signaling pathways cross-linked with cancer metabolism, discovery, and development of multi-targeted and safe natural compounds has been a high priority. Natural secondary metabolites have exhibited promising anticancer effects by targeting dysregulated signaling pathways linked to cancer metabolism. The present review reveals the metabolism and cross-linked dysregulated signaling pathways in cancer. The promising therapeutic targets in cancer, as well as the critical role of natural secondary metabolites for significant anticancer enhancements, have also been highlighted to find novel/potential therapeutic agents for cancer treatment.
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Affiliation(s)
- Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran
| | - Seyed Zachariah Moradi
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran; Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran
| | - Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran.
| | - Anupam Bishayee
- Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA.
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Mo H, Jeter R, Bachmann A, Yount ST, Shen CL, Yeganehjoo H. The Potential of Isoprenoids in Adjuvant Cancer Therapy to Reduce Adverse Effects of Statins. Front Pharmacol 2019; 9:1515. [PMID: 30662405 PMCID: PMC6328495 DOI: 10.3389/fphar.2018.01515] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 12/11/2018] [Indexed: 12/11/2022] Open
Abstract
The mevalonate pathway provides sterols for membrane structure and nonsterol intermediates for the post-translational modification and membrane anchorage of growth-related proteins, including the Ras, Rac, and Rho GTPase family. Mevalonate-derived products are also essential for the Hedgehog pathway, steroid hormone signaling, and the nuclear localization of Yes-associated protein and transcriptional co-activator with PDZ-binding motif, all of which playing roles in tumorigenesis and cancer stem cell function. The phosphatidylinositol-4,5-bisphosphate 3-kinase-AKT-mammalian target of rapamycin complex 1 pathway, p53 with gain-of-function mutation, and oncoprotein MYC upregulate the mevalonate pathway, whereas adenosine monophosphate-activated protein kinase and tumor suppressor protein RB are the downregulators. The rate-limiting enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), is under a multivalent regulation. Sterol regulatory element binding protein 2 mediates the sterol-controlled transcriptional downregulation of HMGCR. UbiA prenyltransferase domain-containing protein-1 regulates the ubiquitination and proteasome-mediated degradation of HMGCR, which is accelerated by 24, 25-dihydrolanosterol and the diterpene geranylgeraniol. Statins, competitive inhibitors of HMGCR, deplete cells of mevalonate-derived intermediates and consequently inhibit cell proliferation and induce apoptosis. Clinical application of statins is marred by dose-limiting toxicities and mixed outcomes on cancer risk, survival and mortality, partially resulting from the statin-mediated compensatory upregulation of HMGCR and indiscriminate inhibition of HMGCR in normal and tumor cells. Tumor HMGCR is resistant to the sterol-mediated transcriptional control; consequently, HMGCR is upregulated in cancers derived from adrenal gland, blood and lymph, brain, breast, colon, connective tissue, embryo, esophagus, liver, lung, ovary, pancreas, prostate, skin, and stomach. Nevertheless, tumor HMGCR remains sensitive to isoprenoid-mediated degradation. Isoprenoids including monoterpenes (carvacrol, L-carvone, geraniol, perillyl alcohol), sesquiterpenes (cacalol, farnesol, β-ionone), diterpene (geranylgeranyl acetone), “mixed” isoprenoids (tocotrienols), and their derivatives suppress the growth of tumor cells with little impact on non-malignant cells. In cancer cells derived from breast, colon, liver, mesothelium, prostate, pancreas, and skin, statins and isoprenoids, including tocotrienols, geraniol, limonene, β-ionone and perillyl alcohol, synergistically suppress cell proliferation and associated signaling pathways. A blend of dietary lovastatin and δ-tocotrienol, each at no-effect doses, suppress the growth of implanted murine B16 melanomas in C57BL6 mice. Isoprenoids have potential as adjuvant agents to reduce the toxicities of statins in cancer prevention or therapy.
