|
1
|
Liu CY, Li Z, Cheng FE, Nan Y, Li WQ. Radix Codonopsis: a review of anticancer pharmacological activities. Front Pharmacol 2025; 15:1498707. [PMID: 39840099 PMCID: PMC11747557 DOI: 10.3389/fphar.2024.1498707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 12/12/2024] [Indexed: 01/23/2025] Open
Abstract
Radix Codonopsis (Dangshen), derived from the dried root of plants in the Campanulaceae family, is a widely used Chinese herbal medicine. It is renowned for its pharmacological effects, including tonifying the middle qi, invigorating the spleen, benefiting the lungs, enhancing immunity, and nourishing the blood. Codonopsis extract is frequently incorporated into health products such as tablets and capsules, making it accessible for daily health maintenance. Additionally, it is commonly used in dietary applications like soups, teas, and porridges to nourish qi, enrich blood, and promote overall vitality. In recent years, increasing attention has been given to the anti-cancer potential of Radix Codonopsis. Studies have identified key active components such as luteolin, stigmasterol, polyacetylenes, lobetyolin, and glycitein, which exhibit anti-tumor properties through mechanisms like inhibiting cancer cell growth and proliferation, suppressing epithelial-mesenchymal transition (EMT), and inducing apoptosis. This review highlights the research progress on Radix Codonopsis, including its active constituents, anti-cancer mechanisms, and its role in the convergence of medicine and food in modern life. By doing so, it aims to provide valuable insights and references for future scientific studies and clinical applications of Radix Codonopsis.
Collapse
Affiliation(s)
- Cai-Yue Liu
- Ningxia Medical University, Ningxia of Traditional Chinese Medicine, Yinchuan, China
| | - Zheng Li
- Ningxia Medical University, Ningxia of Traditional Chinese Medicine, Yinchuan, China
| | - Fan-E. Cheng
- Ningxia Medical University, Ningxia of Traditional Chinese Medicine, Yinchuan, China
| | - Yi Nan
- Ningxia Medical University, Ningxia of Traditional Chinese Medicine, Yinchuan, China
- Key Laboratory of Ningxia Minority Medicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan, China
| | - Wei-Qiang Li
- Ningxia Medical University, Ningxia of Traditional Chinese Medicine, Yinchuan, China
- Key Laboratory of Ningxia Minority Medicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan, China
| |
Collapse
|
|
2
|
Ezelarab HAA, Ali TFS, Abbas SH, Sayed AM, Beshr EAM, Hassan HA. New antiproliferative 3-substituted oxindoles inhibiting EGFR/VEGFR-2 and tubulin polymerization. Mol Divers 2024; 28:563-580. [PMID: 36790582 PMCID: PMC11070402 DOI: 10.1007/s11030-023-10603-z] [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: 12/03/2022] [Accepted: 01/06/2023] [Indexed: 02/16/2023]
Abstract
New 3-substituted oxindole derivatives were designed and synthesized as antiproliferative agents. The antiproliferative activity of compounds 6a-j was evaluated against 60 NCI cell lines. Among these tested compounds, compounds 6f and 6g showed remarkable antiproliferative activity, specifically against leukemia and breast cancer cell lines. Compound 6f was the most promising antiproliferative agent against MCF-7 (human breast cancer) with an IC50 value of 14.77 µM compared to 5-fluorouracil (5FU) (IC50 = 2.02 µM). Notably, compound 6f hampered receptor tyrosine EGFR fundamentally with an IC50 value of 1.38 µM, compared to the reference sunitinib with an IC50 value of 0.08 µM. Moreover, compound 6f afforded anti-tubulin polymerization activity with an IC50 value of 7.99 µM as an outstanding observable activity compared with the reference combretastatin A4 with an IC50 value of 2.64 µM. In silico molecular-docking results of compound 6f in the ATP-binding site of EGFR agreed with the in vitro results. Besides, the investigation of the physicochemical properties of compound 6f via the egg-boiled method clarified good lipophilicity, GIT absorption, and blood-brain barrier penetration properties.
Collapse
Affiliation(s)
- Hend A A Ezelarab
- Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519-Mini, Minia, Egypt
| | - Taha F S Ali
- Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519-Mini, Minia, Egypt.
| | - Samar H Abbas
- Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519-Mini, Minia, Egypt.
| | - Ahmed M Sayed
- Department of Pharmacognosy, Faculty of Pharmacy, Nahda University, Beni-Suef, 62513, Egypt
| | - Eman A M Beshr
- Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519-Mini, Minia, Egypt.
| | - Heba A Hassan
- Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519-Mini, Minia, Egypt
| |
Collapse
|
|
3
|
Whaley AO, Whaley AK, Toporkova V, Fock E, Rukoyatkina N, Smirnov SN, Satimov GB, Abduraxmanov BA, Gambaryan S. Bracteatinine and isogroenlandicine, two new isoquinoline alkaloids isolated from Corydalis bracteata and their effect on platelet function. Fitoterapia 2023; 171:105697. [PMID: 37797794 DOI: 10.1016/j.fitote.2023.105697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 09/29/2023] [Accepted: 10/02/2023] [Indexed: 10/07/2023]
Abstract
Two previously undescribed isoquinoline alkaloids, bracteatinine (1) and isogroenlandicine (2), together with four known alkaloids - coptisine (3), dehydrocorydaline (4), palmatine (5) and jatrorrhizine (6) were isolated from the aerial parts of Corydalis bracteata (Steph. Ex. Willd.) Pers. The structures of the compounds were elucidated using 1D and 2D NMR data along with HRESI-MS. The isolated new compounds bracteatinine and isogroenlandicine are close structural derivatives and isomers of corgoine and groenlandicine, respectively. Bracteatinine is also notable, being a representative of the rare 2-benzylisoquinoline alkaloids. Many natural products isolated from different plants are used as adjuvants, in addition to standard chemotherapy, in treatment of different cancers. Cancer-associated thrombosis remains a common complication and leading cause of mortality for cancer patients. Because platelets play the key role in thrombotic complications, we investigated effects of the isolated alkaloids 1-6 on platelet reactivity and showed that they did not significantly affect platelet function.
Collapse
Affiliation(s)
- Anastasiia O Whaley
- Saint Petersburg State Chemical Pharmaceutical University, Saint Petersburg, Department of Pharmacognosy, 14 Prof. Popov, 197376 Saint Petersburg, Russian Federation; Laboratory of Cellular Mechanisms of Blood Homeostasis, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 44 Torez avenue, 194223 Saint Petersburg, Russia.
| | - Andrei K Whaley
- Saint Petersburg State Chemical Pharmaceutical University, Saint Petersburg, Department of Pharmacognosy, 14 Prof. Popov, 197376 Saint Petersburg, Russian Federation
| | - Valeria Toporkova
- Saint Petersburg State Chemical Pharmaceutical University, Saint Petersburg, Department of Pharmacognosy, 14 Prof. Popov, 197376 Saint Petersburg, Russian Federation
| | - Ekaterina Fock
- Laboratory of Cellular Mechanisms of Blood Homeostasis, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 44 Torez avenue, 194223 Saint Petersburg, Russia
| | - Natalia Rukoyatkina
- Laboratory of Cellular Mechanisms of Blood Homeostasis, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 44 Torez avenue, 194223 Saint Petersburg, Russia
| | - Sergey N Smirnov
- Saint Petersburg State University, Universitetskii pr. 26, St. Petersburg 198504, Russian Federation
| | - Gayrat B Satimov
- S.Yu. Yunusov Institute of the Chemistry of Plant Substances, Sciences Academy of the Republic of Uzbekistan, 77, Mirzo Ulugbek st., Tashkent, 100170, Uzbekistan
| | - Baxtiyar A Abduraxmanov
- S.Yu. Yunusov Institute of the Chemistry of Plant Substances, Sciences Academy of the Republic of Uzbekistan, 77, Mirzo Ulugbek st., Tashkent, 100170, Uzbekistan
| | - Stepan Gambaryan
- Laboratory of Cellular Mechanisms of Blood Homeostasis, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 44 Torez avenue, 194223 Saint Petersburg, Russia
| |
Collapse
|
|
4
|
Hegde M, Girisa S, Naliyadhara N, Kumar A, Alqahtani MS, Abbas M, Mohan CD, Warrier S, Hui KM, Rangappa KS, Sethi G, Kunnumakkara AB. Natural compounds targeting nuclear receptors for effective cancer therapy. Cancer Metastasis Rev 2023; 42:765-822. [PMID: 36482154 DOI: 10.1007/s10555-022-10068-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 11/03/2022] [Indexed: 12/13/2022]
Abstract
Human nuclear receptors (NRs) are a family of forty-eight transcription factors that modulate gene expression both spatially and temporally. Numerous biochemical, physiological, and pathological processes including cell survival, proliferation, differentiation, metabolism, immune modulation, development, reproduction, and aging are extensively orchestrated by different NRs. The involvement of dysregulated NRs and NR-mediated signaling pathways in driving cancer cell hallmarks has been thoroughly investigated. Targeting NRs has been one of the major focuses of drug development strategies for cancer interventions. Interestingly, rapid progress in molecular biology and drug screening reveals that the naturally occurring compounds are promising modern oncology drugs which are free of potentially inevitable repercussions that are associated with synthetic compounds. Therefore, the purpose of this review is to draw our attention to the potential therapeutic effects of various classes of natural compounds that target NRs such as phytochemicals, dietary components, venom constituents, royal jelly-derived compounds, and microbial derivatives in the establishment of novel and safe medications for cancer treatment. This review also emphasizes molecular mechanisms and signaling pathways that are leveraged to promote the anti-cancer effects of these natural compounds. We have also critically reviewed and assessed the advantages and limitations of current preclinical and clinical studies on this subject for cancer prophylaxis. This might subsequently pave the way for new paradigms in the discovery of drugs that target specific cancer types.
