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Upadhyay S, Rajan Swami, Shrivastava S, Jeengar MK. Molecular insights into anti-inflammatory activities of selected Indian herbs. J Ayurveda Integr Med 2025; 16:101081. [PMID: 40154100 PMCID: PMC11986983 DOI: 10.1016/j.jaim.2024.101081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 09/29/2024] [Accepted: 10/01/2024] [Indexed: 04/01/2025] Open
Abstract
Inflammation is a universal response of mammalian tissue to harm, comprising reactions to injuries, pathogens, and foreign particles. Chronic inflammation, often present in allergies and autoimmune disorders, poses significant risks, potentially leading to conditions such as rheumatoid arthritis, Alzheimer's disease, asthma, and inflammatory bowel disease. It can also be a common precursor to cancer. However, Contemporary therapies like NSAIDs and corticosteroids often provide incomplete relief from chronic inflammation and carry significant side effects, underscoring the need for exploring traditional and plant-based medicines for new, effective treatments. As such, there is a growing demand for natural bioactive substances for health maintenance and disease risk reduction. Traditional and plant-based medicines, long-used in managing inflammation and other disorders, hold promise for the discovery of bioactive lead compounds and subsequent drug development for treating inflammatory disorders. This review encompasses an extensive study of the anti-inflammatory potential of selected traditional Indian herbal medicines and the associated pharmacological mechanisms of action. The inflammatory process often entails the activation of transcription factors, induction of various signaling cascades, gene expression, activation of inflammatory enzymes, and release of pro-inflammatory cytokines in inflammatory or immune cells. Detailed exploration of active components in traditional herbal medicines such as the Neem (Azadirachta indica), Salai guggul (Boswellia serrata), Green tea (Camellia sinensis), Saffron (Crocus sativus), Turmeric (Curcuma longa), Mangosteen (Garcinia mangostana), Indian mulberry (Morinda citrifolia), Black cumin (Nigella sativa), Ashwagandha (Withania somnifera), and Ginger (Zingiber officinale) reveals their potential anti-inflammatory properties. The in-depth study of these plants provides insight into their potential applications in managing inflammatory disorders. Further research and development are necessary to substantiate these findings and translate them into clinically effective therapeutics.
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Affiliation(s)
- Saumya Upadhyay
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, 682041, Kerala, India
| | - Rajan Swami
- Chitkara College of Pharmacy, Chitkara University, 140 401, Punjab, India
| | - Shweta Shrivastava
- School of Pharmacy, School of Health & Allied Sciences, ARKA JAIN University, Gamaharia, Seraikela Kharsawan, 832108, Jharkhand, India
| | - Manish Kumar Jeengar
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, 682041, Kerala, India.
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Kumari GS, Andugulapati SB, Ramalingam V, Suresh Babu K. Synthesis of epoxyazadiradione-thiazole hybrid derivatives and evaluation of their cytotoxic activities. Nat Prod Res 2024:1-6. [PMID: 39555584 DOI: 10.1080/14786419.2024.2429130] [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: 07/23/2024] [Revised: 10/15/2024] [Accepted: 11/03/2024] [Indexed: 11/19/2024]
Abstract
In an attempt to develop natural product-based anticancer agents, a series of novel epoxyazadiradione-thiazole hybrids (6a-j) were synthesised and evaluated for their anticancer activity. All the synthesised derivatives were assessed for in vitro cytotoxic activity against a panel of human cancer and normal cell lines and the results showed that most of the compounds exhibited significant cytotoxic activity against cancer cells and as well some of the compounds showed less cytotoxicity against normal cells. In particular, compound 4 showed potent cytotoxic activity against tongue cancer cell lines. In consideration of the potent activity, the compound 4 was further assessed for cell cycle analysis and the results showed that the compound arrests the cell cycle progression at the G0/G1 phase in the tongue cancer cell lines. Consequently, the annexin V/PI staining assay demonstrated that compound 4 induced early apoptosis against tongue cancer. Taken together, the results inferred that the epoxyazadiradione is promising anticancer candidate for developing novel anticancer drugs against tongue cancer.
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Affiliation(s)
- Gaja Swarna Kumari
- Department of Natural Products & Medicinal Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
| | | | - Vaikundamoorthy Ramalingam
- Department of Natural Products & Medicinal Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
| | - K Suresh Babu
- Department of Natural Products & Medicinal Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
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Rajendran P, Renu K, Abdallah BM, Ali EM, Veeraraghavan VP, Sivalingam K, Rustagi Y, Abdelsalam SA, Ibrahim RIH, Al-Ramadan SY. Nimbolide: promising agent for prevention and treatment of chronic diseases (recent update). Food Nutr Res 2024; 68:9650. [PMID: 38571915 PMCID: PMC10989234 DOI: 10.29219/fnr.v68.9650] [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: 04/28/2023] [Revised: 10/09/2023] [Accepted: 10/16/2023] [Indexed: 04/05/2024] Open
Abstract
Background Nimbolide, a bioactive compound derived from the neem tree, has garnered attention as a potential breakthrough in the prevention and treatment of chronic diseases. Recent updates in research highlight its multifaceted pharmacological properties, demonstrating anti-inflammatory, antioxidant, and anticancer effects. With a rich history in traditional medicine, nimbolide efficacy in addressing the molecular complexities of conditions such as cardiovascular diseases, diabetes, and cancer positions it as a promising candidate for further exploration. As studies progress, the recent update underscores the growing optimism surrounding nimbolide as a valuable tool in the ongoing pursuit of innovative therapeutic strategies for chronic diseases. Methods The comprehensive search of the literature was done until September 2020 on the MEDLINE, Embase, Scopus and Web of Knowledge databases. Results Most studies have shown the Nimbolide is one of the most potent limonoids derived from the flowers and leaves of neem (Azadirachta indica), which is widely used to treat a variety of human diseases. In chronic diseases, nimbolide reported to modulate the key signaling pathways, such as Mitogen-activated protein kinases (MAPKs), Wingless-related integration site-β (Wnt-β)/catenin, NF-κB, PI3K/AKT, and signaling molecules, such as transforming growth factor (TGF-β), Matrix metalloproteinases (MMPs), Vascular Endothelial Growth Factor (VEGF), inflammatory cytokines, and epithelial-mesenchymal transition (EMT) proteins. Nimbolide has anti-inflammatory, anti-microbial, and anti-cancer properties, which make it an intriguing compound for research. Nimbolide demonstrated therapeutic potential for osteoarthritis, rheumatoid arthritis, cardiovascular, inflammation and cancer. Conclusion The current review mainly focused on understanding the molecular mechanisms underlying the therapecutic effects of nimbolide in chronic diseases.
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Affiliation(s)
- Peramaiyan Rajendran
- Department of Biological Sciences, College of Science, King Faisal University, Al Ahsa, Saudi Arabia
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India
| | - Kaviyarasi Renu
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India
| | - Basem M. Abdallah
- Department of Biological Sciences, College of Science, King Faisal University, Al Ahsa, Saudi Arabia
| | - Enas M. Ali
- Department of Biological Sciences, College of Science, King Faisal University, Al Ahsa, Saudi Arabia
- Department of Botany and Microbiology, Faculty of Science, Cairo University, Cairo, Egypt
| | - Vishnu Priya Veeraraghavan
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India
| | - Kalaiselvi Sivalingam
- Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA
| | - Yashika Rustagi
- Centre for Cancer Genomics, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Salaheldin Abdelraouf Abdelsalam
- Department of Biological Sciences, College of Science, King Faisal University, Al Ahsa, Saudi Arabia
- Department of Zoology, Faculty of Science, Assiut University, Assiut, Egypt
| | - Rashid Ismael Hag Ibrahim
- Department of Biological Sciences, College of Science, King Faisal University, Al Ahsa, Saudi Arabia
- Department of Botany, Faculty of Science, University of Khartoum, Sudan
| | - Saeed Yaseen Al-Ramadan
- Department of Anatomy, College of Veterinary Medicine, King Faisal University, Al-Ahsa, Saudi Arabia
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Nagini S, Palrasu M, Bishayee A. Limonoids from neem (Azadirachta indica A. Juss.) are potential anticancer drug candidates. Med Res Rev 2024; 44:457-496. [PMID: 37589457 DOI: 10.1002/med.21988] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 07/06/2023] [Accepted: 08/06/2023] [Indexed: 08/18/2023]
Abstract
Neem (Azadirachta indica A. Juss.), a versatile evergreen tree recognized for its ethnopharmacological value, is a rich source of limonoids of the triterpenoid class, endowed with potent medicinal properties. Extracts of neem have been documented to display anticancer effects in diverse malignant cell lines as well as in preclinical animal models that has largely been attributed to the constituent limonoids. Of late, neem limonoids have become the cynosure of research attention as potential candidate agents for cancer prevention and therapy. Among the various limonoids found in neem, azadirachtin, epoxyazadiradione, gedunin, and nimbolide, have been extensively investigated for anticancer activity. Azadirachtin, a potent biodegradable pesticide, exhibits profound antiproliferative effects by preventing mitotic spindle formation and cell division. The antiproliferative activity of gedunin has been demonstrated to be mediated primarily via inhibition of heat shock protein90 and its client proteins. Epoxyazadiradione inhibits pro-inflammatory and kinase-driven signaling pathways to block tumorigenesis. Nimbolide, the most potent cytotoxic neem limonoid, inhibits the growth of cancer cells by regulating the phosphorylation of keystone kinases that drive oncogenic signaling besides modulating the epigenome. There is overwhelming evidence to indicate that neem limonoids exert anticancer effects by preventing the acquisition of hallmark traits of cancer, such as cell proliferation, apoptosis evasion, inflammation, invasion, angiogenesis, and drug resistance. Neem limonoids are value additions to the armamentarium of natural compounds that target aberrant oncogenic signaling to inhibit cancer development and progression.