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Affiliation(s)
- Huanbiao Mo
- Department of Nutrition, Byrdine F. Lewis College of Nursing and Health Professions, Georgia State University, Atlanta, GA, United States
| | - Rayna Jeter
- Department of Clinical Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Andrea Bachmann
- Department of Clinical Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Sophie T Yount
- Department of Chemistry, Georgia State University, Atlanta, GA, United States
| | - Chwan-Li Shen
- Department of Pathology, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Hoda Yeganehjoo
- Department of Clinical Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, United States
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Chemoinformatic Analysis of Selected Cacalolides from Psacalium decompositum (A. Gray) H. Rob. & Brettell and Psacalium peltatum (Kunth) Cass. and Their Effects on FcεRI-Dependent Degranulation in Mast Cells. Molecules 2018; 23:molecules23123367. [PMID: 30572603 PMCID: PMC6321304 DOI: 10.3390/molecules23123367] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 12/06/2018] [Accepted: 12/15/2018] [Indexed: 11/17/2022] Open
Abstract
Cacalolides are a kind of sesquiterpenoids natural compounds synthesized by Psacalium decompositum (A. Gray) H. Rob. & Brettell or Psacalium peltatum (Kunth) Cass. Antioxidant and hypoglycemic effects have been found for cacalolides such as cacalol, cacalone or maturine, however, their effects on inflammatory processes are still largely unclear. The main aim of this study was to investigate the biological activities of secondary metabolites from P. decompositum and P. peltatum through two approaches: (1) chemoinformatic and toxicoinformatic analysis based on ethnopharmacologic background; and (2) the evaluation of their potential anti-inflammatory/anti-allergic effects in bone marrow-derived mast cells by IgE/antigen complexes. The bioinformatics properties of the compounds: cacalol; cacalone; cacalol acetate and maturin acetate were evaluated through Osiris DataWarrior software and Molinspiration and PROTOX server. In vitro studies were performed to test the ability of these four compounds to inhibit antigen-dependent degranulation and intracellular calcium mobilization, as well as the production of reactive oxygen species in bone marrow-derived mast cells. Our findings showed that cacalol displayed better bioinformatics properties, also exhibited a potent inhibitory activity on IgE/antigen-dependent degranulation and significantly reduced the intracellular calcium mobilization on mast cells. These data suggested that cacalol could reduce the negative effects of the mast cell-dependent inflammatory process.
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Li B, Ma C, Zhao X, Hu Z, Du T, Xu X, Wang Z, Lin J. YaTCM: Yet another Traditional Chinese Medicine Database for Drug Discovery. Comput Struct Biotechnol J 2018; 16:600-610. [PMID: 30546860 PMCID: PMC6280608 DOI: 10.1016/j.csbj.2018.11.002] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 11/04/2018] [Accepted: 11/06/2018] [Indexed: 12/13/2022] Open
Abstract
Traditional Chinese Medicine (TCM) has a long history of widespread clinical applications, especially in East Asia, and is becoming frequently used in Western countries. However, owing to extreme complicacy in both chemical ingredients and mechanism of action, a deep understanding of TCM is still difficult. To accelerate the modernization and popularization of TCM, a single comprehensive database is required, containing a wealth of TCM-related information and equipped with complete analytical tools. Here we present YaTCM (Yet another Traditional Chinese Medicine database), a free web-based toolkit, which provides comprehensive TCM information and is furnished with analysis tools. YaTCM allows a user to (1) identify the potential ingredients that are crucial to TCM herbs through similarity search and substructure search, (2) investigate the mechanism of action for TCM or prescription through pathway analysis and network pharmacology analysis, (3) predict potential targets for TCM molecules by multi-voting chemical similarity ensemble approach, and (4) explore functionally similar herb pairs. All these functions can lead to one systematic network for visualization of TCM recipes, herbs, ingredients, definite or putative protein targets, pathways, and diseases. This web service would help in uncovering the mechanism of action of TCM, revealing the essence of TCM theory and then promoting the drug discovery process. YaTCM is freely available at http://cadd.pharmacy.nankai.edu.cn/yatcm/home.