Collapse
Affiliation(s)
- Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India
| | - Nikunj Naliyadhara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India
| | - Aviral Kumar
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha, 61421, Saudi Arabia
- BioImaging Unit, Space Research Centre, University of Leicester, Michael Atiyah Building, Leicester, LE1 7RH, UK
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha, 61421, Saudi Arabia
- Electronics and Communications Department, College of Engineering, Delta University for Science and Technology, 35712, Gamasa, Egypt
| | | | - Sudha Warrier
- Division of Cancer Stem Cells and Cardiovascular Regeneration, School of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, 560065, India
- Cuor Stem Cellutions Pvt Ltd, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, 560065, India
| | - Kam Man Hui
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore, 169610, Singapore
| | | | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India.
| |
Collapse
|
|
5
|
Sewariya S, Sehrawat H, Mishra N, Singh MB, Singh P, Kukreti S, Chandra R. Comparative assessment of 9-bromo noscapine ionic liquid and noscapine: Synthesis, in-vitro studies plus computational & biophysical evaluation with human hemoglobin. Int J Biol Macromol 2023; 247:125791. [PMID: 37442512 DOI: 10.1016/j.ijbiomac.2023.125791] [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: 04/15/2023] [Revised: 06/23/2023] [Accepted: 07/09/2023] [Indexed: 07/15/2023]
Abstract
Noscapine is a proficient anticancer drug active against wide variety of tumors including lung cancer. Over time, several noscapine analogues have been assessed to maximize the efficiency of the drug, amongst which 9-bromo noscapine remains one of the most potent analogues till date. In the present work, we have synthesized 9-bromo noscapine ionic liquid [9-Br-Nos]IBr2, an active pharmaceutical ingredient based ionic liquid (API-IL) to address the existing issues of solubility and targeted drug delivery in the parent alkaloid as well as the synthesized analogues. We have devised a novel two-step synthesis route (first-ever ionic to ionic bromination) to obtain the desired [9-Br-Nos]IBr2 which is advantageous to its organic analogue in terms of increased solubility, lesser reaction time and better yield. Furthermore, we have compared 9-bromo noscapine ionic liquid with noscapine based on its binding interaction with human hemoglobin (Hb) studied via computational along with spectroscopic studies, and bioactivity against non-small cell lung cancer. We inferred formation of a complex between [9-Br-Nos]IBr2 and Hb in the stoichiometric ratio of 1:1, similar to noscapine. At 298 K, [9-Br-Nos]IBr2-Hb binding was found to exhibit Kb and ∆G of 36,307 M-1 and -11.5 KJmol-1, respectively, as compared to 159 M-1 and -12.5 KJmol-1 during Noscapine-Hb binding. This indicates a more stronger and viable interaction between [9-Br-Nos]IBr2 and Hb than the parent compound. From computational studies, the observed higher stability of [9-Br-Nos]I and better binding affinity with Hb with a binding energy of -91.75 kcalmol-1 supported the experimental observations. In the same light, novel [9-Br-Nos]IBr2 was found to exhibit an IC50 = 95.02 ± 6.32 μM compared to IC50 = 128.82 ± 2.87 μM for noscapine on A549 (non-small lung cancer) cell line at 48 h. Also, the desired ionic liquid proved to be more cytotoxic inducing a mortality rate of 87 % relative to 66 % evoked by noscapine at concentrations of 200 μM after 72 h.
Collapse
Affiliation(s)
- Shubham Sewariya
- Department of Chemistry, University of Delhi, Delhi 110007, India; Maharaja Surajmal Brij University, Rajasthan - 321201, India
| | - Hitesh Sehrawat
- Department of Chemistry, University of Delhi, Delhi 110007, India
| | - Nistha Mishra
- Department of Chemistry, University of Delhi, Delhi 110007, India
| | - Madhur Babu Singh
- Atma Ram Sanatan Dharma College, University of Delhi, Delhi 110007, India
| | - Prashant Singh
- Atma Ram Sanatan Dharma College, University of Delhi, Delhi 110007, India
| | - Shrikant Kukreti
- Department of Chemistry, University of Delhi, Delhi 110007, India
| | - Ramesh Chandra
- Department of Chemistry, University of Delhi, Delhi 110007, India; Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi 110007, India; Institute of Nano Medical Sciences, University of Delhi, Delhi 110007, India; Maharaja Surajmal Brij University, Rajasthan - 321201, India.
| |
Collapse
|
|
6
|
Wu KJ, Liu PP, Chen MY, Zhou MX, Liu X, Yang Q, Xu L, Gong Z. The Hepatoprotective Effect of Leonurine Hydrochloride Against Alcoholic Liver Disease Based on Transcriptomic and Metabolomic Analysis. Front Nutr 2022; 9:904557. [PMID: 35873419 PMCID: PMC9301321 DOI: 10.3389/fnut.2022.904557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 06/06/2022] [Indexed: 11/13/2022] Open
Abstract
Excessive alcohol consumption can eventually progress to alcoholic liver disease (ALD). The underlying mechanism of ALD toxicity is primarily associated with oxidative damage. Many alkaloids have been reported to possess potential antioxidative efficacy, while the mechanism of their hepatoprotective activity against ALD is still not clear. In this study, eight alkaloids were selected from a monomer library of Traditional Chinese Medicine and evaluated for their antioxidant activity against ALD by the evaluation of Glutathione (GSH) and Malondialdehyde (MDA). The result suggested that Leonurine hydrochloride (LH) was a potent antioxidant that could reduce alcoholic liver damage. To further investigate the underlying mechanism of LH against ALD, the molecular pathway induced by LH was identified by RNA-seq analyses. Transcriptome data revealed the principal mechanism for the protective effect of LH against ALD might be attributed to the differentially expressed genes (DEGs) of PI3K-AKT, AMPK, and HIF-1 signaling pathways involved in the lipid metabolism. Given the hepatoprotective mechanism of LH is involved in lipid metabolism, the lipid metabolism induced by LH was further analyzed by UHPLC-MS/MS. Metabolome analysis indicated that LH significantly regulated glycerophospholipid metabolism including phosphatidylcholine, 1-acyl-sn-glycero-3-phosphocholine, phosphatidylethanolamine and 1-acyl-sn-glycero-3-phosphoethanolamine in the liver. Overall, this study revealed that the hepatoprotective mechanism of LH against alcoholic liver damage might be associated with the genes involved in glycerophospholipid metabolism.
Collapse
|
|
7
|
Abookleesh FL, Al-Anzi BS, Ullah A. Potential Antiviral Action of Alkaloids. Molecules 2022; 27:903. [PMID: 35164173 PMCID: PMC8839337 DOI: 10.3390/molecules27030903] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 01/24/2022] [Accepted: 01/26/2022] [Indexed: 12/30/2022] Open
Abstract
Viral infections and outbreaks have become a major concern and are one of the main causes of morbidity and mortality worldwide. The development of successful antiviral therapeutics and vaccines remains a daunting challenge. The discovery of novel antiviral agents is a public health emergency, and extraordinary efforts are underway globally to identify safe and effective treatments for different viral diseases. Alkaloids are natural phytochemicals known for their biological activities, many of which have been intensively studied for their broad-spectrum of antiviral activities against different DNA and RNA viruses. The purpose of this review was to summarize the evidence supporting the efficacy of the antiviral activity of plant alkaloids at half-maximum effective concentration (EC50) or half-maximum inhibitory concentration (IC50) below 10 μM and describe the molecular sites most often targeted by natural alkaloids acting against different virus families. This review highlights that considering the devastating effects of virus pandemics on humans, plants, and animals, the development of high efficiency and low-toxicity antiviral drugs targeting these viruses need to be developed. Furthermore, it summarizes the current research status of alkaloids as the source of antiviral drug development, their structural characteristics, and antiviral targets. Overall, the influence of alkaloids at the molecular level suggests a high degree of specificity which means they could serve as potent and safe antiviral agents waiting for evaluation and exploitation.
Collapse
Affiliation(s)
- Frage L. Abookleesh
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2R3, Canada;
| | - Bader S. Al-Anzi
- Department of Environment Technologies and Management, Kuwait University, P.O. Box 5969, Kuwait City 13060, Kuwait;
| | - Aman Ullah
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2R3, Canada;
| |
Collapse
|
|
8
|
Ali Reza ASM, Nasrin MS, Hossen MA, Rahman MA, Jantan I, Haque MA, Sobarzo-Sánchez E. Mechanistic insight into immunomodulatory effects of food-functioned plant secondary metabolites. Crit Rev Food Sci Nutr 2021; 63:5546-5576. [PMID: 34955042 DOI: 10.1080/10408398.2021.2021138] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Medicinally important plant-foods offer a balanced immune function, which is essential for protecting the body against antigenic invasion, mainly by microorganisms. Immunomodulators play pivotal roles in supporting immune function either suppressing or stimulating the immune system's response to invading pathogens. Among different immunomodulators, plant-based secondary metabolites have emerged as high potential not only for immune defense but also for cellular immunoresponsiveness. These natural immunomodulators can be developed into safer alternatives to the clinically used immunosuppressants and immunostimulant cytotoxic drugs which possess serious side effects. Many plants of different species have been reported to possess strong immunomodulating properties. The immunomodulatory effects of plant extracts and their bioactive metabolites have been suggested due to their diverse mechanisms of modulation of the complex immune system and their multifarious molecular targets. Phytochemicals such as alkaloids, flavonoids, terpenoids, carbohydrates and polyphenols have been reported as responsible for the immunomodulatory effects of several medicinal plants. This review illustrates the potent immunomodulatory effects of 65 plant secondary metabolites, including dietary compounds and their underlying mechanisms of action on cellular and humoral immune functions in in vitro and in vivo studies. The clinical potential of some of the compounds to be used for various immune-related disorders is highlighted.