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Affiliation(s)
- Siddavaram Nagini
- Department of Biochemistry & Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, Tamil Nadu, India
| | - Manikandan Palrasu
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, USA
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, Florida, USA
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Sakib R, Caruso F, Belli S, Rossi M. Azadiradione, a Component of Neem Oil, Behaves as a Superoxide Dismutase Mimic When Scavenging the Superoxide Radical, as Shown Using DFT and Hydrodynamic Voltammetry. Biomedicines 2023; 11:3091. [PMID: 38002091 PMCID: PMC10669394 DOI: 10.3390/biomedicines11113091] [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: 10/30/2023] [Revised: 11/14/2023] [Accepted: 11/16/2023] [Indexed: 11/26/2023] Open
Abstract
The neem tree, Azadirachta indica, belongs to the Meliaceae family, and its use in the treatment of medical disorders from ancient times to the present in the traditional medical practices of Asia, Africa and the Middle East is well-documented. Neem oil, extracted from the seeds of the fruit, is widely used, with promising medicinal benefits. Azadiradione, a principal antioxidant component of the seeds of A. indica, is known to reduce oxidative stress and has anti-inflammatory effects. To directly measure the antioxidant ability of neem oil, we used Rotating Ring Disk Electrode (RRDE) hydrodynamic voltammetry to quantify how it can scavenge superoxide radical anions. The results of these experiments show that neem oil is approximately 26 times stronger than other natural products, such as olive oil, propolis and black seed oil, which were previously measured using this method. Next, computational Density Functional Theory (DFT) methods were used to arrive at a mechanism for the scavenging of superoxide radical anions with azadiradione. Our work indicates that azadiradione is an effective antioxidant and, according to our DFT study, its scavenging of the superoxide radical anion occurs through a reaction mechanism in which azadiradione mimics the antioxidant action of superoxide dismutase (SOD). In this mechanism, analogous to the SOD enzymatic reaction, azadiradione is regenerated, along with the production of two products: hydrogen peroxide and molecular oxygen. This antioxidant process provides an explanation for azadiradione's more general and protective biochemical effects.
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Affiliation(s)
| | - Francesco Caruso
- Department of Chemistry, Vassar College, Poughkeepsie, NY 12604, USA
| | | | - Miriam Rossi
- Department of Chemistry, Vassar College, Poughkeepsie, NY 12604, USA
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Tewari D, Rawat K, Bisht A, Almoyad MAA, Wahab S, Chandra S, Pande V. Screening of potential inhibitors of Leishmania major N-myristoyltransferase from Azadirachta indica phytochemicals for leishmaniasis drug discovery by molecular docking, molecular dynamics simulation and density functional theory methods. J Biomol Struct Dyn 2023; 42:13953-13970. [PMID: 37922151 DOI: 10.1080/07391102.2023.2279281] [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: 07/24/2023] [Accepted: 10/30/2023] [Indexed: 11/05/2023]
Abstract
Leishmaniasis is one of the most neglected parasitic diseases worldwide. The toxicity of current drugs used for its treatment is a major obstacle to their effectiveness, necessitating the discovery and development of new therapeutic agents for better disease control. In Leishmania parasites, N-Myristoyltransferase (NMT) has been identified as a promising target for drug development. Thus, exploring well-known medicinal plants such as Azadirachta indica and their phytochemicals can offer a diverse range of treatment options, potentially leading to disease prevention and control. To assess the therapeutic potential of these compounds, their ADMET prediction and drug-likeness properties were analyzed. The top 4 compounds were selected which had better and significantly low binding energy than the reference molecule QMI. Based on the binding energy score of the top compounds, the results show that Isonimocinolide has the highest binding affinity (-9.8 kcal/mol). In addition, a 100 ns MD simulation of the four best compounds showed that Isonimocinolide and Nimbolide have good stability with LmNMT. These compounds were then subjected to MMPBSA (last 30 ns) calculation to analyze protein-ligand stability and dynamic behavior. Nimbolide and Meldenin showed lowest binding free energy i.e. -84.301 kJ/mol and -91.937 kJ/mol respectively. DFT was employed to calculate the HOMO-LUMO energy gap, global reactivity parameters, and molecular electrostatic potential of all hit molecules. The promising results obtained from MD simulations and MMPBSA analyses provide compelling evidence for the potential use of these compounds in future drug development efforts for the treatment of leishmaniasis.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Disha Tewari
- Department of Biotechnology, Kumaun University, Bhimtal, Uttarakhand, India
| | - Kalpana Rawat
- Computational Biology & Biotechnology Laboratory, Department of Botany, Soban Singh Jeena University, Almora, Uttarakhand, India
| | - Amisha Bisht
- Department of Botany, P.G. College Bageshwar, Soban Singh Jeena University, Almora, Uttarakhand, India
| | - Mohammad Ali Abdullah Almoyad
- Department of Basic Medical Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Khamis Mushyt, Saudi Arabia
| | - Shadma Wahab
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Subhash Chandra
- Computational Biology & Biotechnology Laboratory, Department of Botany, Soban Singh Jeena University, Almora, Uttarakhand, India
| | - Veena Pande
- Department of Biotechnology, Kumaun University, Bhimtal, Uttarakhand, India
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Iman M, Taheri M, Bahari Z. The anti-cancer properties of neem ( Azadirachta indica) through its antioxidant activity in the liver: its pharmaceutics and toxic dosage forms. A literature review. JOURNAL OF COMPLEMENTARY & INTEGRATIVE MEDICINE 2022; 19:203-211. [PMID: 33964199 DOI: 10.1515/jcim-2021-0009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 04/07/2021] [Indexed: 06/12/2023]
Abstract
OBJECTIVES The neem (Azadirachta indica) have been used in herbal medicine for the treatment of multiple diseases, particularly cancer. The mechanism of anti-cancer properties of neem are far from clear. However, it is well accepted that anti-cancer effects of neem is mediated via its hepatic anti-oxidant activity. In the present review, we are going to classify in vitro and in vivo studies about anti-cancer activity of neem via its hepatic anti-oxidant activity. We also summarize its active ingredients and some therapeutic and toxic dosage forms. METHODS A systematic search in the literature was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, as well as Google Scholar pre-print database using all available MeSH terms for neem, A. indica, anti-cancer, anti-tumor, carcinogen, liver, antioxidant activity, neem ingredients, and glutathione. Electronic database searches combined and duplicates were removed. RESULTS The neem plant have been used in herbal medicine for the treatment of various diseases, particularly cancer. The mechanisms of anti-cancer effects of neem are far from clear. Cancerous cells growth can induce imbalance the oxidant and anti-oxidant activity in various organs particularly in the liver. Therefore, it seems that neem have anti-cancer effects via restore of the antioxidant disturbances close to the control ones in the liver. Additionally, administration of neem extract can induce oncostatic potential via several mechanism including; suppression of the NF-κβ pathway, increased expression of tumor suppressor (such as p53 and pTEN), decreased expression of oncogenes (such as c-Myc), and increased apoptosis in cancerous cells. The median lethal dose (LD50) value for extracts of neem was higher than 2,500 mg/kg. CONCLUSIONS It is suggested that neem plays pivotal role in the prevention and treatment of cancer via its hepatic antioxidant activity. Indeed, application of neem extract can decreased tumor growth via restore of the antioxidant disturbances close to the control ones in the liver.
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Affiliation(s)
- Maryam Iman
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Taheri
- Department of Chemistry, Faculty of Sciences, Golestan University, Gorgan, Iran
| | - Zahra Bahari
- Department of Physiology and Medical Physics, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
- Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Nivetha R, Arvindhvv S, Baba AB, Gade DR, Gopal G, K C, Kallamadi KPR, Reddy GB, Nagini S. Nimbolide, a Neem Limonoid, Inhibits Angiogenesis in Breast Cancer by Abrogating Aldose Reductase Mediated IGF-1/PI3K/Akt Signaling. Anticancer Agents Med Chem 2022; 22:2619-2636. [DOI: 10.2174/1871520622666220204115151] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 12/13/2021] [Accepted: 12/17/2021] [Indexed: 11/22/2022]
Abstract
Background & Objectives:
There is growing evidence to implicate the insulin/IGF-1R/PI3K/Akt signaling cascade in breast cancer development and the central role of aldose reductase (AR) in mediating the crosstalk between this pathway and angiogenesis. The current study was designed to investigate whether nimbolide, a neem limonoid, targets this oncogenic signaling network to prevent angiogenesis in breast cancer.