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Affiliation(s)
- Baiqing Li
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, China
| | - Chunfeng Ma
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, China.,Platform of Pharmaceutical Intelligence, Tianjin International Joint Academy of Biomedicine, Tianjin 300457, China
| | - Xiaoyong Zhao
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, China
| | - Zhigang Hu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, China
| | - Tengfei Du
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, China
| | - Xuanming Xu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, China
| | - Zhonghua Wang
- Biodesign Center, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 West 7th Avenue, Tianjin Airport Economic Area, Tianjin 300308, China
| | - Jianping Lin
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, China.,Biodesign Center, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 West 7th Avenue, Tianjin Airport Economic Area, Tianjin 300308, China.,Platform of Pharmaceutical Intelligence, Tianjin International Joint Academy of Biomedicine, Tianjin 300457, China
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16
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Guerra AR, Duarte MF, Duarte IF. Targeting Tumor Metabolism with Plant-Derived Natural Products: Emerging Trends in Cancer Therapy. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2018; 66:10663-10685. [PMID: 30227704 DOI: 10.1021/acs.jafc.8b04104] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Recognition of neoplastic metabolic reprogramming as one of cancer's hallmarks has paved the way for developing novel metabolism-targeted therapeutic approaches. The use of plant-derived natural bioactive compounds for this endeavor is especially promising, due to their diverse structures and multiple targets. Hence, over the past decade, a growing number of studies have assessed the impact of phytochemicals on tumor cell metabolism, aiming at improving current knowledge on their mechanisms of action and, at the same time, evaluating their potential as anti-cancer metabolic modulators. In this Review, we focus on three classes of plant-derived compounds with promising anti-cancer activity-phenolic compounds, isoprenoids, and alkaloids-to describe their effects on major energetic and biosynthetic pathways of human tumor cells. Such a comprehensive and integrated account of the ability of these compounds to hit different metabolic targets is expected to contribute to the rational design and critical assessment of novel anti-cancer therapies based on natural-product-mediated metabolic reprogramming.
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Affiliation(s)
- Angela R Guerra
- Centro de Biotecnologia Agrícola e Agro-Alimentar do Alentejo (CEBAL), Instituto Politécnico de Beja , Apartado 6158 , 7801-908 Beja , Portugal
- CICECO - Instituto de Materiais de Aveiro, Departamento de Quı́mica , Universidade de Aveiro , Campus de Santiago , 3810-193 Aveiro , Portugal
| | - Maria F Duarte
- Centro de Biotecnologia Agrícola e Agro-Alimentar do Alentejo (CEBAL), Instituto Politécnico de Beja , Apartado 6158 , 7801-908 Beja , Portugal
- ICAAM - Instituto de Ciências Agrárias e Ambientais Mediterrânicas , Universidade de Évora , Pólo da Mitra, 7006-554 Évora , Portugal
| | - Iola F Duarte
- CICECO - Instituto de Materiais de Aveiro, Departamento de Quı́mica , Universidade de Aveiro , Campus de Santiago , 3810-193 Aveiro , Portugal
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17
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Zhang JS, Lei JP, Wei GQ, Chen H, Ma CY, Jiang HZ. Natural fatty acid synthase inhibitors as potent therapeutic agents for cancers: A review. PHARMACEUTICAL BIOLOGY 2016; 54:1919-1925. [PMID: 26864638 DOI: 10.3109/13880209.2015.1113995] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Revised: 09/02/2015] [Accepted: 10/24/2015] [Indexed: 06/05/2023]
Abstract
Context Fatty acid synthase (FAS) is the only mammalian enzyme to catalyse the synthesis of fatty acid. The expression level of FAS is related to cancer progression, aggressiveness and metastasis. In recent years, research on natural FAS inhibitors with significant bioactivities and low side effects has increasingly become a new trend. Herein, we present recent research progress on natural fatty acid synthase inhibitors as potent therapeutic agents. Objective This paper is a mini overview of the typical natural FAS inhibitors and their possible mechanism of action in the past 10 years (2004-2014). Method The information was collected and compiled through major databases including Web of Science, PubMed, and CNKI. Results Many natural products induce cancer cells apoptosis by inhibiting FAS expression, with fewer side effects than synthetic inhibitors. Conclusion Natural FAS inhibitors are widely distributed in plants (especially in herbs and foods). Some natural products (mainly phenolics) possessing potent biological activities and stable structures are available as lead compounds to synthesise promising FAS inhibitors.