Collapse
Affiliation(s)
- A S M Ali Reza
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong, Bangladesh
- Department of Pharmacy, International Islamic University Chittagong, Chittagong, Bangladesh
| | - Mst Samima Nasrin
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong, Bangladesh
- Department of Pharmacy, International Islamic University Chittagong, Chittagong, Bangladesh
| | - Md Amjad Hossen
- Department of Pharmacy, International Islamic University Chittagong, Chittagong, Bangladesh
| | - Md Atiar Rahman
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong, Bangladesh
| | - Ibrahim Jantan
- Institute of Systems Biology (INBIOSIS), Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia
| | - Md Areeful Haque
- Department of Pharmacy, International Islamic University Chittagong, Chittagong, Bangladesh
- Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | | |
Collapse
|
|
9
|
Tilaoui M, Ait Mouse H, Zyad A. Update and New Insights on Future Cancer Drug Candidates From Plant-Based Alkaloids. Front Pharmacol 2021; 12:719694. [PMID: 34975465 PMCID: PMC8716855 DOI: 10.3389/fphar.2021.719694] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 11/23/2021] [Indexed: 02/06/2023] Open
Abstract
Cancer is a complex multifactorial disease that results from alterations in many physiological and biochemical functions. Over the last few decades, it has become clear that cancer cells can acquire multidrug resistance to conventional anticancer drugs, resulting in tumor relapse. Thus, there is a continuous need to discover new and effective anticancer drugs. Natural products from plants have served as a primary source of cancer drugs and continue to provide new plant-derived anticancer drugs. The present review describes plant-based alkaloids, which have been reported as active or potentially active in cancer treatment within the past 4 years (2017-2020), both in preclinical research and/or in clinical trials. In addition, recent insights into the possible molecular mechanism of action of alkaloid prodrugs naturally present in plants are also highlighted.
Collapse
Affiliation(s)
- Mounir Tilaoui
- Experimental Oncology and Natural Substances Team, Cellular and Molecular Immuno-pharmacology, Faculty of Sciences and Technology, Sultan Moulay Slimane University, Beni-Mellal, Morocco
| | | | | |
Collapse
|
|
10
|
Patel A, Vanecha R, Patel J, Patel D, Shah U, Bambharoliya T. Development of Natural Bioactive Alkaloids: Anticancer perspective. Mini Rev Med Chem 2021; 22:200-212. [PMID: 34254913 DOI: 10.2174/1389557521666210712111331] [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: 10/07/2020] [Revised: 01/11/2021] [Accepted: 04/20/2021] [Indexed: 11/22/2022]
Abstract
Cancer is a frightful disease that still poses a 'nightmare' worldwide, causing millions of casualties annually due to one of the human race's most significant healthcare challenges that requires a pragmatic treatment strategy. However, plants and plant-derived products revolutionize the field as they are quick, cleaner, eco-friendly, low-cost, effective, and less toxic than conventional treatment methods. Plants are repositories for new chemical entities and have a promising cancer research path, supplying 60% of the anticancer agents currently used. Alkaloids are important chemical compounds that serve as a rich reservoir for drug discovery and development. However, some alkaloids derived from natural herbs display anti-proliferation and antimetastatic activity on different forms of cancer, both in vitro and in vivo. Alkaloids have also been widely formulated as anticancer medications, such as camptothecin and vinblastine. Still, more research and clinical trials are required before final recommendations can be made on specific alkaloids. This review focuses on the naturally-derived bioactive alkaloids with prospective anticancer properties based on the information in the literature.
Collapse
Affiliation(s)
- Ashish Patel
- Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, CHARUSAT-Campus, Changa-388421, Anand, Gujarat, India
| | - Ravi Vanecha
- Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, CHARUSAT-Campus, Changa-388421, Anand, Gujarat, India
| | - Jay Patel
- Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, CHARUSAT-Campus, Changa-388421, Anand, Gujarat, India
| | - Divy Patel
- Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, CHARUSAT-Campus, Changa-388421, Anand, Gujarat, India
| | - Umang Shah
- Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, CHARUSAT-Campus, Changa-388421, Anand, Gujarat, India
| | | |
Collapse
|
|
11
|
Bhaktavalsala Suresh A, Kilingar Nadumane V. The metabolite 5-methyl-1,3-benzenediol and its derivative methyl-2,4-dihydroxy-6-methylbenzoate from the lichen Parmotrema tinctorum with potent apoptotic and anti-angiogenesis effects. 3 Biotech 2021; 11:346. [PMID: 34178568 PMCID: PMC8212346 DOI: 10.1007/s13205-021-02883-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Accepted: 06/06/2021] [Indexed: 01/21/2023] Open
Abstract
Nature has been a rich resource of novel anticancer agents, one such source being lichens, which represent the symbiosis between algae and fungi with diverse range of secondary metabolites having therapeutic significance. With respect to this, the present study evaluates the in vitro apoptogenic profile of secondary metabolites from the lichen Parmotrema tinctorum towards cancer cell lines. Treatment with TLC-purified fraction 1 from P. tinctorum resulted in significant reduction in the cell viabilities of cancer cells with IC50 values ranging between 1.2 and 12.8 μg/ml. The potential anticancer effect of the bioactive fraction was further supported by Trypan blue cell viability, LDH and DNA fragmentation assays. At the cellular level, induction of apoptosis was confirmed through the activation of the caspase cascade and apoptotic cells accumulating in the Sub-G1 phase of cell cycle. Angiogenesis being one of the major characteristics needed for cancer growth, the ability of the lichen fraction to inhibit angiogenesis was checked through in ovo Yolk Sac Membrane (YSM) assay and was found to be significant. The study also verified the non-toxic nature of the bioactive fraction towards normal human peripheral lymphocytes. HPLC analysis and GC-MS characterisation of the bioactive fraction indicated the presence of 5-methyl-1,3-benzenediol and its derivative methyl-2,4-dihydroxy-6-methylbenzoate.
Collapse
Affiliation(s)
- Ashrini Bhaktavalsala Suresh
- Department of Biotechnology, School of Sciences, Block-I, Jain (Deemed-to-be-University), #18/3, 9th Main, III Block, Jayanagar, Bangalore, 560 011 India
| | - Varalakshmi Kilingar Nadumane
- Department of Biotechnology, School of Sciences, Block-I, Jain (Deemed-to-be-University), #18/3, 9th Main, III Block, Jayanagar, Bangalore, 560 011 India
| |
Collapse
|
|
12
|
Diversity in Chemical Structures and Biological Properties of Plant Alkaloids. Molecules 2021; 26:molecules26113374. [PMID: 34204857 PMCID: PMC8199754 DOI: 10.3390/molecules26113374] [Citation(s) in RCA: 148] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 04/23/2021] [Accepted: 04/23/2021] [Indexed: 12/13/2022] Open
Abstract
Phytochemicals belonging to the group of alkaloids are signature specialized metabolites endowed with countless biological activities. Plants are armored with these naturally produced nitrogenous compounds to combat numerous challenging environmental stress conditions. Traditional and modern healthcare systems have harnessed the potential of these organic compounds for the treatment of many ailments. Various chemical entities (functional groups) attached to the central moiety are responsible for their diverse range of biological properties. The development of the characterization of these plant metabolites and the enzymes involved in their biosynthesis is of an utmost priority to deliver enhanced advantages in terms of biological properties and productivity. Further, the incorporation of whole/partial metabolic pathways in the heterologous system and/or the overexpression of biosynthetic steps in homologous systems have both become alternative and lucrative methods over chemical synthesis in recent times. Moreover, in-depth research on alkaloid biosynthetic pathways has revealed numerous chemical modifications that occur during alkaloidal conversions. These chemical reactions involve glycosylation, acylation, reduction, oxidation, and methylation steps, and they are usually responsible for conferring the biological activities possessed by alkaloids. In this review, we aim to discuss the alkaloidal group of plant specialized metabolites and their brief classification covering major categories. We also emphasize the diversity in the basic structures of plant alkaloids arising through enzymatically catalyzed structural modifications in certain plant species, as well as their emerging diverse biological activities. The role of alkaloids in plant defense and their mechanisms of action are also briefly discussed. Moreover, the commercial utilization of plant alkaloids in the marketplace displaying various applications has been enumerated.
Collapse
|
|
13
|
Zhang G, Zhang C, Sun J, Xiong Y, Wang L, Chen D. Phytochemical Regulation of RNA in Treating Inflammatory Bowel Disease and Colon Cancer: Inspirations from Cell and Animal Studies. J Pharmacol Exp Ther 2021; 376:464-472. [PMID: 33397676 DOI: 10.1124/jpet.120.000354] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 12/30/2020] [Indexed: 12/14/2022] Open
Abstract
Recent studies suggest an important role for RNA, especially noncoding RNA, in inflammatory bowel disease (IBD) and colon cancer. Drug development based on regulating RNA rather than protein is a promising new area. Phytochemicals are naturally occurring plant-derived compounds with chemical diversity, biologic activity, easy availability, and low toxicity. Many phytochemicals have been shown to exert protective effects on IBD and colon cancer through modulation of RNAs. The aim of this study was to summarize the advancements of phytochemicals in regulating RNA for the treatment of IBD and colon cancer. This review involves many phytochemicals, including polyphenols, flavones, and alkaloids, which can influence various types of RNAs, including microRNA, long noncoding RNA, as well as messenger RNA, by influencing a variety of upstream molecules or regulating epigenetic processes. The limitation for many current studies is that the specific mechanisms of phytochemicals regulating RNA have not been fully uncovered. Accompanied by more identified functions of RNAs, especially noncoding RNA functions, the screening of RNA-regulating phytochemicals has presented challenges as well as opportunities for the prevention and treatment of IBD and colon cancer. SIGNIFICANCE STATEMENT: Noncoding RNAs, which constitute the majority of the human transcriptional genome, play a key role in the disease state and are considered as important therapeutic targets in inflammatory bowel disease (IBD) and colon cancer. Recent studies have shown that phytochemicals regulate the expression of many noncoding RNAs involved in IBD and colon cancer. Therefore, identifying the specific molecular mechanism of phytochemicals regulating noncoding RNA in disease models may result in novel and effective therapeutic opportunities.