Methods:
Breast cancer cells (MCF-7, MDA-MB-231), EAhy926 endothelial cells, MDA-MB-231 xenografted nude mice, and tumour tissues from breast cancer patients were used for the study. Expression of AR and key players in IGF-1/PI3K/Akt signaling and angiogenesis was evaluated by qRT-PCR, immunoblotting, and immunohistochemistry. Molecular docking and simulation, overexpression, and knockdown experiments were performed to determine whether nimbolide targets AR and IGF-1R
Results:
Nimbolide inhibited AR with consequent blockade of the IGF-1/PI3K/Akt and HIF-1/VEGF signaling circuit by influencing the phosphorylation and intracellular localisation of key signaling molecules. Downregulation of DNMT-1, HDAC-6, miR-21, HOTAIR, and H19 with upregulation of miR-148a/miR-152 indicated that nimbolide regulates AR and IGF-1/PI3K/Akt signaling via epigenetic modifications. Coadministration of nimbolide with metformin and the chemotherapeutic drugs tamoxifen/cisplatin displayed higher efficacy than single agents in inhibiting IGF-1/PI3K/Akt/AR signaling. Grade-wise increases in IGF-1R and AR expression in breast cancer tissues underscore their value as biomarkers of progression.
Conclusions:
This study provides evidence for the anticancer effects of nimbolide in cellular and mouse models of breast cancer besides providing leads for new drug combinations. It has also opened up avenues for investigating potential molecules such as AR for therapeutic targeting of cancer.
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Affiliation(s)
- Ramesh Nivetha
- Department of Biochemistry & Biotechnology, Faculty of Science, Annamalai University, Annamalainagar-608002, Tamil Nadu, India
| | - Soundararajan Arvindhvv
- Department of Biochemistry & Biotechnology, Faculty of Science, Annamalai University, Annamalainagar-608002, Tamil Nadu, India
| | - Abdul Basit Baba
- Department of Biochemistry & Biotechnology, Faculty of Science, Annamalai University, Annamalainagar-608002, Tamil Nadu, India
| | - Deepak Reddy Gade
- Centre for Molecular Cancer Research, Vishnu Institute of Pharmaceutical Education and Research, Narsapur, India
| | - Gopisetty Gopal
- Department of Molecular Oncology, Cancer Institute (WIA), Adyar, Chennai 600020, Tamil Nadu, India
| | - Chitrathara K
- Department of Surgical & Gynecologic Oncology, VPS Lakeshore Hospital, Nettoor, Maradu, Kochi, Kerala 682040
| | | | - G. Bhanuprakash Reddy
- Department of Biochemistry, ICMR-National Institute of Nutrition, Hyderabad-500007, India
| | - Siddavaram Nagini
- Department of Biochemistry & Biotechnology, Faculty of Science, Annamalai University, Annamalainagar-608002, Tamil Nadu, India
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Amadi PU, Agomuo EN, Ukaga CN, Njoku UC, Amadi JA, Nwaekpe CG. Preclinical Trial of Traditional Plant Remedies for the Treatment of Complications of Gestational Malaria. MEDICINES (BASEL, SWITZERLAND) 2021; 8:79. [PMID: 34940291 PMCID: PMC8703497 DOI: 10.3390/medicines8120079] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/14/2021] [Accepted: 12/14/2021] [Indexed: 12/16/2022]
Abstract
Background: Most pregnant women living in high malaria endemic regions of Nigeria use herbal remedies for the management of malaria-in-pregnancy, rather than the commonly prescribed drugs. Remedies common to this area involve a suspension of A. indica (AI) leaves and in some cases, a suspension containing a mixture of AI and D.edulis (PS). Aim: This study examined the therapeutic efficacies of AI, PS, or a combination of AI and PS in a pregnant rat model for exoerythrocytic stages of Plasmodium falciparum parasite. Method: A predetermined sample size of 30 dams was used (for a power level and confidence interval of 95%), and divided equally into six groups made up of non-malarous dams, untreated malarous dams, and malarous dams either treated exclusively with 1 mL of 3000 mg/kg b.w AI, 1000 mg/kg b.w PS, AI + PS (50% v/v), or 25 mg/kg b.w CQ. Result: No maternal mortality was recorded. AI significantly improved maternal weight gain from 32.4 to 82.2 g and placental weight from 0.44 to 0.53 g. In the curative test, AI and AI + PS significantly reduced the average percentage parasitemia (APP) in the pregnant rats from >80% to <20%. No significant difference in the APP was found between the pregnant rats treated with any of CQ or AI during the suppressive test. Results for the prophylactic test of the study groups showed that the APP was significantly reduced from 24.69% to 3.90% when treated with AI and 3.67% when combined with PS. AI + PS reduced diastolic blood pressure from 89.0 to 81.0 mm/Hg and compared with that of the non malarous dams. AI or AI + PS significantly increased the platelet counts (103 µL) from 214.1 to 364.5 and 351.2, respectively. AI and AI + PS improved birth weight from 2.5 to 3.9 g and crown rump length from 2.6 to 4.1 cm. For biomarkers of preeclampsia, combining AI and PS led to the reversal of the altered levels of creatine kinase, lactate dehydrogenase, cardiac troponin, soluble Fms-Like Tyrosine Kinase-1, and placental growth factor. Conclusions: This study validates the use of A. indica for the treatment of gestational malaria due to its antiplasmodial and related therapeutic effects and in combination with pear seeds for the management of malaria-in-pregnancy-induced preeclampsia.
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Affiliation(s)
| | | | - Chinyere Nneka Ukaga
- Department of Animal and Environmental Biology, Imo State University, Owerri 460102, Nigeria;
| | - Uche Chinedu Njoku
- Department of Biochemistry, University of Port Harcourt, Choba 500102, Nigeria;
| | - Joy Adaku Amadi
- Department of Nutrition and Dietetics, Imo State University, Owerri 460102, Nigeria;
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Attah AF, Fagbemi AA, Olubiyi O, Dada-Adegbola H, Oluwadotun A, Elujoba A, Babalola CP. Therapeutic Potentials of Antiviral Plants Used in Traditional African Medicine With COVID-19 in Focus: A Nigerian Perspective. Front Pharmacol 2021; 12:596855. [PMID: 33981214 PMCID: PMC8108136 DOI: 10.3389/fphar.2021.596855] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 01/20/2021] [Indexed: 12/12/2022] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic is caused by an infectious novel strain of coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which was earlier referred to as 2019-nCoV. The respiratory disease is the most consequential global public health crisis of the 21st century whose level of negative impact increasingly experienced globally has not been recorded since World War II. Up till now, there has been no specific globally authorized antiviral drug, vaccines, supplement or herbal remedy available for the treatment of this lethal disease except preventive measures, supportive care and non-specific treatment options adopted in different countries via divergent approaches to halt the pandemic. However, many of these interventions have been documented to show some level of success particularly the Traditional Chinese Medicine while there is paucity of well reported studies on the impact of the widely embraced Traditional African Medicines (TAM) adopted so far for the prevention, management and treatment of COVID-19. We carried out a detailed review of publicly available data, information and claims on the potentials of indigenous plants used in Sub-Saharan Africa as antiviral remedies with potentials for the prevention and management of COVID-19. In this review, we have provided a holistic report on evidence-based antiviral and promising anti-SARS-CoV-2 properties of African medicinal plants based on in silico evidence, in vitro assays and in vivo experiments alongside the available data on their mechanistic pharmacology. In addition, we have unveiled knowledge gaps, provided an update on the effort of African Scientific community toward demystifying the dreadful SARS-CoV-2 micro-enemy of man and have documented popular anti-COVID-19 herbal claims emanating from the continent for the management of COVID-19 while the risk potentials of herb-drug interaction of antiviral phytomedicines when used in combination with orthodox drugs have also been highlighted. This review exercise may lend enough credence to the potential value of African medicinal plants as possible leads in anti-COVID-19 drug discovery through research and development.
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Affiliation(s)
- Alfred Francis Attah
- Department of Pharmacognosy and Drug Development, Faculty of Pharmaceutical Sciences, University of Ilorin, Ilorin, Nigeria
| | - Adeshola Adebayo Fagbemi
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ibadan, Ibadan, Nigeria
| | - Olujide Olubiyi
- Department of Pharmaceutical Chemistry, Obafemi Awolowo University, Ile-Ife, Nigeria
- Institute of Biological Information Processing, Structural Biochemistry (IBI-7), Forschungszentrum Jülich, Jülich, Germany
| | - Hannah Dada-Adegbola
- Department of Medical Microbiology and Parasitology, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | | | - Anthony Elujoba
- Department of Pharmacognosy, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria
| | - Chinedum Peace Babalola
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ibadan, Ibadan, Nigeria
- Centre for Drug Discovery, Development and Production, University of Ibadan, Ibadan, Nigeria
- College of Basic Medical Sciences, Chrisland University, Abeokuta, Nigeria
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Nagini S, Nivetha R, Palrasu M, Mishra R. Nimbolide, a Neem Limonoid, Is a Promising Candidate for the Anticancer Drug Arsenal. J Med Chem 2021; 64:3560-3577. [PMID: 33739088 DOI: 10.1021/acs.jmedchem.0c02239] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Nimbolide, a major limonoid constituent of Azadirachta indica, commonly known as neem, has attracted increasing research attention owing to its wide spectrum of pharmacological properties, predominantly anticancer activity. Nimbolide is reported to exert potent antiproliferative effects on a myriad cancer cell lines and chemotherapeutic efficacy in preclinical animal tumor models. The potentiality of nimbolide to circumvent multidrug resistance and aid in targeted protein degradation broaden its utility in enhancing therapeutic modalities and outcome. Accumulating evidence indicates that nimbolide prevents the acquisition of cancer hallmarks such as sustained proliferation, apoptosis evasion, invasion, angiogenesis, metastasis, and inflammation by modulating kinase-driven oncogenic signaling networks. Nimbolide has been demonstrated to abrogate aberrant activation of cellular signaling by influencing the subcellular localization of transcription factors and phosphorylation of kinases in addition to influencing the epigenome. Nimbolide, with its ever-expanding repertoire of molecular targets, is a valuable addition to the anticancer drug arsenal.