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Affiliation(s)
- Jia-Sui Zhang
- a School of Life Science and Engineering, Southwest Jiaotong University , Chengdu , China
| | - Jie-Ping Lei
- a School of Life Science and Engineering, Southwest Jiaotong University , Chengdu , China
| | - Guo-Qing Wei
- a School of Life Science and Engineering, Southwest Jiaotong University , Chengdu , China
| | - Hui Chen
- a School of Life Science and Engineering, Southwest Jiaotong University , Chengdu , China
| | - Chao-Ying Ma
- a School of Life Science and Engineering, Southwest Jiaotong University , Chengdu , China
- b School of Medicine, Southwest Jiaotong University , Chengdu , China
| | - He-Zhong Jiang
- a School of Life Science and Engineering, Southwest Jiaotong University , Chengdu , China
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18
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Lo PK, Wolfson B, Zhou Q. Cancer stem cells and early stage basal-like breast cancer. World J Obstet Gynecol 2016; 5:150-161. [PMID: 28239564 PMCID: PMC5321620 DOI: 10.5317/wjog.v5.i2.150] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 10/21/2015] [Accepted: 01/22/2016] [Indexed: 02/05/2023] Open
Abstract
Ductal carcinoma in situ (DCIS) is a category of early stage, non-invasive breast tumor defined by the intraductal proliferation of malignant breast epithelial cells. DCIS is a heterogeneous disease composed of multiple molecular subtypes including luminal, HER2 and basal-like types, which are characterized by immunohistochemical analyses and gene expression profiling. Following surgical and radiation therapies, patients with luminal-type, estrogen receptor-positive DCIS breast tumors can benefit from adjuvant endocrine-based treatment. However, there are no available targeted therapies for patients with basal-like DCIS (BL-DCIS) tumors due to their frequent lack of endocrine receptors and HER2 amplification, rendering them potentially susceptible to recurrence. Moreover, multiple lines of evidence suggest that DCIS is a non-obligate precursor of invasive breast carcinoma. This raises the possibility that targeting precursor BL-DCIS is a promising strategy to prevent BL-DCIS patients from the development of invasive basal-like breast cancer. An accumulating body of evidence demonstrates the existence of cancer stem-like cells (CSCs) in BL-DCIS, which potentially determine the features of BL-DCIS and their ability to progress into invasive cancer. This review encompasses the current knowledge in regard to the characteristics of BL-DCIS, identification of CSCs, and their biological properties in BL-DCIS. We summarize recently discovered relevant molecular signaling alterations that promote the generation of CSCs in BL-DCIS and the progression of BL-DCIS to invasive breast cancer, as well as the influence of the tissue microenvironment on CSCs and the invasive transition. Finally, we discuss the translational implications of these findings for the prognosis and prevention of BL-DCIS relapse and progression.