Collapse
Affiliation(s)
- Guolin Zhang
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian City, China (G.Z., C.Z., J.S., L.W., D.C.) and Central Laboratory, First Affiliated Hospital of Dalian Medical University, Dalian, China (Y.X.)
| | - Chi Zhang
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian City, China (G.Z., C.Z., J.S., L.W., D.C.) and Central Laboratory, First Affiliated Hospital of Dalian Medical University, Dalian, China (Y.X.)
| | - Jia'ao Sun
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian City, China (G.Z., C.Z., J.S., L.W., D.C.) and Central Laboratory, First Affiliated Hospital of Dalian Medical University, Dalian, China (Y.X.)
| | - Yongjian Xiong
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian City, China (G.Z., C.Z., J.S., L.W., D.C.) and Central Laboratory, First Affiliated Hospital of Dalian Medical University, Dalian, China (Y.X.)
| | - Liang Wang
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian City, China (G.Z., C.Z., J.S., L.W., D.C.) and Central Laboratory, First Affiliated Hospital of Dalian Medical University, Dalian, China (Y.X.)
| | - Dapeng Chen
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian City, China (G.Z., C.Z., J.S., L.W., D.C.) and Central Laboratory, First Affiliated Hospital of Dalian Medical University, Dalian, China (Y.X.)
| |
Collapse
|
|
14
|
Khan YH, Uttra AM, Qasim S, Mallhi TH, Alotaibi NH, Rasheed M, Alzarea AI, Iqbal MS, Alruwaili NK, Khan SUD, Alanazi AS. Potential Role of Phytochemicals Against Matrix Metalloproteinase Induced Breast Cancer; An Explanatory Review. Front Chem 2021; 8:592152. [PMID: 33520928 PMCID: PMC7843438 DOI: 10.3389/fchem.2020.592152] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 11/20/2020] [Indexed: 12/02/2022] Open
Abstract
World Health Organization (WHO) estimated breast cancer as one of the most prevailed malignancy around the globe. Its incident cases are gradually increasing every year, resulting in considerable healthcare burden. The heterogeneity of breast cancer accounts for its differential molecular subtyping, interaction between pathways, DNA damaging, and chronic inflammation. Matrix metalloproteinases (MMPs) are a group of zinc-containing, calcium dependent endopeptidases which play a substantial role in breast carcinogenesis through several mechanisms. These mechanisms include remodeling of extracellular matrix (ECM), cell proliferation, and angiogenesis which promote metastasis and result in tumor progression. In this context, compounds bearing MMP inhibitory potential can serve as potent therapeutic agents in combating MMPs provoked breast cancer. Current systematic review aimed to encompass the details of potent natural lead molecules that can deter MMPs-provoked breast cancer. Following the critical appraisal of literature, a total of n = 44 studies that explored inhibitory effect of phytochemicals on MMPs were included in this review. These phytoconstituents include alkaloids (n = 11), flavonoids (n = 23), terpenoids (n = 7), and lignans (n = 2). The most common inhibitory methods used to evaluate efficacy of these phytoconstituents included Gelatin Zymography, Western Blotting, and real time polymerase chain reaction (RT-PCR) analysis. Moreover, current limitations, challenges, and future directions of using such compounds have been critically discussed. This review underscores the potential implications of phytochemicals in the management of breast cancer which could lessen the growing encumbrance of disease.
Collapse
Affiliation(s)
- Yusra Habib Khan
- Department of Clinical Pharmacy, College of Pharmacy, Jouf University, Sakakah, Saudi Arabia
| | | | - Sumera Qasim
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakakah, Saudi Arabia
| | - Tauqeer Hussain Mallhi
- Department of Clinical Pharmacy, College of Pharmacy, Jouf University, Sakakah, Saudi Arabia
| | - Nasser Hadal Alotaibi
- Department of Clinical Pharmacy, College of Pharmacy, Jouf University, Sakakah, Saudi Arabia
| | - Maria Rasheed
- Institute of Pharmacy, Lahore College for Women University, Lahore, Pakistan
| | | | - Muhammad Shahid Iqbal
- Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | | | - Salah-Ud-Din Khan
- Department of Biochemistry, College of Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Abdullah Salah Alanazi
- Department of Clinical Pharmacy, College of Pharmacy, Jouf University, Sakakah, Saudi Arabia
| |
Collapse
|
|
15
|
Zhu T, Wang SH, Li D, Wang SY, Liu X, Song J, Wang YT, Zhang SY. Progress of tubulin polymerization activity detection methods. Bioorg Med Chem Lett 2021; 37:127698. [PMID: 33468346 DOI: 10.1016/j.bmcl.2020.127698] [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: 08/18/2020] [Revised: 11/05/2020] [Accepted: 11/14/2020] [Indexed: 12/13/2022]
Abstract
Tubulin, an important target in tumor therapy, is one of the hotspots in the field of antineoplastic drugs in recent years, and it is of great significance to design and screen new inhibitors for this target. Natural products and chemical synthetic drugs are the main sources of tubulin inhibitors. However, due to the variety of compound structure types, it has always been difficult for researchers to screen out polymerization inhibitors with simple operation, high efficiency and low cost. A large number of articles have reported the screening methods of tubulin inhibitors and their biological activity. In this article, the biological activity detection methods of tubulin polymerization inhibitors are reviewed. Thus, it provides a theoretical basis for the further study of tubulin polymerization inhibitors and the selection of methods for tubulin inhibitors.
Collapse
Affiliation(s)
- Ting Zhu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Sheng-Hui Wang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Dong Li
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Shu-Yu Wang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Xu Liu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Jian Song
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
| | - Ya-Ting Wang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
| | - Sai-Yang Zhang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou 450001, China.
| |
Collapse
|
|
16
|
Selvaraj J, Vishnupriya V, Sardar H, Balakrishna JP, Rex J, Mohan SK, Vijayalakshmi P, Ponnulakshmi R. Molecular docking analysis of COX-2 for potential inhibitors. Bioinformation 2020; 16:753-758. [PMID: 34675461 PMCID: PMC8503776 DOI: 10.6026/97320630016753] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/21/2020] [Accepted: 08/23/2020] [Indexed: 11/23/2022] Open
Abstract
Cyclooxygenase-2 (COX-2) is liked with breast cancer. Therefore, it is of interest to design and develop new yet effective compounds against COX-2 from medicinal plants such as the natural alkaloid compounds. We document the optimal binding features of aristolochicacid with COX-2 protein for further consideration.
Collapse
Affiliation(s)
- Jayaraman Selvaraj
- Department of Biochemistry, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai - 600 077, India
| | - Veeraraghavan Vishnupriya
- Department of Biochemistry, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai - 600 077, India
| | - Hussain Sardar
- Department of Biotechnology, Government Science College, Chitradurga-577501, Karnataka, India
| | - Janardhana Papayya Balakrishna
- Department of Stem Cell Biology, Stellixir Biotech Pvt Ltd, No.V-31, 2nd floor, 10th Main Road, Peenya 2nd Stage Industrial Area, Bangalore - 560058, Karnataka, India
| | - Josephine Rex
- Department of Biochemistry, Panimalar Medical College Hospital & Research Institute, Varadharajapuram, Poonamallee, Chennai - 600 123, India
| | - Surapaneni Krishna Mohan
- Department of Biochemistry and Department of Clinical Skills & Simulation, Panimalar Medical College Hospital & Research Institute, Varadharajapuram, Poonamallee, Chennai - 600 123, India
| | - Periyasamy Vijayalakshmi
- PG & Research Department of Biotechnology & Bioinformatics, Holy Cross College (Autonomous), Trichy- 620002, Tamil Nadu, India
| | - Rajagopal Ponnulakshmi
- Central Research Laboratory, Meenakshi Academy of Higher Education and Research (Deemed to be University), Chennai-600 078, India
| |
Collapse
|
|
17
|
Muniyandi K, George B, Parimelazhagan T, Abrahamse H. Role of Photoactive Phytocompounds in Photodynamic Therapy of Cancer. Molecules 2020; 25:E4102. [PMID: 32911753 PMCID: PMC7570746 DOI: 10.3390/molecules25184102] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/26/2020] [Accepted: 09/04/2020] [Indexed: 01/10/2023] Open
Abstract
Cancer is one of the greatest life-threatening diseases conventionally treated using chemo- and radio-therapy. Photodynamic therapy (PDT) is a promising approach to eradicate different types of cancers. PDT requires the administration of photosensitisers (PSs) and photoactivation using a specific wavelength of light in the presence of molecular oxygen. This photoactivation exerts an anticancer effect via apoptosis, necrosis, and autophagy of cancer cells. Recently, various natural compounds that exhibit photosensitising potentials have been identified. Photoactive substances derived from medicinal plants have been found to be safe in comparison with synthetic compounds. Many articles have focused on PDT mechanisms and types of PSs, but limited attention has been paid to the phototoxic activities of phytocompounds. The reduced toxicity and side effects of natural compounds inspire the researchers to identify and use plant extracts or phytocompounds as a potent natural PS candidate for PDT. This review focusses on the importance of common photoactive groups (furanocoumarins, polyacetylenes, thiophenes, curcumins, alkaloids, and anthraquinones), their phototoxic effects, anticancer activity and use as a potent PS for an effective PDT outcome in the treatment of various cancers.
Collapse
Affiliation(s)
- Kasipandi Muniyandi
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, 17011, Doornfontein 2028, South Africa; (K.M.); (B.G.)
- Bioprospecting Laboratory, Department of Botany, School of Life Sciences, Bharathiar University, Coimbatore, Tamil Nadu 641046, India;
| | - Blassan George
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, 17011, Doornfontein 2028, South Africa; (K.M.); (B.G.)
| | - Thangaraj Parimelazhagan
- Bioprospecting Laboratory, Department of Botany, School of Life Sciences, Bharathiar University, Coimbatore, Tamil Nadu 641046, India;
| | - Heidi Abrahamse
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, 17011, Doornfontein 2028, South Africa; (K.M.); (B.G.)
| |
Collapse
|
|
18
|
Piperine suppresses the Wnt/β-catenin pathway and has anti-cancer effects on colorectal cancer cells. Sci Rep 2020; 10:11681. [PMID: 32669593 PMCID: PMC7363889 DOI: 10.1038/s41598-020-68574-2] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 12/08/2019] [Indexed: 01/12/2023] Open
Abstract
More than 94% of colorectal cancer cases have mutations in one or more Wnt/β-catenin signaling pathway components. Inactivating mutations in APC or activating mutations in β-catenin (CTNNB1) lead to signaling overactivation and subsequent intestinal hyperplasia. Numerous classes of medicines derived from synthetic or natural small molecules, including alkaloids, have benefited the treatment of different diseases, including cancer, Piperine is a true alkaloid, derived from lysine, responsible for the spicy taste of black pepper (Piper nigrum) and long pepper (Piper longum). Studies have shown that piperine has a wide range of pharmacological properties; however, piperine molecular mechanisms of action are still not fully understood. By using Wnt/β-catenin pathway epistasis experiment we show that piperine inhibits the canonical Wnt pathway induced by overexpression of β-catenin, β-catenin S33A or dnTCF4 VP16, while also suppressing β-catenin nuclear localization in HCT116 cell line. Additionally, piperine impairs cell proliferation and migration in HCT116, SW480 and DLD-1 colorectal tumor cell lines, while not affecting the non-tumoral cell line IEC-6. In summary, piperine inhibits the canonical Wnt signaling pathway and displays anti-cancer effects on colorectal cancer cell lines.