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Affiliation(s)
- Siddavaram Nagini
- Department of Biochemistry & Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, Tamil Nadu 608002, India
| | - Ramesh Nivetha
- Department of Biochemistry & Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, Tamil Nadu 608002, India
| | - Manikandan Palrasu
- Department of Surgery, University of Miami Miller School of Medicine, Rosenstiel Medical Sciences Building, Suite 4116, 1600 NW 10th Avenue, Miami, Florida 33136, United States
| | - Rajakishore Mishra
- Centre for Life Sciences, School of Natural Sciences, Central University of Jharkhand, Ratu-Lohardaga Road, Brambe, Ranchi, Jharkhand 835205, India
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Ram AK, Vairappan B, Srinivas BH. Nimbolide inhibits tumor growth by restoring hepatic tight junction protein expression and reduced inflammation in an experimental hepatocarcinogenesis. World J Gastroenterol 2020; 26:7131-7152. [PMID: 33362373 PMCID: PMC7723674 DOI: 10.3748/wjg.v26.i45.7131] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 09/28/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Altered tight junction (TJ) proteins are correlated with carcinogenesis and tumor development. Nimbolide is a tetranotriterpenoid that has been shown to have antioxidant and anti-proliferative properties; however, its anticancer effects and molecular mechanism in hepatocellular carcinoma (HCC) remains obscure. AIM To investigate the effect of nimbolide on TJ proteins, cell cycle progression, and hepatic inflammation in a mouse model of HCC. METHODS HCC was induced in male Swiss albino mice (CD-1 strain) by a single intraperitoneal injection of 100 mg/kg diethylnitrosamine (DEN) followed by 80 ppm N-nitrosomorpholine (NMOR) in drinking water for 28 wk. After 28 wk, nimbolide (6 mg/kg) was given orally for four consecutive weeks in DEN/NMOR induced HCC mice. At the end of the 32nd week, all the mice were sacrificed and blood and liver samples were collected for various analyses. Macroscopic examinations of hepatic nodules were assessed. Liver histology and HCC tumor markers such as alpha-fetoprotein (AFP) and glypican-3 were measured. Expression of TJ proteins, cell proliferation, and cell cycle markers, inflammatory markers, and oxidative stress markers were analyzed. In silico analysis was performed to confirm the binding and modulatory effect of nimbolide on zonula occludens 1 (ZO-1), nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB), and tumor necrosis factor alpha (TNF-α). RESULTS We found nimbolide treatment at a concentration of 6 mg/kg to HCC mice reduced hepatic tumor size by 52.08% and tumor volume (P < 0.01), and delayed tumor growth in HCC mice with a concomitant reduction in tumor markers such as AFP levels (P < 0.01) and glypican-3 expression (P < 0.05). Furthermore, nimbolide treatment increased tight junction proteins such as ZO-1 and occludin expression (P < 0.05, respectively) and reduced ZO-1 associated nucleic acid binding protein expression (P < 0.001) in HCC mice liver. Nimbolide treatment to HCC mice also inhibited cell proliferation and suppressed cell cycle progression by attenuating proliferating cell nuclear antigen (P < 0.01), cyclin dependent kinase (P < 0.05), and CyclinD1 (P < 0.05) expression. In addition, nimbolide treatment to HCC mice ameliorated hepatic inflammation by reducing NF-κB, interleukin 1 beta and TNF-α expression (P < 0.05, respectively) and abrogated oxidative stress by attenuating 4-hydroxynonenal expression (P < 0.01). Molecular docking studies further confirmed that nimbolide interacts with ZO-1, NF-κB, and TNF-α. CONCLUSION Our current study showed for the first time that nimbolide exhibits anticancer effect by reducing tumor size, tumor burden and by suppressing cell cycle progression in HCC mice. Furthermore, nimbolide treatment to HCC mice ameliorated inflammation and oxidative stress, and improved TJ proteins expression. Consequently, nimbolide could be potentially used as a natural therapeutic agent for HCC treatment, however further human studies are warranted.
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Affiliation(s)
- Amit Kumar Ram
- Liver Diseases Research Lab,Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Dhanvantari Nagar, Puducherry 605006, India
| | - Balasubramaniyan Vairappan
- Liver Diseases Research Lab,Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Dhanvantari Nagar, Puducherry 605006, India
| | - BH Srinivas
- Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Dhanvantari Nagar, Puducherry 605006, India
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Islas JF, Acosta E, G-Buentello Z, Delgado-Gallegos JL, Moreno-Treviño MG, Escalante B, Moreno-Cuevas JE. An overview of Neem (Azadirachta indica) and its potential impact on health. J Funct Foods 2020; 74:104171. [DOI: https:/doi.org/10.1016/j.jff.2020.104171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
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Mitra T, Bhattacharya R. Phytochemicals modulate cancer aggressiveness: A review depicting the anticancer efficacy of dietary polyphenols and their combinations. J Cell Physiol 2020; 235:7696-7708. [PMID: 32324275 DOI: 10.1002/jcp.29703] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 03/28/2020] [Accepted: 04/01/2020] [Indexed: 12/11/2022]
Abstract
Cancer is referred to as the "Emperor of all maladies" accounting for the second-highest mortality rates worldwide. Major factors associated with cancer lethality are uncontrolled proliferation, metastasis, and frequent recurrence. The conventional therapeutic drugs used in cancer therapy have been associated with numerous damaging side-effects that call for the use of alternative therapeutic options. The natural plant compounds (NPCs) have been found to be effective against diverse groups of diseases including cancer. Among the different types, the polyphenolic phytochemicals like curcumin, (-)epigallocatechin-3-gallate, Resveratrol, and nimbolide which are predominant parts of daily dietary intake have proved their potency in reducing the aggressive properties of cancer. Here, we have highlighted the mechanisms through which these NPCs influence growth, metastatic potential, and the drug-resistant behavior of different cancer types. Moreover, we have also emphasized on their function as modulators of the immune system as well as the metabolic properties of the tumor. The role of these phytochemicals in reducing cancer progression has been highlighted when administered unaided or in combination with similar group of compounds. Moreover, their ability to enhance the drug-sensitivity of cancer cells which accounts for their use in combination with conventional chemotherapeutics has also been discussed in this article. Therefore, co-administration of these phytochemicals with chemically similar group members or with conventional chemotherapeutics may prove to be an effective treatment strategy for cancer.
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Affiliation(s)
- Tulika Mitra
- Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Rahul Bhattacharya
- Amity Institute of Biotechnology, Amity University, Kolkata, Kolkata, West Bengal, India
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A review of the anticancer activity of Azadirachta indica (Neem) in oral cancer. J Oral Biol Craniofac Res 2020; 10:206-209. [PMID: 32489822 DOI: 10.1016/j.jobcr.2020.04.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 04/09/2020] [Accepted: 04/11/2020] [Indexed: 02/07/2023] Open
Abstract
Background Azadirachta indica (neem), belongs to the family of Meliaceae plants, is found in the Indian subcontinent. The neem tree is colloquially referred to as the village pharmacy due to its array of biological properties. Every part of the neem tree like its bark, leaves, sap, fruit, seeds, and twigs find a multitude of uses. It is customary to use them for management of skin diseases and various other infections.The anticancer properties of neem have been studied in the past and these include its ability to modulate the tumour environment, increase the cytotoxic ability of host monocytes and suppress the proliferation of tumour cells. The present review was conducted with the objective of scrutinizing and assimilating data about the usefulness Azadirachta indica in oral cancer from all the previously done work. Material and methods A planned review was conducted of all the studies that investigated the role of Azadirachta indica in oral cancer. Literature search was carried out using PubMed, Scopus and Google scholar databases. In addition to electronic searching, hand searching, cross referencing and various internet engines were also used to collect data. The articles were perused and articles not pertinent to our search were omitted. Results and conclusion The anticancer properties of neem were evaluated and the active constituents of neem have been demonstrated to unequivocally have preventive and therapeutic potential against oral cancer. Although, greater exploration of the anticancer properties of neem are required in order to effectively integrate it into the routine management of oral cancer.
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Bansod S, Aslam Saifi M, Khurana A, Godugu C. Nimbolide abrogates cerulein-induced chronic pancreatitis by modulating β-catenin/Smad in a sirtuin-dependent way. Pharmacol Res 2020; 156:104756. [PMID: 32194177 DOI: 10.1016/j.phrs.2020.104756] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 12/28/2019] [Accepted: 03/13/2020] [Indexed: 12/18/2022]
Abstract
Chronic pancreatitis (CP) is one of the leading causes of mortality worldwide with no clinically approved therapeutic interventions. The present study was designed to investigate the protective effect of nimbolide (NB), an active constituent of neem tree (Azadirachta indica), by targeting β-catenin/Smad/SIRT1 in cerulein-induced CP model. The effects of NB was investigated on cerulein (50 μg/kg/hr*6 exposures /day, 3 days a week for 3 weeks) induced CP in mice. Amylase and lipase activity were measured and histopathological evaluation was performed. Collagen deposition in the pancreatic tissue was estimated by hydroxyproline assay, and collagen specific staining picrosirius red and Masson's trichrome. Cerulein-induced CP was significantly controlled by NB treatment, as shown by the downregulation of β-catenin/Smad signaling in a SIRT1 dependent manner. NB treatment significantly decreased α-SMA, MMP-2, collagen1a, fibronectin, TGF-β1, p-Smad-2/3 expression and extracellular matrix (ECM) deposition in pancreatic tissue. However, the protective effects of NB on cerulein-induced CP were undermined by nicotinamide (NMD) or splitomicin, sirtuin 1 (SIRT1) inhibitors treatment. NB treatment modulated protein expression by activating SIRT1 and decreasing the expression of β-catenin/Smad proteins in CP mice. However, the expression of SIRT1 in pancreatic tissue was elevated by NB treatment and it was decreased by NMD or splitomicin treatment. In summary, our results strongly suggest that NB exerted promising protective effects in cerulein-induced CP model by inhibiting β-catenin/Smad in a sirtuin-dependent manner, which could be attributed to its anti-inflammatory and antifibrotic effects. Our study suggests that NB could be an effective therapeutic intervention for the treatment of CP.