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Li S, Oh YT, Yue P, Khuri FR, Sun SY. Inhibition of mTOR complex 2 induces GSK3/FBXW7-dependent degradation of sterol regulatory element-binding protein 1 (SREBP1) and suppresses lipogenesis in cancer cells. Oncogene 2016; 35:642-650. [PMID: 25893295 PMCID: PMC4615269 DOI: 10.1038/onc.2015.123] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Revised: 03/05/2015] [Accepted: 03/20/2015] [Indexed: 01/01/2023]
Abstract
Cancer cells feature increased de novo lipogenesis. Sterol regulatory element-binding protein 1 (SREBP1), when presented in its mature form (mSREBP1), enhances lipogenesis by increasing transcription of several of its target genes. Mammalian target of rapamycin (mTOR) complexes, mTORC1 and mTORC2, are master regulators of cellular survival, growth and metabolism. A role for mTORC1 in the regulation of SREBP1 activity has been suggested; however, the connection between mTORC2 and SREBP1 has not been clearly established and hence is the focus of this study. mTOR kinase inhibitors (for example, INK128), which inhibit both mTORC1 and mTORC2, decreased mSREBP1 levels in various cancer cell lines. Knockdown of rictor, but not raptor, also decreased mSREBP1. Consistently, reduced mSREBP1 levels were detected in cells deficient in rictor or Sin1 compared with parent or rictor-deficient cells with re-expression of ectopic rictor. Hence it is mTORC2 inhibition that causes mSREBP1 reduction. As a result, expression of the mSREBP1 target genes acetyl-CoA carboxylase and fatty-acid synthase was suppressed, along with suppressed lipogenesis in cells exposed to INK128. Moreover, mSREBP1 stability was reduced in cells treated with INK128 or rictor knockdown. Inhibition of proteasome, GSK3 or the E3 ubiquitin ligase, FBXW7, prevented mSREBP1 reduction induced by mTORC2 inhibition. Thus mTORC2 inhibition clearly facilitates GSK3-dependent, FBXW7-mediated mSREBP1 degradation, leading to mSREBP1 reduction. Accordingly, we conclude that mTORC2 positively regulates mSREBP1 stability and lipogenesis. Our findings reveal a novel biological function of mTORC2 in the regulation of lipogenesis and warrant further study in this direction.
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Affiliation(s)
- Shaohua Li
- Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA
- Beijing Institute of Basic Medical Sciences, Beijing, P. R. China
| | - You-Take Oh
- Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA
| | - Ping Yue
- Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA
| | - Fadlo R. Khuri
- Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA
| | - Shi-Yong Sun
- Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA
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Yeo SK, Ali AY, Hayward OA, Turnham D, Jackson T, Bowen ID, Clarkson R. β-Bisabolene, a Sesquiterpene from the Essential Oil Extract of Opoponax (Commiphora guidottii), Exhibits Cytotoxicity in Breast Cancer Cell Lines. Phytother Res 2015; 30:418-25. [PMID: 26666387 DOI: 10.1002/ptr.5543] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Revised: 10/11/2015] [Accepted: 11/21/2015] [Indexed: 11/09/2022]
Abstract
The essential oils from Commiphora species have for centuries been recognized to possess medicinal properties. Here, we performed gas chromatography-mass spectrometry on the essential oil from opoponax (Commiphora guidotti) and identified bisabolene isomers as the main constituents of this essential oil. Opoponax essential oil, a chemical component; β-bisabolene and an alcoholic analogue, α-bisabolol, were tested for their ability to selectively kill breast cancer cells. Only β-bisabolene, a sesquiterpene constituting 5% of the essential oil, exhibited selective cytotoxic activity for mouse cells (IC50 in normal Eph4: >200 µg/ml, MG1361: 65.49 µg/ml, 4T1: 48.99 µg/ml) and human breast cancer cells (IC50 in normal MCF-10A: 114.3 µg/ml, MCF-7: 66.91 µg/ml, MDA-MB-231: 98.39 µg/ml, SKBR3: 70.62 µg/ml and BT474: 74.3 µg/ml). This loss of viability was because of the induction of apoptosis as shown by Annexin V-propidium iodide and caspase-3/7 activity assay. β-bisabolene was also effective in reducing the growth of transplanted 4T1 mammary tumours in vivo (37.5% reduction in volume by endpoint). In summary, we have identified an anti-cancer agent from the essential oil of opoponax that exhibits specific cytotoxicity to both human and murine mammary tumour cells in vitro and in vivo, and this warrants further investigation into the use of β-bisabolene in the treatment of breast cancers.