Collapse
|
|
19
|
Syari DM, Rosidah R, Hasibuan PAZ, Haro G, Satria D. Evaluation of Cytotoxic Activity Alkaloid Fractions of Zanthoxylum acanthopodium DC. Fruits. Open Access Maced J Med Sci 2019; 7:3745-3747. [PMID: 32127967 PMCID: PMC7048336 DOI: 10.3889/oamjms.2019.495] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 10/17/2019] [Accepted: 10/18/2019] [Indexed: 11/09/2022] Open
Abstract
AIM: This study was carried out to investigate cytotoxic activity towards T47D, 4T1, MCF-7, HeLa, and Raji cells of alkaloid fractions of Zanthoxylum acanthopodium DC. fruits. Zanthoxylum acanthopodium DC. METHODS: The fruit was extracted by maceration. The ethanol extract was fractionated with liquid-liquid extraction using n-hexane, chloroform at pH 3, 7, and 9 to obtained alkaloid fractions. Cytotoxic activity for fraction chloroform at pH 7 and 9 was determined with MTT assay. RESULTS: The IC50 of fraction chloroform at pH 7 and 9 was (92.67 ± 1.37; 71.87 ± 1.04; 159.87 ± 0.63; 123.39 ± 0.81; and 103.09 ± 0.58 µg/mLfor pH 7) and (451.29 ± 25.48; 247.18 ± 2.82; 318.46 ± 5.40; 303.96 ± 8.75; and 181.45 ± 1.35 µg/mL for pH 9) respectively. CONCLUSION: The results reveal that alkaloid fractions at pH 7 and 9 of Zanthoxylum acanthopodium DC. Fruits have cytotoxic activity. Our further study is to isolate and assesses anticancer activity from alkaloid compounds.
Collapse
Affiliation(s)
- Dina Maya Syari
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia
| | - Rosidah Rosidah
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia
| | | | - Ginda Haro
- Department of Biochemistry, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia
| | - Denny Satria
- Department of Pharmaceutical Biology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia
| |
Collapse
|
|
20
|
Lin MS, Hong TM, Chou TH, Yang SC, Chung WC, Weng CW, Tsai ML, Cheng TJR, Chen JJW, Lee TC, Wong CH, Chein RJ, Yang PC. 4(1H)-quinolone derivatives overcome acquired resistance to anti-microtubule agents by targeting the colchicine site of β-tubulin. Eur J Med Chem 2019; 181:111584. [PMID: 31419740 DOI: 10.1016/j.ejmech.2019.111584] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 07/30/2019] [Accepted: 08/01/2019] [Indexed: 12/14/2022]
Abstract
Developing new therapeutic strategies to overcome drug resistance of cancer cells is an ongoing endeavor. From among 2 million chemicals, we identified ethyl 4-oxo-2-phenyl-1,4-dihydroquinoline-6-carboxylate (AS1712) as a low-toxicity inhibitor of lung cancer cell proliferation and xenograft tumor growth. We show that AS1712 is active against broad cancer cell lines and is able to bind in the colchicine-binding pocket of β-tubulin, thereby inhibiting microtubule assembly and, consequently, inducing mitotic arrest and apoptosis. Our cell-based structure-activity relationship study identified a new lead compound, RJ-LC-15-8, which had a greater anti-proliferative potency for H1975 cells than did AS1712, while maintaining a similar mechanism of action. Notably, AS1712 and RJ-LC-15-8 overcame P-glycoprotein efflux pump and β-tubulin alterations that lead to acquired resistance against microtubule-targeting drugs of cancer cells. AS1712 and RJ-LC-15-8 may be lead compounds that overcome acquired resistance to microtubule-targeting agents of cancer cells.
Collapse
Affiliation(s)
- Ming-Shiu Lin
- Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan
| | - Tse-Ming Hong
- Institute of Clinical Medicine, National Cheng Kung University, Tainan, 701, Taiwan
| | - Ting-Hung Chou
- Institute of Chemistry, Academia Sinica, Taipei, 115, Taiwan
| | - Shuenn-Chen Yang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan
| | - Wei-Chia Chung
- Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan
| | - Chia-Wei Weng
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 402, Taiwan
| | - Mei-Ling Tsai
- Institute of Chemistry, Academia Sinica, Taipei, 115, Taiwan
| | | | - Jeremy J W Chen
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 402, Taiwan
| | - Te-Chang Lee
- Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan
| | - Chi-Huey Wong
- The Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan
| | - Rong-Jie Chein
- Institute of Chemistry, Academia Sinica, Taipei, 115, Taiwan.
| | - Pan-Chyr Yang
- Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan; Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, 100, Taiwan.
| |
Collapse
|
|
21
|
Rodrigues L, Majik MS. Progress towards the Total Syntheses of
Lycopodium
Alkaloid, Lycopladine A. ASIAN J ORG CHEM 2019. [DOI: 10.1002/ajoc.201900262] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Lima Rodrigues
- School of Chemical SciencesGoa University Taleigao Plateau Goa India
| | - Mahesh Satu Majik
- School of Chemical SciencesGoa University Taleigao Plateau Goa India
- Department of ChemistryDnyanprassarak Mandal's College and Research Centre Assago Goa 403 507
| |
Collapse
|
|
22
|
Mondal A, Gandhi A, Fimognari C, Atanasov AG, Bishayee A. Alkaloids for cancer prevention and therapy: Current progress and future perspectives. Eur J Pharmacol 2019; 858:172472. [PMID: 31228447 DOI: 10.1016/j.ejphar.2019.172472] [Citation(s) in RCA: 161] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 06/17/2019] [Accepted: 06/18/2019] [Indexed: 12/13/2022]
Abstract
Alkaloids are important chemical compounds that serve as a rich source for drug discovery. Numerous alkaloids screened from medicinal plants and herbs showed antiproliferative and anticancer effects on wide category of cancers both in vitro and in vivo. Vinblastine, vinorelbine, vincristine, and vindesine have already been successfully developed as anticancer drugs. The available and up-to-date information on the ethnopharmacological uses in traditional medicine, phytochemistry, pharmacology and clinical utility of alkaloids were collected using various resources (PubMed, ScienceDirect, Google Scholar and Springerlink). In this article, we provide a comprehensive and critical overview on naturally-occurring alkaloids with anticancer activities and highlight the molecular mechanisms of action of these secondary metabolites. Furthermore, this review also presents a summary of synthetic derivatives and pharmacological profiles useful to researchers for the therapeutic development of alkaloids. Based on the literature survey compiled in this review, alkaloids represent an important group of anticancer drugs of plant origin with enormous potential for future development of drugs for cancer therapy and management.
Collapse
Affiliation(s)
- Arijit Mondal
- Department of Pharmacy, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, 700 053, West Bengal, India.
| | - Arijit Gandhi
- Department of Pharmaceutics, Bengal College of Pharmaceutical Science and Research, Durgapur, 713 212, West Burdwan, West Bengal, India
| | - Carmela Fimognari
- Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921, Rimini, Italy
| | - Atanas G Atanasov
- Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, 05-552, Jastrzebiec, Poland; Department of Pharmacognosy, University of Vienna, 1090, Vienna, Austria; Institute of Neurobiology, Bulgarian Academy of Sciences, 23 Acad. G. Bonchev Street, Sofia, 1113, Bulgaria
| | - Anupam Bishayee
- Lake Erie College of Osteopathic Medicine, Bradenton, FL, 34211, USA.
| |
Collapse
|
|
23
|
Rani S, Rana R, Saraogi GK, Kumar V, Gupta U. Self-Emulsifying Oral Lipid Drug Delivery Systems: Advances and Challenges. AAPS PharmSciTech 2019; 20:129. [PMID: 30815765 DOI: 10.1208/s12249-019-1335-x] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 02/02/2019] [Indexed: 12/20/2022] Open
Abstract
The attempts to oral delivery of lipids can be challenging. Self-emulsifying drug delivery system (SEDDS) plays a vital role to tackle this problem. SEDDS is composed of an oil phase, surfactants, co-surfactants, emulsifying agents, and co-solvents. SEDDS can be categorized into self-nano-emulsifying agents (SNEDDS) and self-micro-emulsifying agents (SMEDDS). The characterization of SEDDS includes size, zeta potential analysis, and surface morphology via electron microscopy and phase separation methods. SEDDS can be well characterized through different techniques for size and morphology. Supersaturation is the phenomenon applied in case of SEDDS, in which polymers and copolymers are used for SEDDS preparation. A supersaturated SEDDS formulation kinetically and thermodynamically inhibits the precipitation of drug molecules by retarding nucleation and crystal growth in the aqueous medium. Self-emulsification approach has been successful in the delivery of anti-cancer agents, anti-viral drugs, anti-bacterial, immunosuppressant, and natural products such as antioxidants as well as alkaloids. At present, more than four SEDDS drug products are available in the market. SEDDS have tremendous capabilities which are yet to be explored which would be beneficial in oral lipid delivery.