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Affiliation(s)
- Sapana Bansod
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, 500037, India
| | - Mohd Aslam Saifi
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, 500037, India
| | - Amit Khurana
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, 500037, India
| | - Chandraiah Godugu
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, 500037, India.
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Ashokhan S, Othman R, Abd Rahim MH, Karsani SA, Yaacob JS. Effect of Plant Growth Regulators on Coloured Callus Formation and Accumulation of Azadirachtin, an Essential Biopesticide in Azadirachta indica. PLANTS (BASEL, SWITZERLAND) 2020; 9:E352. [PMID: 32168737 PMCID: PMC7154880 DOI: 10.3390/plants9030352] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 01/17/2020] [Accepted: 01/18/2020] [Indexed: 11/16/2022]
Abstract
For centuries, Azadirachta indica or neem has been utilized as a primary source of medicine due to its antimicrobial, larvacidal, antimalarial and antifungal properties. Recently, its potential as an effective biopesticide has garnered attention, especially towards efficient and continuous production of its bioactive compounds. The present study investigated the effect of the plant growth regulators (PGRs) thiadiazuron (TDZ) and 2,4-dichlorophenoxyacetic acid (2,4-D) on the induction of colored callus formation and subsequent accumulation of azadirachtin (AZA) in A. indica. An efficient protocol was established for micropropagation and colored callus production of this species, followed by quantification of AZA (a mixture of azadirachtin A and B) and its safety assessment. For induction of the callus, leaf and petiole explants obtained from a young growing neem plant were excised and cultured on Murashige and Skoog (MS) medium supplemented with TDZ (0.2-0.6 mg L-1) and 2,4-D (0.2-0.6 mg L-1), either applied singly or in combination. Callus was successfully induced from both explant types at different rates, where media with 0.6 mg L-1 of TDZ resulted in the highest fresh weight (3.38 ± 0.08 g). In general, media with a single hormone (particularly TDZ) was more effective in producing a high mass of callus compared to combined PGRs. A culture duration of six weeks resulted in the production of green, brown and cream colored callus. The highest callus weight and accumulation of AZA was recorded in green callus (214.53 ± 33.63 mg g-1 dry weight (DW)) induced using TDZ. On the other hand, small amounts of AZA were detected in both brown and cream callus. Further experimentation indicated that the green callus with the highest AZA was found to be non-toxic (LC50 at 4606 µg mL-1) to the zebrafish animal model. These results suggested that the addition of different PGRs during in vitro culture could prominently affect callus and secondary metabolite production and can further be manipulated as a sustainable method for the production of a natural and environmentally friendly pesticide.
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Affiliation(s)
- Sharmilla Ashokhan
- Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia; (S.A.); (S.A.K.)
| | - Rashidi Othman
- International Institute for Halal Research and Training (INHART), Herbarium Unit, Department of Landscape Architecture, Kulliyyah of Architecture and Environment Design, International Islamic University Malaysia, Kuala Lumpur 53100, Malaysia;
| | - Muhamad Hafiz Abd Rahim
- Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, UPM Serdang 43400, Malaysia
| | - Saiful Anuar Karsani
- Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia; (S.A.); (S.A.K.)
| | - Jamilah Syafawati Yaacob
- Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia; (S.A.); (S.A.K.)
- Centre for Research in Biotechnology for Agriculture (CEBAR), University of Malaya, Kuala Lumpur 50603, Malaysia
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Patra A, Satpathy S, Hussain MD. Nanodelivery and anticancer effect of a limonoid, nimbolide, in breast and pancreatic cancer cells. Int J Nanomedicine 2019; 14:8095-8104. [PMID: 31632020 PMCID: PMC6789415 DOI: 10.2147/ijn.s208540] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 08/28/2019] [Indexed: 11/23/2022] Open
Abstract
Introduction Nimbolide (Nim), a limonoid obtained from the neem tree, Azadirachta indica, has several pharmacological properties, including anticancer effects in different type of cancers. No drug-delivery system has been reported for enhancing the therapeutic application of this novel hydrophobic molecule. Methods In the present research, poly(lactic-co-glycolic acid) (PLGA) nanoparticles of Nim (Nim-nano) were formulated by nanoprecipitation, characterized for physicochemical properties, and screened for anticancer potential in breast (MCF-7 and MDA-MB-231) and pancreatic (AsPC-1) cancer cell lines. Results The Nim-nano had a particle size of 183.73±2.22 nm and 221.20±11.03 nm before and after lyophilization, respectively. Cryoprotectants (mannitol and sucrose) significantly inhibited growth in particle size due to lyophilization. The ζ-potential of the Nim-nano was −22.40±4.40 mV. Drug loading and encapsulation efficiency of Nim-nano were 5.25%±1.12% and 55.67%±12.42%, respectively. The Nim-nano exhibited sustained release of Nim for more than 6 days in PBS (pH 7.4) and showed two- to three-fold enhanced cytotoxicity in breast and pancreatic cancer cell lines compared with free Nim. Conclusion The Nim-nano formulation has great potential for treatment of cancers, such as pancreatic and breast cancer. Further, the PLGA-polymer surface can be modified by conjugation with polyethylene glycol, receptor-binding ligands (eg, folic acid), and other that which may lead to targeted delivery of Nim in the treatment of cancer.
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Affiliation(s)
- Arjun Patra
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Health Sciences University, Clovis, CA, USA.,Institute of Pharmacy, Guru Ghasidas University, Bilaspur, CG, India
| | - Swaha Satpathy
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Health Sciences University, Clovis, CA, USA.,Institute of Pharmacy, Guru Ghasidas University, Bilaspur, CG, India
| | - Muhammad Delwar Hussain
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Health Sciences University, Clovis, CA, USA
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Qamar H, Rehman S, Chauhan D. Current Status and Future Perspective for Research on Medicinal Plants with Anticancerous Activity and Minimum Cytotoxic Value. Curr Drug Targets 2019; 20:1227-1243. [DOI: 10.2174/1389450120666190429120314] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 04/18/2019] [Accepted: 04/18/2019] [Indexed: 12/14/2022]
Abstract
Cancer is the second leading cause of morbidity and mortality worldwide. Although chemotherapy
and radiotherapy enhance the survival rate of cancerous patients but they have several acute
toxic effects. Therefore, there is a need to search for new anticancer agents having better efficacy and
lesser side effects. In this regard, herbal treatment is found to be a safe method for treating and preventing
cancer. Here, an attempt has been made to screen some less explored medicinal plants like
Ammania baccifera, Asclepias curassavica, Azadarichta indica, Butea monosperma, Croton tiglium,
Hedera nepalensis, Jatropha curcas, Momordica charantia, Moringa oleifera, Psidium guajava, etc.
having potent anticancer activity with minimum cytotoxic value (IC50 >3μM) and lesser or negligible
toxicity. They are rich in active phytochemicals with a wide range of drug targets. In this study, these
medicinal plants were evaluated for dose-dependent cytotoxicological studies via in vitro MTT assay
and in vivo tumor models along with some more plants which are reported to have IC50 value in the
range of 0.019-0.528 mg/ml. The findings indicate that these plants inhibit tumor growth by their antiproliferative,
pro-apoptotic, anti-metastatic and anti-angiogenic molecular targets. They are widely
used because of their easy availability, affordable price and having no or sometimes minimal side effects.
This review provides a baseline for the discovery of anticancer drugs from medicinal plants having
minimum cytotoxic value with minimal side effects and establishment of their analogues for the
welfare of mankind.
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Affiliation(s)
- Hina Qamar
- Department of Zoology, Chaudhary Charan Singh University, Meerut, India
| | - Sumbul Rehman
- Department of Ilmul Advia (Unani Pharmacology), A.K. Tibbiya College, Aligarh Muslim University, Aligarh, India
| | - D.K. Chauhan
- Department of Zoology, Chaudhary Charan Singh University, Meerut, India
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Nimbolide ameliorates unilateral ureteral obstruction-induced renal fibrosis by inhibition of TGF-β and EMT/Slug signalling. Mol Immunol 2019; 112:247-255. [PMID: 31202101 DOI: 10.1016/j.molimm.2019.06.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 05/22/2019] [Accepted: 06/02/2019] [Indexed: 12/30/2022]
Abstract
Chronic kidney disease (CKD) involves interstitial fibrosis as an underlying pathological process associated with compromised renal function irrespective of etiological cause of the injury. The transforming growth factor-β (TGF-β) plays a pivotal role in progression of renal fibrosis. TGF-β transduces its downstream signalling by phosphorylation of smad2/3 and also regulates epithelial-mesenchymal-transition (EMT), a program centrally involved in activation of fibroblasts. Renal fibrosis was induced in Swiss albino mice by unilateral ureteral obstruction of animals. Kidney tissues were evaluated for fibrotic protein expression by western blot and immunohistochemistry. The administration of nimbolide (NB) to UUO animals reduced the oxidative stress, expression of ECM proteins, TGF-β, p-smad and EMT program. Further, NB administration also improved histoarchitecture of obstructed kidney and reduced the collagen deposition in kidney. Our results provided compelling evidence to support antifibrotic activity of NB by reduction in oxidative stress, TGF-β, and EMT program in fibrotic kidney. The administration of NB in animals blunted the UUO-induced renal injury, inflammation and reduced fibrogenesis in obstructed kidney.