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Affiliation(s)
- Syn Kok Yeo
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cathays, Cardiff, CF24 4HQ, UK
| | - Ahmed Y Ali
- School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AX, UK
| | - Olivia A Hayward
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cathays, Cardiff, CF24 4HQ, UK
| | - Daniel Turnham
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cathays, Cardiff, CF24 4HQ, UK
| | - Troy Jackson
- School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AX, UK
| | - Ifor D Bowen
- School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AX, UK
| | - Richard Clarkson
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cathays, Cardiff, CF24 4HQ, UK
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Gómez-Vidales V, Granados-Oliveros G, Nieto-Camacho A, Reyes-Solís M, Jiménez-Estrada M. Cacalol and cacalol acetate as photoproducers of singlet oxygen and as free radical scavengers, evaluated by EPR spectroscopy and TBARS. RSC Adv 2014. [DOI: 10.1039/c3ra42848f] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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Pandey PR, Xing F, Sharma S, Watabe M, Pai SK, Iiizumi-Gairani M, Fukuda K, Hirota S, Mo YY, Watabe K. Elevated lipogenesis in epithelial stem-like cell confers survival advantage in ductal carcinoma in situ of breast cancer. Oncogene 2012. [PMID: 23208501 DOI: 10.1038/onc.2012.519] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Upregulation of lipogenesis is a hallmark of cancer and blocking the lipogenic pathway is known to cause tumor cell death by apoptosis. However, the exact role of lipogenesis in tumor initiation is as yet poorly understood. We examined the expression profile of key lipogenic genes in clinical samples of ductal carcinoma in situ (DCIS) of breast cancer and found that these genes were significantly upregulated in DCIS. We also isolated cancer stem-like cells (CSCs) from DCIS.com cell line using cell surface markers (CS24(-)CD44(+)ESA(+)) and found that this cell population has significantly higher tumor-initiating ability to generate DCIS compared with the non-stem-like population. Furthermore, the CSCs showed significantly higher level of expression of all lipogenic genes than the counterpart population from non-tumorigenic breast cancer cell line, MCF10A. Importantly, ectopic expression of SREBP1, the master regulator of lipogenic genes, in MCF10A significantly enhanced lipogenesis in stem-like cells and promoted cell growth as well as mammosphere formation. Moreover, SREBP1 expression significantly increased the ability of cell survival of CSCs from MCF10AT, another cell line that is capable of generating DCIS, in mouse and in cell culture. These results indicate that upregulation of lipogenesis is a pre-requisite for DCIS formation by endowing the ability of cell survival. We have also shown that resveratrol was capable of blocking the lipogenic gene expression in CSCs and significantly suppressed their ability to generate DCIS in animals, which provides us with a strong rationale to use this agent for chemoprevention against DCIS.
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Affiliation(s)
- P R Pandey
- Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA
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Shin JA, Kim JJ, Choi ES, Shim JH, Ryu MH, Kwon KH, Park HM, Seo JY, Lee SY, Lim DW, Cho NP, Cho SD. In vitro apoptotic effects of methanol extracts ofDianthus chinensisandAcalypha australisL. targeting specificity protein 1 in human oral cancer cells. Head Neck 2012; 35:992-8. [DOI: 10.1002/hed.23072] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/18/2012] [Indexed: 12/17/2022] Open
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24
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Current world literature. Lipid metabolism. Curr Opin Lipidol 2012; 23:248-254. [PMID: 22576583 DOI: 10.1097/mol.0b013e3283543033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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25
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Cleavage mechanism and anti-tumor activity of 3,6-epidioxy-1,10-bisaboladiene isolated from edible wild plants. Bioorg Med Chem 2012; 20:3887-97. [DOI: 10.1016/j.bmc.2012.04.025] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Revised: 04/08/2012] [Accepted: 04/09/2012] [Indexed: 11/23/2022]
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