Collapse
|
|
24
|
Biological activity, phytochemistry and traditional uses of genus Lobelia (Campanulaceae): A systematic review. Fitoterapia 2019; 134:23-38. [PMID: 30664918 DOI: 10.1016/j.fitote.2018.12.021] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 12/18/2018] [Accepted: 12/29/2018] [Indexed: 12/20/2022]
|
|
25
|
Iqbal W, Alkarim S, Kamal T, Choudhry H, Sabir J, Bora RS, Saini KS. Rhazyaminine from Rhazya stricta Inhibits Metastasis and Induces Apoptosis by Downregulating Bcl-2 Gene in MCF7 Cell Line. Integr Cancer Ther 2018; 18:1534735418809901. [PMID: 30373413 PMCID: PMC7240879 DOI: 10.1177/1534735418809901] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background: The role of alkaloids isolated from Rhazya
stricta Decne (Apocynaceae family) (RS) in targeting genes involved
in cancer and metastasis remains to be elucidated. Objective:
Identify and characterize new compounds from RS, which inhibit gene(s) involved
in the survival, invasion, self-renewal, and metastatic processes of cancer
cells. Methods: Bioinformatics study was performed using HISAT2,
stringtie, and ballgown pipeline to understand expressional differences between
a normal epithelial cell line-MCF10A and MCF7. NMR and ATR-FTIR were performed
to elucidate the structure of rhazyaminine (R.A), isolated from
R stricta. Cell viability assay was performed using 0, 25,
and 50 μg/mL of total extract of R stricta (TERS) and R.A,
respectively, for 0, 24, and 48 hours, followed by scratch assay. In addition,
total RNA was isolated for RNA-seq analysis of MCF7 cell line
treated with R.A followed by qRT-PCR analysis of Bcl-2 gene.
Results: Deptor, which is upregulated in MCF7 compared with
MCF10A as found in our bioinformatics study was downregulated by R.A.
Furthermore, R.A effectively reduced cell viability to around 50%
(P < .05) and restricted cell migration in scratch
assay. Thirteen genes, related to metastasis and cancer stem cells, were
downregulated by R.A according to RNA-seq analysis.
Additionally, qRT-PCR validated the downregulation of Bcl-2
gene in R.A-treated cells by less than 0.5 folds (P < .05).
Conclusion: R.A successfully downregulated key genes involved
in apoptosis, cell survival, epithelial-mesenchymal transition, cancer stem cell
proliferation, and Wnt signal transduction pathway making it an
excellent “lead candidate” molecule for in vivo proof-of-concept studies.
Collapse
Affiliation(s)
- Waqas Iqbal
- 1 Department of Biology, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Saleh Alkarim
- 1 Department of Biology, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Tahseen Kamal
- 2 Department of Chemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Hani Choudhry
- 3 Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Jamal Sabir
- 1 Department of Biology, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Roop S Bora
- 1 Department of Biology, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Kulvinder S Saini
- 1 Department of Biology, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| |
Collapse
|
|
26
|
Xu H, Fan X, Zhang G, Liu X, Li Z, Li Y, Jiang B. LLDT-288, a novel triptolide analogue exhibits potent antitumor activity in vitro and in vivo. Biomed Pharmacother 2017; 93:1004-1009. [DOI: 10.1016/j.biopha.2017.06.041] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 05/22/2017] [Accepted: 06/09/2017] [Indexed: 01/01/2023] Open
|
|
27
|
Yehya AH, Asif M, Tan YJ, Sasidharan S, Abdul Majid AM, Oon CE. Broad spectrum targeting of tumor vasculature by medicinal plants: An updated review. J Herb Med 2017. [DOI: 10.1016/j.hermed.2017.03.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
|
|
28
|
Moradi MT, Karimi A, Lorigooini Z. Alkaloids as the natural anti-influenza virus agents: a systematic review. TOXIN REV 2017. [DOI: 10.1080/15569543.2017.1323338] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Affiliation(s)
- Mohammad-Taghi Moradi
- Students Research Committee, Shahrekord University of Medical Sciences, Shahrekord, Iran and
| | - Ali Karimi
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Zahra Lorigooini
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| |
Collapse
|
|
29
|
Zheng YB, Gong JH, Liu XJ, Wu SY, Li Y, Xu XD, Shang BY, Zhou JM, Zhu ZL, Si SY, Zhen YS. A Novel Nitrobenzoate Microtubule Inhibitor that Overcomes Multidrug Resistance Exhibits Antitumor Activity. Sci Rep 2016; 6:31472. [PMID: 27510727 PMCID: PMC4980604 DOI: 10.1038/srep31472] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 07/20/2016] [Indexed: 12/21/2022] Open
Abstract
Multidrug resistance is a major limitation for microtubule-binding agents in cancer treatment. Here we report a novel microtubule inhibitor (2-morpholin-4-yl-5-nitro-benzoic acid 4-methylsulfanyl-benzyl ester, IMB5046), its cytotoxicity against multidrug-resistant cell lines and its antitumor efficacy in animal models. IMB5046 disrupted microtubule structures in cells and inhibited purified tubulin polymerization in vitro. It bound to the colchicine pocket of tubulin. IMB5046 displayed potent cytotoxicity against multiple tumor cell lines with an IC50 range of 0.037-0.426 μM. Notably, several multidrug-resistant cell lines which were resistant to colchicine, vincristine and paclitaxel remained sensitive to IMB5046. IMB5046 was not a P-glycoprotein substrate. IMB5046 blocked cell cycle at G2/M phase and induced cell apoptosis. Microarray assay indicated that the differentially expressed genes after IMB5046 treatment were highly related to immune system, cell death and cancer. In a mouse xenograft model IMB5046 inhibited the growth of human lung tumor xenograft by 83% at a well-tolerated dose. It is concluded that IMB5046 is a tubulin polymerization inhibitor with novel chemical structure and can overcome multidrug resistance. It is a promising lead compound for cancer chemotherapy, especially for treatment of multidrug-resistant tumors.
Collapse
Affiliation(s)
- Yan-Bo Zheng
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R.China
| | - Jian-Hua Gong
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R.China
| | - Xiu-Jun Liu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R.China
| | - Shu-Ying Wu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R.China
| | - Yi Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R.China
| | - Xian-Dong Xu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R.China
| | - Bo-Yang Shang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R.China
| | - Jin-Ming Zhou
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R.China
| | - Zhi-Ling Zhu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R.China
| | - Shu-Yi Si
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R.China
| | - Yong-Su Zhen
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R.China
| |
Collapse
|
|
30
|
Adeosun AM, Oni SO, Ighodaro OM, Durosinlorun OH, Oyedele OM. Phytochemical, minerals and free radical scavenging profiles of Phoenix dactilyfera L. seed extract. J Taibah Univ Med Sci 2016. [DOI: 10.1016/j.jtumed.2015.11.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
|
|
31
|
Proteomic analysis of β-asarone induced cytotoxicity in human glioblastoma U251 cells. J Pharm Biomed Anal 2015; 115:292-9. [DOI: 10.1016/j.jpba.2015.07.036] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 07/24/2015] [Accepted: 07/26/2015] [Indexed: 01/22/2023]
|
|
32
|
Ashraf S, Beech RN, Hancock MA, Prichard RK. Ivermectin binds to Haemonchus contortus tubulins and promotes stability of microtubules. Int J Parasitol 2015; 45:647-54. [DOI: 10.1016/j.ijpara.2015.03.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Revised: 03/27/2015] [Accepted: 03/30/2015] [Indexed: 11/16/2022]
|
|
33
|
Diab S, Fidanzi C, Léger DY, Ghezali L, Millot M, Martin F, Azar R, Esseily F, Saab A, Sol V, Diab-Assaf M, Liagre B. Berberis libanotica extract targets NF-κB/COX-2, PI3K/Akt and mitochondrial/caspase signalling to induce human erythroleukemia cell apoptosis. Int J Oncol 2015; 47:220-230. [PMID: 25997834 DOI: 10.3892/ijo.2015.3012] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Accepted: 04/07/2015] [Indexed: 11/06/2022] Open
Abstract
The aim of this study was to describe and understand the relationship between cyclooxygenase-2 (COX-2) expression and apoptosis rate in erythroleukemia cells after apoptosis induction by Berberis libanotica (Bl) extract. To achieve this goal we used erythroleukemia cell lines expressing COX‑2 (HEL cell line) or not (K562 cell line). Moreover, we made use of COX‑2 cDNA to overexpress COX‑2 in K562 cells. In light of the reported chemopreventive and chemosensitive effects of natural products on various tumor cells and animal models, we postulated that our Bl extract may mediate their effects through apoptosis induction with suppression of cell survival pathways. Our study is the first report on the specific examination of intrinsic apoptosis and Akt/NF-κB/COX‑2 pathways in human erythroleukemia cells upon Bl extract exposure. Even if Bl extract induced apoptosis of three human erythroleukemia cell lines, a dominant effect of Bl extract treatment on K562 cells was observed resulting in activation of the late markers of apoptosis with caspase-3 activation, PARP cleavage and DNA fragmentation. Whereas, we showed that Bl extract reduced significantly expression of COX‑2 by a dose-dependent manner in HEL and K562 (COX‑2+) cells. Furthermore, in regard to our results, it is clear that the simultaneous inhibition of Akt and NF-κB signalling can significantly contribute to the anticancer effects of Bl extract in human erythroleukemia cells. We observed that the Bl extract is clearly more active than the berberine alone on the induction of DNA fragmentation in human erythro-leukemia cells.