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Cytotoxicity of nimbolide towards multidrug-resistant tumor cells and hypersensitivity via cellular metabolic modulation. Oncotarget 2018; 9:35762-35779. [PMID: 30515268 PMCID: PMC6254660 DOI: 10.18632/oncotarget.26299] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 10/24/2018] [Indexed: 12/20/2022] Open
Abstract
Nimbolide is considered a promising natural product in cancer prevention and treatment. However, it is not known yet, whether the different mechanisms of multidrug resistance (MDR) influence its anticancer activity. In this study, well-known MDR mechanisms (ABCB1, ABCG2, ABCB5, TP53, EGFR) were evaluated against nimbolide. The P-glycoprotein (ABCB1/MDR1)-overexpressing CEM/ADR5000 cell line displayed remarkable hypersensitivity to nimbolide, which was mediated through upregulation of the tumor suppressor, PTEN, and its downstream components resulted in significant downregulation in ABCB1/MDR1 mRNA and P-glycoprotein. In addition, nimbolide targeted essential cellular metabolic-regulating elements including HIF1α, FoxO1, MYC and reactive oxygen species. The expression of breast cancer resistance protein (BCRP) as well as epidermal growth factor receptor (EGFR) and mutant tumor suppressor TP53 did not correlate to nimbolide’s activity. Furthermore, this paper looked for other molecular determinants that might determine tumor cellular response towards nimbolide. COMPARE and hierarchical cluster analyses of transcriptome-wide microarray-based mRNA expressions of the NCI 60 cell line panel were performed, and a set of 40 genes from different functional groups was identified. The data suggested NF-κB as master regulator of nimbolide’s activity. Interestingly, HIF1α was determined by COMPARE analysis to mediate sensitivity to nimbolide, which would be of great benefit in targeted therapy.
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Sophia J, Kowshik J, Dwivedi A, Bhutia SK, Manavathi B, Mishra R, Nagini S. Nimbolide, a neem limonoid inhibits cytoprotective autophagy to activate apoptosis via modulation of the PI3K/Akt/GSK-3β signalling pathway in oral cancer. Cell Death Dis 2018; 9:1087. [PMID: 30352996 PMCID: PMC6199248 DOI: 10.1038/s41419-018-1126-4] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 09/24/2018] [Accepted: 10/04/2018] [Indexed: 02/08/2023]
Abstract
Of late, nimbolide, a limonoid from the neem tree (Azadirachta indica) has gained increasing research attention owing to its potent antiproliferative and apoptosis-inducing effects. The present study was designed to investigate the effect of nimbolide on autophagy and the time point at which the phosphorylation status of GSK-3β and PI3K dictate the choice between autophagy and apoptosis in SCC131 and SCC4 oral cancer cells. Additionally, we analysed changes in the expression of proteins involved in autophagy and apoptosis after therapeutic intervention with nimbolide in a hamster model of oral oncogenesis. Furthermore, we also demonstrate changes in the expression of key genes involved in apoptosis and autophagy during the stepwise evolution of hamster and human OSCCs. Nimbolide-induced stereotypical changes in oral cancer cells characteristic of both apoptosis and autophagy. Time-course experiments revealed that nimbolide induces autophagy as an early event and then switches over to apoptosis. Nimbolide negatively regulates PI3K/Akt signalling with consequent increase in p-GSK-3βTyr216, the active form of GSK-3β that inhibits autophagy. Downregulation of HOTAIR, a competing endogenous RNA that sponges miR-126 may be a major contributor to the inactivation of PI3K/Akt/GSK3 signalling by nimbolide. Analysis of key markers of apoptosis and autophagy as well as p-AktSer473 during sequential progression of hamster and human OSCC revealed a gradual evolution to a pro-autophagic and antiapoptotic phenotype that could confer a survival advantage to tumors. In summary, the results of the present study provide insights into the molecular mechanisms by which nimbolide augments apoptosis by overcoming the shielding effects of cytoprotective autophagy through modulation of the phosphorylation status of Akt and GSK-3β as well as the ncRNAs miR-126 and HOTAIR. Development of phytochemicals such as nimbolide that target the complex interaction between proteins and ncRNAs that regulate the autophagy/apoptosis flux is of paramount importance in cancer prevention and therapeutics.
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Affiliation(s)
- Josephraj Sophia
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, 608 002, Tamil Nadu, India
| | - Jaganathan Kowshik
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, 608 002, Tamil Nadu, India
| | - Anju Dwivedi
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India
| | - Sujit K Bhutia
- Department of Life Science, National Institute of Technology Rourkela, Rourkela, 769008, Odisha, India
| | - Bramanandam Manavathi
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India
| | - Rajakishore Mishra
- Centre for Life Sciences, School of Natural Sciences, Central University of Jharkhand, Ranchi, 835205, Jharkhand, India
| | - Siddavaram Nagini
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, 608 002, Tamil Nadu, India.
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A Sensitive Liquid Chromatography-Tandem Mass Spectrometry Method for the Determination of Nimbolide in Mouse Serum: Application to a Preclinical Pharmacokinetics Study. Pharmaceutics 2018; 10:pharmaceutics10030123. [PMID: 30096831 PMCID: PMC6161292 DOI: 10.3390/pharmaceutics10030123] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 07/30/2018] [Accepted: 07/31/2018] [Indexed: 02/02/2023] Open
Abstract
A sensitive and robust liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the determination of nimbolide in mouse serum. Exemestane was used as the internal standard (IS). Here, we employed acetonitrile-based protein precipitation (PPT) for serum sample preparation, and performed chromatographic separation using an ODS Hypersil C18 column (100 mm × 2.1 mm, 5 µm) with gradient elution (0.1% formic acid in water vs 100% acetonitrile). The run time was 6 min. Instrumental analysis was performed by electrospray ionization tandem mass spectrometry (ESI-MS/MS) in the multiple-reaction monitoring (MRM) under positive mode. A good linear calibration was achieved in the 5–1000 ng/mL range. The intra- and inter-day precisions for nimbolide were ≤12.6% and ≤13.9% respectively. Intra-day accuracy ranged from 96.9–109.3%, while inter-day accuracy ranged from 94.3–110.2%. The matrix effect of nimbolide, detected but consistent at low and high concentrations, do not affect linearity of standard curve. In conclusion, we have developed and validated a sensitive analytical method for determination of a novel natural compound nimbolide in mouse serum, and it has been successfully applied to our preclinical study in investigating the pharmacokinetic properties of nimbolide, which could greatly facilitate the preclinical development of the promising lead compound for anticancer therapy.
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First report on the pharmacokinetic profile of nimbolide, a novel anticancer agent in oral and intravenous administrated rats by LC/MS method. J Chromatogr B Analyt Technol Biomed Life Sci 2018; 1092:191-198. [DOI: 10.1016/j.jchromb.2018.06.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 05/08/2018] [Accepted: 06/01/2018] [Indexed: 12/17/2022]
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Kumar S, Inigo JR, Kumar R, Chaudhary AK, O'Malley J, Balachandar S, Wang J, Attwood K, Yadav N, Hochwald S, Wang X, Chandra D. Nimbolide reduces CD44 positive cell population and induces mitochondrial apoptosis in pancreatic cancer cells. Cancer Lett 2017; 413:82-93. [PMID: 29107110 DOI: 10.1016/j.canlet.2017.10.029] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 10/16/2017] [Accepted: 10/19/2017] [Indexed: 12/15/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive disease and current treatment regimens fail to effectively cure PDAC. Development of resistance to current therapy is one of the key reasons for this outcome. Nimbolide (NL), a triterpenoid obtained from Azadirachta indica, exhibits anticancer properties in various cancer including PDAC cells. However, the underlying mechanism of this anticancer agent in PDAC cells remains undefined. We show that NL exerts a higher level of apoptotic cell death compared to the first-line agent gemcitabine for PDAC, as well as other anticancer agents including sorafenib and curcumin. The anticancer efficacy of NL was further evidenced by a reduction in the CD44+ as well as cancer stem-like cell (CSC) population, as it causes decreased sphere formation. Mechanistically, the anticancer efficacy of NL associates with reduced mutant p53 as well as increased mitochondrial activity in the form of increased mitochondrial reactive oxygen species and mitochondrial mass. Together, this study highlights the therapeutic potential of NL in mutant p53 expressing pancreatic cancer.