Collapse
Affiliation(s)
- Saada Diab
- Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France
| | - Chloe Fidanzi
- Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France
| | - David Y Léger
- Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France
| | - Lamia Ghezali
- Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France
| | - Marion Millot
- Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France
| | - Frédérique Martin
- Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France
| | - Rania Azar
- Molecular Tumorigenesis and Anticancer Pharmacology, EDST, Lebanese University, Hadath, Lebanon
| | - Fadi Esseily
- Laboratory Science Department, Faculty of Public Health, Lebanese University, Jdeidet El Metn, Lebanon
| | - Antoine Saab
- Faculty of Sciences II, Chemistry Department, Lebanese University, Beirut, Lebanon
| | - Vincent Sol
- Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France
| | - Mona Diab-Assaf
- Molecular Tumorigenesis and Anticancer Pharmacology, EDST, Lebanese University, Hadath, Lebanon
| | - Bertrand Liagre
- Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France
| |
Collapse
|
|
34
|
Gupta AP, Pandotra P, Kushwaha M, Khan S, Sharma R, Gupta S. Alkaloids: A Source of Anticancer Agents from Nature. STUDIES IN NATURAL PRODUCTS CHEMISTRY 2015. [DOI: 10.1016/b978-0-444-63462-7.00009-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
|
|
35
|
Elkady AI, Hussein RAEH, Abu-Zinadah OA. Differential control of growth, apoptotic activity and gene expression in human colon cancer cells by extracts derived from medicinal herbs, Rhazya stricta and Zingiber officinale and their combination. World J Gastroenterol 2014; 20:15275-88. [PMID: 25386076 PMCID: PMC4223261 DOI: 10.3748/wjg.v20.i41.15275] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Revised: 06/29/2014] [Accepted: 07/11/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effects of extracts from Rhazya stricta (R. stricta) and Zingiber officinale (Z. officinale) on human colorectal cancer cells. METHODS Human colorectal cancer cells (HCT116) were subjected to increasing doses of crude alkaloid extracts from R. stricta (CAERS) and crude flavonoid extracts from Z. officinale (CFEZO). Cells were then harvested after 24, 48 or 72 h and cell viability was examined by trypan blue exclusion dye test; clonogenicity and soft agar colony-forming assays were also carried out. Nuclear stain (Hoechst 33342), acridine orange/ethidium bromide double staining, agarose gel electrophoresis and comet assays were performed to assess pro-apoptotic potentiality of the extracts. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR), using gene-specific primers and Western blot analyses were performed to assess the impact of CAERS and CFEZO on the expression levels of key regulatory proteins in HCT116 cells. RESULTS Treatment with a combination of CAERS and CFEZO synergistically suppressed the proliferation, colony formation and anchorage-independent growth of HCT116 cells. Calculated IC50, after 24, 48 and 72 h, were 70, 90 and 130 μg/mL for CAERS, 65, 85 and 120 μg/mL for CFEZO and 20, 25 and 45 μg/mL for both agents, respectively. CAERS- and CFEZO-treated cells exhibited morphologic and biochemical features of apoptotic cell death. The induction of apoptosis was associated with the release of mitochondrial cytochrome c, an increase in the Bax/Bcl-2 ratio, activation of caspases 3 and 9 and cleavage of poly ADP-ribose polymerase. CAERS and CFEZO treatments downregulated expression levels of anti-apoptotic proteins including Bcl-2, Bcl-X, Mcl-1, survivin and XIAP, and upregulated expression levels of proapoptotic proteins such as Bad and Noxa. CAERS and CFEZO treatments elevated expression levels of the oncosuppressor proteins, p53, p21 and p27, and reduced levels of the oncoproteins, cyclin D1, cyclin/cyclin-dependent kinase-4 and c-Myc. CONCLUSION These data suggest that a combination of CAERS and CFEZO is a promising treatment for the prevention of colon cancer.
Collapse
|
|
36
|
El-Merahbi R, Liu YN, Eid A, Daoud G, Hosry L, Monzer A, Mouhieddine TH, Hamade A, Najjar F, Abou-Kheir W. Berberis libanotica Ehrenb extract shows anti-neoplastic effects on prostate cancer stem/progenitor cells. PLoS One 2014; 9:e112453. [PMID: 25380390 PMCID: PMC4224486 DOI: 10.1371/journal.pone.0112453] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Accepted: 10/08/2014] [Indexed: 01/11/2023] Open
Abstract
Cancer stem cells (CSCs), including those of advanced prostate cancer, are a suggested reason for tumor resistance toward conventional tumor therapy. Therefore, new therapeutic agents are urgently needed for targeting CSCs. Despite the minimal understanding of their modes of action, natural products and herbal therapies have been commonly used in the prevention and treatment of many cancers. Berberis libanotica Ehrenb (BLE) is a plant rich in alkaloids which may possess anti-cancer activity and a high potential for eliminating CSCs. We tested the effect of BLE on prostate cancer cells and our data indicated that this extract induced significant reduction in cell viability and inhibited the proliferation of human prostate cancer cell lines (DU145, PC3 and 22Rv1) in a dose- and time-dependent manner. BLE extract induced a perturbation of the cell cycle, leading to a G0-G1 arrest. Furthermore, we noted 50% cell death, characterized by the production of high levels of reactive oxidative species (ROS). Inhibition of cellular migration and invasion was also achieved upon treatment with BLE extract, suggesting a role in inhibiting metastasis. Interestingly, BLE extract had a major effect on CSCs. Cells were grown in a 3D sphere-formation assay to enrich for a population of cancer stem/progenitor cells. Our results showed a significant reduction in sphere formation ability. Three rounds of treatment with BLE extract were sufficient to eradicate the self-renewal ability of highly resistant CSCs. In conclusion, our results suggest a high therapeutic potential of BLE extract in targeting prostate cancer and its CSCs.
Collapse
Affiliation(s)
- Rabih El-Merahbi
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Yen-Nien Liu
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Assaad Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Georges Daoud
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Leina Hosry
- Faculty of Pharmacy, Lebanese University, Hadath, Lebanon
| | - Alissar Monzer
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Tarek H. Mouhieddine
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Aline Hamade
- Department of Biology, Faculty of Sciences II, Lebanese University, Fanar, Lebanon
| | - Fadia Najjar
- Department of Chemistry and Biochemistry, Faculty of Sciences II, Lebanese University, Fanar, Lebanon
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| |
Collapse
|
|
37
|
Elkady AI, Hussein RAEH, Abu-Zinadah OA. Effects of crude extracts from medicinal herbs Rhazya stricta and Zingiber officinale on growth and proliferation of human brain cancer cell line in vitro. BIOMED RESEARCH INTERNATIONAL 2014; 2014:260210. [PMID: 25136570 PMCID: PMC4130191 DOI: 10.1155/2014/260210] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Revised: 06/12/2014] [Accepted: 06/13/2014] [Indexed: 12/18/2022]
Abstract
Hitherto, limited clinical impact has been achieved in the treatment of glioblastoma (GBMs). Although phytochemicals found in medicinal herbs can provide mankind with new therapeutic remedies, single agent intervention has failed to bring the expected outcome in clinical trials. Therefore, combinations of several agents at once are gaining increasing attractiveness. In the present study, we investigated the effects of crude alkaloid (CAERS) and flavonoid (CFEZO) extracts prepared from medicinal herbs, Rhazya stricta and Zingiber officinale, respectively, on the growth of human GBM cell line, U251. R. stricta and Z. officinale are traditionally used in folkloric medicine and have antioxidant, anticarcinogenic, and free radical scavenging properties. Combination of CAERS and CFEZO treatments synergistically suppressed proliferation and colony formation and effectively induced morphological and biochemical features of apoptosis in U251 cells. Apoptosis induction was mediated by release of mitochondrial cytochrome c, increased Bax : Bcl-2 ratio, enhanced activities of caspase-3 and -9, and PARP-1 cleavage. CAERS and CFEZO treatments decreased expression levels of nuclear NF-κBp65, survivin, XIAP, and cyclin D1 and increased expression level of p53, p21, and Noxa. These results suggest that combination of CAERS and CFEZO provides a useful foundation for studying and developing novel chemotherapeutic agents for the treatment of GBM.
Collapse
Affiliation(s)
- Ayman I. Elkady
- Department of Biological Sciences, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Zoology Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Rania Abd El Hamid Hussein
- Department of Clinical Nutrition, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Gamal Abd El Nasser Hospital, Alexandria, Egypt
| | - Osama A. Abu-Zinadah
- Department of Biological Sciences, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| |
Collapse
|
|
38
|
Law BYK, Chan WK, Xu SW, Wang JR, Bai LP, Liu L, Wong VKW. Natural small-molecule enhancers of autophagy induce autophagic cell death in apoptosis-defective cells. Sci Rep 2014; 4:5510. [PMID: 24981420 PMCID: PMC4076737 DOI: 10.1038/srep05510] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Accepted: 06/11/2014] [Indexed: 02/07/2023] Open
Abstract
Resistance of cancer cells to chemotherapy is a significant problem in oncology, and the development of sensitising agents or small-molecules with new mechanisms of action to kill these cells is needed. Autophagy is a cellular process responsible for the turnover of misfolded proteins or damaged organelles, and it also recycles nutrients to maintain energy levels for cell survival. In some apoptosis-resistant cancer cells, autophagy can also enhance the efficacy of anti-cancer drugs through autophagy-mediated mechanisms of cell death. Because the modulation of autophagic processes can be therapeutically useful to circumvent chemoresistance and enhance the effects of cancer treatment, the identification of novel autophagic enhancers for use in oncology is highly desirable. Many novel anti-cancer compounds have been isolated from natural products; therefore, we worked to discover natural, anti-cancer small-molecule enhancers of autophagy. Here, we have identified a group of natural alkaloid small-molecules that function as novel autophagic enhancers. These alkaloids, including liensinine, isoliensinine, dauricine and cepharanthine, stimulated AMPK-mTOR dependent induction of autophagy and autophagic cell death in a panel of apoptosis-resistant cells. Taken together, our work provides novel insights into the biological functions, mechanisms and potential therapeutic values of alkaloids for the induction of autophagy.