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Affiliation(s)
- Sandeep Kumar
- Department of Pharmacology and Therapeutics, Center for Genetics and Pharmacology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA
| | - Joseph R Inigo
- Department of Pharmacology and Therapeutics, Center for Genetics and Pharmacology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA
| | - Rahul Kumar
- Department of Pharmacology and Therapeutics, Center for Genetics and Pharmacology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA
| | - Ajay K Chaudhary
- Department of Pharmacology and Therapeutics, Center for Genetics and Pharmacology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA
| | - Jordan O'Malley
- Department of Pharmacology and Therapeutics, Center for Genetics and Pharmacology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA
| | - Srimmitha Balachandar
- Department of Pharmacology and Therapeutics, Center for Genetics and Pharmacology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA
| | - Jianmin Wang
- Department of Bioinformatics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA
| | - Kristopher Attwood
- Department of Biostatistics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA
| | - Neelu Yadav
- Department of Pharmacology and Therapeutics, Center for Genetics and Pharmacology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA
| | - Steven Hochwald
- Department of Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA
| | - Xinjiang Wang
- Department of Pharmacology and Therapeutics, Center for Genetics and Pharmacology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA
| | - Dhyan Chandra
- Department of Pharmacology and Therapeutics, Center for Genetics and Pharmacology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA.
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Gupta SC, Prasad S, Tyagi AK, Kunnumakkara AB, Aggarwal BB. Neem (Azadirachta indica): An indian traditional panacea with modern molecular basis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2017; 34:14-20. [PMID: 28899496 DOI: 10.1016/j.phymed.2017.07.001] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2016] [Revised: 05/29/2017] [Accepted: 07/01/2017] [Indexed: 05/18/2023]
Abstract
BACKGROUND For centuries, agents derived from natural sources (mother nature), especially plants have been the primary source of medicine. Neem, also referred to as Azadirachta indica is one such plant that has been so named because it provides freedom from all diseases, and used for thousands of years in Indian and African continents. Different parts of the plant including flowers, leaves, seeds and bark have been used to treat both acute and chronic human diseases; and used as insecticide; antimicrobial, larvicidal, antimalarial, antibacterial, antiviral, and spermicidal. PURPOSE What is there in neem and how it manifests its wide variety of effects is the focus of this review. How neem and its constituents modulate various cellular pathways is discussed. The animal and human studies carried out with neem and its constituents is also discussed. CONCLUSION Over 1000 research articles published on neem has uncovered over 300 structurally diverse constituents, one third of which are limonoids including nimbolide, azadarachtin, and gedunin. These agents manifest their effects by modulating multiple cell signaling pathways.
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Affiliation(s)
- Subash Chandra Gupta
- Laboratory for Translational Cancer Research, Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India.
| | - Sahdeo Prasad
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Amit K Tyagi
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, USA
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Raja Singh P, Sugantha Priya E, Balakrishnan S, Arunkumar R, Sharmila G, Rajalakshmi M, Arunakaran J. Inhibition of cell survival and proliferation by nimbolide in human androgen-independent prostate cancer (PC-3) cells: involvement of the PI3K/Akt pathway. Mol Cell Biochem 2016; 427:69-79. [PMID: 28025797 DOI: 10.1007/s11010-016-2898-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 12/02/2016] [Indexed: 01/12/2023]
Abstract
Prostate cancer is most common malignancy among men in the world. PI3K-Akt signaling appears to be critical to prostate cancer cell proliferation and survival. Our earlier study reveals that nimbolide (2 µM) prevents cell survival via IGF signaling pathway through PI3K/Akt and induces apoptosis in PC-3 cell line. Akt mediates the phosphorylation and activation of mTOR that plays a critical role in the regulation of protein translation and synthesis, angiogenesis, and cell cycle progression. The present study was aimed to investigate the effect of nimbolide on tPI3K, tAkt, pAkt, tmTOR, GSK3β, pGSK3β, PCNA, c-Myc, Cyclin D1, and Survivin protein levels by western blot analysis. Apoptosis was visualized by Ao/EtBr dual staining (20×), and protein expression of PCNA by immunocytochemistry was performed. Molecular docking was performed to understand the possible interaction between nimbolide and Akt, PCNA, and Cyclin D1. Nimbolide altered the PI3K-Akt-mediated cell survival and proliferative molecules. Thus, nimbolide exerted anticancer effects in vitro by representing the PI3K-Akt-mTOR pathway in PC-3 cells. Thereby, it acts as a potent anticancer drug for prostate cancer.
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Affiliation(s)
- Paulraj Raja Singh
- Department of Endocrinology, Dr. A.L.M. Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 600 113, India
| | - Elayapillai Sugantha Priya
- Department of Endocrinology, Dr. A.L.M. Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 600 113, India
| | - Solaimuthu Balakrishnan
- Department of Endocrinology, Dr. A.L.M. Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 600 113, India
| | - Ramachandran Arunkumar
- Department of Endocrinology, Dr. A.L.M. Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 600 113, India
| | - Govindaraj Sharmila
- Department of Endocrinology, Dr. A.L.M. Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 600 113, India
| | - Manikkam Rajalakshmi
- PG & Research Department of Biotechnology & Bioinformatics, Holy Cross College, Tiruchirapalli, 620 002, India
| | - Jagadeesan Arunakaran
- Department of Endocrinology, Dr. A.L.M. Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 600 113, India.
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Potential of neem ( Azadirachta indica L.) for prevention and treatment of oncologic diseases. Semin Cancer Biol 2016; 40-41:100-115. [DOI: 10.1016/j.semcancer.2016.03.002] [Citation(s) in RCA: 116] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Revised: 03/19/2016] [Accepted: 03/21/2016] [Indexed: 01/05/2023]
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Wang L, Phan DDK, Zhang J, Ong PS, Thuya WL, Soo R, Wong ALA, Yong WP, Lee SC, Ho PCL, Sethi G, Goh BC. Anticancer properties of nimbolide and pharmacokinetic considerations to accelerate its development. Oncotarget 2016; 7:44790-44802. [PMID: 27027349 PMCID: PMC5190135 DOI: 10.18632/oncotarget.8316] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2016] [Accepted: 03/07/2016] [Indexed: 12/12/2022] Open
Abstract
Nimbolide is one of the main components in the leaf extract of Azadirachta indica (A. indica). Accumulating evidence from various in vitro and in vivo studies indicates that nimbolide possesses potent anticancer activity against several types of cancer and also shows potential chemopreventive activity in animal models. The main mechanisms of action of nimbolide include anti-proliferation, induction of apoptosis, inhibition of metastasis and angiogenesis, and modulation of carcinogen-metabolizing enzymes. Although multiple pharmacodynamic (PD) studies have been carried out, nimbolide is still at the infant stage in the drug development pipeline due to the lack of systematic pharmacokinetic (PK) studies and long-term toxicological studies. Preclinical PK and toxicological studies are vital in determining the dosage range to support the safety of nimbolide for first-in-human clinical trials. In this review, we will provide a comprehensive summary for the current status of nimbolide as an anticancer and chemopreventive lead compound, and highlight the importance of systematic preclinical PK and toxicological studies in accelerating the process of application of nimbolide as a therapeutic agent against various malignancies.
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Affiliation(s)
- Lingzhi Wang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- Department of Pharmacology, National University Health System, Singapore
| | - Do Dang Khoa Phan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- Department of Pharmacy, National University of Singapore, Singapore
| | - Jingwen Zhang
- Department of Pharmacology, National University Health System, Singapore
| | - Pei-Shi Ong
- Department of Pharmacy, National University of Singapore, Singapore
| | - Win Lwin Thuya
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- Department of Pharmacy, National University of Singapore, Singapore
| | - Ross Soo
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- Department of Haematology-Oncology, National University Health System, Singapore
| | - Andrea Li-Ann Wong
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- Department of Haematology-Oncology, National University Health System, Singapore
| | - Wei Peng Yong
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- Department of Haematology-Oncology, National University Health System, Singapore
| | - Soo Chin Lee
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- Department of Haematology-Oncology, National University Health System, Singapore
| | - Paul Chi-Lui Ho
- Department of Pharmacy, National University of Singapore, Singapore
| | - Gautam Sethi
- Department of Pharmacology, National University Health System, Singapore
| | - Boon Cher Goh
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- Department of Pharmacology, National University Health System, Singapore
- Department of Haematology-Oncology, National University Health System, Singapore
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Neem tree (Azadirachta indica) extract specifically suppresses the growth of tumors in H22-bearing Kunming mice. ACTA ACUST UNITED AC 2016; 71:201-8. [DOI: 10.1515/znc-2014-4210] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 05/02/2016] [Indexed: 11/15/2022]
Abstract
Abstract
Recently, neem tree (Azadirachta indica) extract (NTE) has been reported to have various antitumor activities against gastric, breast, prostate, and skin cancer, respectively. The current study was designed to evaluate the effect of NTE on hepatic cancer in a mouse model. The possible side effects elicited by NTE were also evaluated. The components in NTE were analyzed by liquid chromatography–mass spectrometry (LC-MS). H22 cells-bearing Kumming mice were generated by injecting H22 cells subcutaneously into the right forelimb armpit of the mice. Then the mice were treated daily for 27 days with NTE (150, 300, and 600 mg/kg body weight) by intragastric administration, using carboxymethyl cellulose (CMC, 1%) as blank control and cyclophosphamide (CTX, 20 mg/kg) as positive control. The antitumor effect of NTE was evaluated by assessment of survival rate, body weight, tumor volume and weight, tumor histology, thymus and spleen indexes, and liver histology. The tumor weight and volume in groups of NTE and CTX were significantly lower than those in the CMC group. The survival rate in the NTE group receiving the high dose (600 mg/kg) was significantly higher than that in the CTX and CMC groups. Compared with CTX, NTE was observed to have a tumor-specific cytotoxicity without impairing the normal liver tissue. Additionally, the higher indexes of thymus and spleen indicated that NTE could facilitate the growth of immune organs. The results indicate that NTE is a promising candidate for the antitumor treatment with high efficacy and safety.