Collapse
Affiliation(s)
- Betty Yuen Kwan Law
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Wai Kit Chan
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Su Wei Xu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Jing Rong Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Li Ping Bai
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Liang Liu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Vincent Kam Wai Wong
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| |
Collapse
|
|
39
|
Design, synthesis and anticancer activity evaluation of novel C14 heterocycle substituted epi-triptolide. Eur J Med Chem 2014; 73:46-55. [DOI: 10.1016/j.ejmech.2013.11.044] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2013] [Revised: 07/31/2013] [Accepted: 11/25/2013] [Indexed: 11/18/2022]
|
|
40
|
Alkaloids isolated from natural herbs as the anticancer agents. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2012; 2012:485042. [PMID: 22988474 PMCID: PMC3440018 DOI: 10.1155/2012/485042] [Citation(s) in RCA: 158] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/11/2012] [Revised: 07/17/2012] [Accepted: 07/30/2012] [Indexed: 01/02/2023]
Abstract
Alkaloids are important chemical compounds that serve as a rich reservoir for drug discovery. Several alkaloids isolated from natural herbs exhibit antiproliferation and antimetastasis effects on various types of cancers both in vitro and in vivo. Alkaloids, such as camptothecin and vinblastine, have already been successfully developed into anticancer drugs. This paper focuses on the naturally derived alkaloids with prospective anticancer properties, such as berberine, evodiamine, matrine, piperine, sanguinarine, and tetrandrine, and summarizes the mechanisms of action of these compounds. Based on the information in the literature that is summarized in this paper, the use of alkaloids as anticancer agents is very promising, but more research and clinical trials are necessary before final recommendations on specific alkaloids can be made.
Collapse
|
|
41
|
Curcumin induces DNA damage and caffeine-insensitive cell cycle arrest in colorectal carcinoma HCT116 cells. Mol Cell Biochem 2011; 354:247-52. [PMID: 21526346 DOI: 10.1007/s11010-011-0824-3] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2011] [Accepted: 04/15/2011] [Indexed: 01/23/2023]
Abstract
Curcumin (CUR), a polyphenol derived from the plant Curcuma longa, displays potential anti-cancer activity. One of the mechanisms stems from its ability to elicit cell cycle arrest followed by suppression of cell proliferation. Herein, we reported that CUR significantly induced DNA damage and mediated S and G2/M phase arrest in colorectal carcinoma HCT116 cells. Unlike etoposide, a classical topoisomerase II inhibitor, CUR-triggered G2/M phase arrest was hardly reversed by caffeine (CAFF) which is an inhibitor of activated ataxia-telangiectasia-mutated (ATM)/ATM- and Rad3-related (ATR), indicating that ATM and ATR signaling pathways may be not involved in CUR-mediated S and G2/M phase arrest in HCT116 cells. Furthermore, we demonstrated that CUR caused mitosis arrest in HCT116 cells by using mitotic protein monoclonal antibody-2 as a mitosis marker and the surface plasmon resonance assay. The findings provide new mechanisms of cell proliferation inhibition triggered by CUR in HCT116 cells.
Collapse
|
|
42
|
Zhou B, Miao Z, Deng G, Ding J, Yang Y, Feng H, Li Y. Synthesis and biological evaluation of novel triptolide analogues for anticancer activity. Bioorg Med Chem Lett 2010; 20:6217-21. [DOI: 10.1016/j.bmcl.2010.08.106] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2010] [Revised: 08/19/2010] [Accepted: 08/20/2010] [Indexed: 11/29/2022]
|
|
43
|
Zhou ZL, Luo ZG, Yu B, Jiang Y, Chen Y, Feng JM, Dai M, Tong LJ, Li Z, Li YC, Ding J, Miao ZH. Increased accumulation of hypoxia-inducible factor-1α with reduced transcriptional activity mediates the antitumor effect of triptolide. Mol Cancer 2010; 9:268. [PMID: 20932347 PMCID: PMC2958983 DOI: 10.1186/1476-4598-9-268] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2010] [Accepted: 10/11/2010] [Indexed: 01/08/2023] Open
Abstract
Background Hypoxia-inducible factor-1α (HIF-1α), a critical transcription factor to reduced O2 availability, has been demonstrated to be extensively involved in tumor survival, aggressive progression, drug resistance and angiogenesis. Thus it has been considered as a potential anticancer target. Triptolide is the main principle responsible for the biological activities of the Traditional Chinese Medicine tripterygium wilfordii Hook F. Triptolide possesses great chemotherapy potential for cancer with its broad-spectrum anticancer, antiangiogenesis, and drug-resistance circumvention activities. Numerous biological molecules inhibited by triptolide have been viewed as its possible targets. However, the anticancer action mechanisms of triptolide remains to be further investigated. Here we used human ovarian SKOV-3 cancer cells as a model to probe the effect of triptolide on HIF-1α. Results Triptolide was observed to inhibit the proliferation of SKOV-3 cells, and meanwhile, to enhance the accumulation of HIF-1α protein in SKOV-3, A549 and DU145 cells under different conditions. Triptolide did not change the kinetics or nuclear localization of HIF-1α protein or the 26 S proteasome activity in SKOV-3 cells. However, triptolide was found to increase the levels of HIF-1α mRNA. Unexpectedly, the HIF-1α protein induced by triptolide appeared to lose its transcriptional activity, as evidenced by the decreased mRNA levels of its target genes including VEGF, BNIP3 and CAIX. The results were further strengthened by the lowered secretion of VEGF protein, the reduced sprout outgrowth from the rat aorta rings and the inhibitory expression of the hypoxia responsive element-driven luciferase reporter gene. Moreover, the silencing of HIF-1α partially prevented the cytotoxicity and apoptosis triggered by triptolide. Conclusions The potent induction of HIF-1α protein involved in its cytotoxicity, together with the suppression of HIF-1 transcriptional activity, indicates the great therapeutic potential of triptolide as an anticancer drug. Meanwhile, our data further stress the possibility that HIF-1α functions in an unresolved nature or condition.
Collapse
Affiliation(s)
- Zhao-Li Zhou
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Li Z, Zhou ZL, Miao ZH, Lin LP, Feng HJ, Tong LJ, Ding J, Li YC. Design and Synthesis of Novel C14-Hydroxyl Substituted Triptolide Derivatives as Potential Selective Antitumor Agents. J Med Chem 2009; 52:5115-23. [DOI: 10.1021/jm900342g] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
| | - Zhao-Li Zhou
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China
| | | | | | | | | | - Jian Ding
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China
| | | |
Collapse
|
|
45
|
Ren X, Dai M, Lin LP, Li PK, Ding J. Anti-angiogenic and vascular disrupting effects of C9, a new microtubule-depolymerizing agent. Br J Pharmacol 2009; 156:1228-38. [PMID: 19302593 DOI: 10.1111/j.1476-5381.2009.00112.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
BACKGROUND AND PURPOSE The critical role of blood supply in the growth of solid tumours makes blood vessels an ideal target for anti-tumour drug discovery. The anti-angiogenic and vascular disrupting activities of C9, a newly synthesized microtubule-depolymerizing agent, were investigated with several in vitro and in vivo models. Possible mechanisms involved in its activity were also assessed. EXPERIMENTAL APPROACH Microtubule-depolymerizing actions were assessed by surface plasmon resonance binding, competitive inhibition and cytoskeleton immunofluorescence. Anti-angiogenic and vascular disrupting activities were tested on proliferation, migration, tube formation with human umbilical vein endothelial cells, and in rat aortic ring, chick chorioallantoic membrane and Matrigel plug assays. Western blots and Rho activation assays were employed to examine the role of Raf-MEK-ERK (mitogen-activated ERK kinase, extracellular signal-regulated kinase) and Rho/Rho kinase signalling. KEY RESULTS C9 inhibited proliferation, migration and tube formation of endothelial cells and inhibited angiogenesis in aortic ring and chick chorioallantoic membrane assays. C9 induced disassembly of microtubules in endothelial cells and down-regulated Raf-MEK-ERK signalling activated by pro-angiogenic factors. In addition, C9 disrupted capillary-like networks and newly formed vessels in vitro and rapidly decreased perfusion of neovasculature in vivo. Endothelial cell contraction and membrane blebbing induced by C9 in neovasculature was dependent on the Rho/Rho kinase pathway. CONCLUSIONS AND IMPLICATIONS Anti-angiogenic and vascular disruption by C9 was associated with changes in morphology and function of endothelial cells, involving the Raf-MEK-ERK and Rho/Rho kinase signalling pathways. These findings strongly suggest that C9 is a new microtubule-binding agent that could effectively target tumour vasculature.
Collapse
Affiliation(s)
- Xuan Ren
- Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | | | | | | | | |
Collapse
|
|
46
|
Ngo QA, Roussi F, Cormier A, Thoret S, Knossow M, Guénard D, Guéritte F. Synthesis and Biological Evaluation of Vinca Alkaloids and Phomopsin Hybrids. J Med Chem 2008; 52:134-42. [DOI: 10.1021/jm801064y] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Quoc Anh Ngo
- Institut de Chimie des Substances Naturelles, UPR2301, CNRS, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France, and Laboratoire d’Enzymologie et Biochimie Structurales, UPR3082, CNRS, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
| | - Fanny Roussi
- Institut de Chimie des Substances Naturelles, UPR2301, CNRS, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France, and Laboratoire d’Enzymologie et Biochimie Structurales, UPR3082, CNRS, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
| | - Anthony Cormier
- Institut de Chimie des Substances Naturelles, UPR2301, CNRS, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France, and Laboratoire d’Enzymologie et Biochimie Structurales, UPR3082, CNRS, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
| | - Sylviane Thoret
- Institut de Chimie des Substances Naturelles, UPR2301, CNRS, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France, and Laboratoire d’Enzymologie et Biochimie Structurales, UPR3082, CNRS, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
| | - Marcel Knossow
- Institut de Chimie des Substances Naturelles, UPR2301, CNRS, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France, and Laboratoire d’Enzymologie et Biochimie Structurales, UPR3082, CNRS, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
| | - Daniel Guénard
- Institut de Chimie des Substances Naturelles, UPR2301, CNRS, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France, and Laboratoire d’Enzymologie et Biochimie Structurales, UPR3082, CNRS, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
| | - Françoise Guéritte
- Institut de Chimie des Substances Naturelles, UPR2301, CNRS, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France, and Laboratoire d’Enzymologie et Biochimie Structurales, UPR3082, CNRS, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
| |
Collapse
|
|
47
|
Harvey MJ, Banwell MG, Lupton DW. The synthesis of compounds related to the indole–indoline core of the vinca alkaloids (+)-vinblastine and (+)-vincristine. Tetrahedron Lett 2008. [DOI: 10.1016/j.tetlet.2008.05.082] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
|