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Alzohairy MA. Therapeutics Role of Azadirachta indica (Neem) and Their Active Constituents in Diseases Prevention and Treatment. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2016; 2016:7382506. [PMID: 27034694 PMCID: PMC4791507 DOI: 10.1155/2016/7382506] [Citation(s) in RCA: 229] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Revised: 01/07/2016] [Accepted: 01/11/2016] [Indexed: 02/08/2023]
Abstract
Neem (Azadirachta indica) is a member of the Meliaceae family and its role as health-promoting effect is attributed because it is rich source of antioxidant. It has been widely used in Chinese, Ayurvedic, and Unani medicines worldwide especially in Indian Subcontinent in the treatment and prevention of various diseases. Earlier finding confirmed that neem and its constituents play role in the scavenging of free radical generation and prevention of disease pathogenesis. The studies based on animal model established that neem and its chief constituents play pivotal role in anticancer management through the modulation of various molecular pathways including p53, pTEN, NF-κB, PI3K/Akt, Bcl-2, and VEGF. It is considered as safe medicinal plants and modulates the numerous biological processes without any adverse effect. In this review, I summarize the role of Azadirachta indica in the prevention and treatment of diseases via the regulation of various biological and physiological pathways.
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Affiliation(s)
- Mohammad A. Alzohairy
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, P.O. Box 6699, Buraidah, Saudi Arabia
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Sophia J, Kiran Kishore T K, Kowshik J, Mishra R, Nagini S. Nimbolide, a neem limonoid inhibits Phosphatidyl Inositol-3 Kinase to activate Glycogen Synthase Kinase-3β in a hamster model of oral oncogenesis. Sci Rep 2016; 6:22192. [PMID: 26902162 PMCID: PMC4763291 DOI: 10.1038/srep22192] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2015] [Accepted: 02/09/2016] [Indexed: 12/14/2022] Open
Abstract
Glycogen synthase kinase-3β (GSK-3β), a serine/threonine kinase is frequently inactivated by the oncogenic signalling kinases PI3K/Akt and MAPK/ERK in diverse malignancies. The present study was designed to investigate GSK-3β signalling circuits in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model and the therapeutic potential of the neem limonoid nimbolide. Inactivation of GSK-3β by phosphorylation at serine 9 and activation of PI3K/Akt, MAPK/ERK and β-catenin was associated with increased cell proliferation and apoptosis evasion during stepwise evolution of HBP carcinomas. Administration of nimbolide inhibited PI3K/Akt signalling with consequent activation of GSK-3β thereby inducing trafficking of β-catenin away from the nucleus and enhancing the expression of miR-126 and let-7. Molecular docking studies confirmed interaction of nimbolide with PI3K, Akt, ERK and GSK-3β. Furthermore, nimbolide attenuated cell proliferation and induced apoptosis as evidenced by increased p-cyclin D1Thr286 and pro-apoptotic proteins. The present study has unravelled aberrant phosphorylation as a key determinant for oncogenic signalling and acquisition of cancer hallmarks in the HBP model. The study has also provided mechanistic insights into the chemotherapeutic potential of nimbolide that may be a useful addition to the armamentarium of natural compounds targeting PI3K for oral cancer treatment.
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Affiliation(s)
- Josephraj Sophia
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar-608 002, Tamil Nadu, India
| | - Kranthi Kiran Kishore T
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar-608 002, Tamil Nadu, India
| | - Jaganathan Kowshik
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar-608 002, Tamil Nadu, India
| | - Rajakishore Mishra
- Centre for Life Sciences, School of Natural Sciences, Central University of Jharkhand, Ratu-Lohardaga Road, Brambe, Ranchi 835205, Jharkhand, India
| | - Siddavaram Nagini
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar-608 002, Tamil Nadu, India
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Kishore T KK, Ganugula R, Gade DR, Reddy GB, Nagini S. Gedunin abrogates aldose reductase, PI3K/Akt/mToR, and NF-κB signaling pathways to inhibit angiogenesis in a hamster model of oral carcinogenesis. Tumour Biol 2015; 37:2083-93. [PMID: 26342697 DOI: 10.1007/s13277-015-4003-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Accepted: 08/25/2015] [Indexed: 01/05/2023] Open
Abstract
Aberrant activation of oncogenic signaling pathways plays a central role in tumor development and progression. The aim of this present study was to investigate the chemopreventive effects of the neem limonoid gedunin in the hamster model of oral cancer based on its ability to modulate aldose reductase (AR), phosphatidyl inositol-3-kinase (PI3K)/Akt, and nuclear factor kappa B (NF-κB) pathways to block angiogenesis. Administration of gedunin suppressed the development of HBP carcinomas by inhibiting PI3K/Akt and NF-κB pathways through the inactivation of Akt and inhibitory kappa B kinase (IKK), respectively. Immunoblot and molecular docking interactions revealed that inhibition of these signaling pathways may be mediated via inactivation of AR by gedunin. Gedunin blocked angiogenesis by downregulating the expression of miR-21 and the pro-angiogenic factors vascular endothelial growth factor and hypoxia inducible factor-1 alpha (HIF-1α). In conclusion, the results of the present study provide compelling evidence that gedunin prevents progression of hamster buccal pouch (HBP) carcinomas via inhibition of the kinases Akt, IKK, and AR, and the oncogenic transcription factors NF-κB and HIF-1α to block angiogenesis.
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Affiliation(s)
- Kranthi Kiran Kishore T
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, 608 002, Tamil Nadu, India
| | - Raghu Ganugula
- Biochemistry Division, National Institute of Nutrition, Hyderabad, 500 007, India
| | - Deepak Reddy Gade
- Medicinal Chemistry Research Division, Vishnu Institute of Pharmaceutical Education and Research, Narsapur, India
| | | | - Siddavaram Nagini
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, 608 002, Tamil Nadu, India.
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35
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Kasala ER, Bodduluru LN, Barua CC. Nimbolide inhibits invasion of breast cancer. Cell Prolif 2015; 48:117-8. [PMID: 25620136 DOI: 10.1111/cpr.12170] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Accepted: 01/01/2015] [Indexed: 12/19/2022] Open
Affiliation(s)
- E R Kasala
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Guwahati, 781032, India
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Elumalai P, Arunakaran J. Review on molecular and chemopreventive potential of nimbolide in cancer. Genomics Inform 2014; 12:156-64. [PMID: 25705153 PMCID: PMC4330249 DOI: 10.5808/gi.2014.12.4.156] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2014] [Revised: 11/09/2014] [Accepted: 11/09/2014] [Indexed: 12/16/2022] Open
Abstract
Cancer is the most dreaded disease in human and also major health problem worldwide. Despite its high occurrence, the exact molecular mechanisms of the development and progression are not fully understood. The existing cancer therapy based on allopathic medicine is expensive, exhibits side effects; and may also alter the normal functioning of genes. Thus, a non-toxic and effective mode of treatment is needed to control cancer development and progression. Some medicinal plants offer a safe, effective and affordable remedy to control the cancer progression. Nimbolide, a limnoid derived from the neem (Azadirachta indica) leaves and flowers of neem, is widely used in traditional medical practices for treating various human diseases. Nimbolide exhibits several pharmacological effects among which its anticancer activity is the most promising. The previous studies carried out over the decades have shown that nimbolide inhibits cell proliferation and metastasis of cancer cells. This review highlights the current knowledge on the molecular targets that contribute to the observed anticancer activity of nimbolide related to induction of apoptosis and cell cycle arrest; and inhibition of signaling pathways related to cancer progression.
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Affiliation(s)
- Perumal Elumalai
- Department of Endocrinology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Chennai 600113, India
| | - Jagadeesan Arunakaran
- Department of Endocrinology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Chennai 600113, India
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Chitta K, Paulus A, Caulfield TR, Akhtar S, Blake MKK, Ailawadhi S, Knight J, Heckman MG, Pinkerton A, Chanan-Khan A. Nimbolide targets BCL2 and induces apoptosis in preclinical models of Waldenströms macroglobulinemia. Blood Cancer J 2014; 4:e260. [PMID: 25382610 PMCID: PMC5424099 DOI: 10.1038/bcj.2014.74] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 09/15/2014] [Accepted: 09/18/2014] [Indexed: 12/31/2022] Open
Abstract
Neem leaf extract (NLE) has medicinal properties, which have been attributed to its limonoid content. We identified the NLE tetranorterpenoid, nimbolide, as being the key limonoid responsible for the cytotoxicity of NLE in various preclinical models of human B-lymphocyte cancer. Of the models tested, Waldenströms macroglobulinemia (WM) cells were most sensitive to nimbolide, undergoing significant mitochondrial mediated apoptosis. Notably, nimbolide toxicity was also observed in drug-resistant (bortezomib or ibrutinib) WM cells. To identify putative targets of nimbolide, relevant in WM, we used chemoinformatics-based approaches comprised of virtual in silico screening, molecular modeling and target–ligand reverse docking. In silico analysis revealed the antiapoptotic protein BCL2 was the preferential binding partner of nimbolide. The significance of this finding was further tested in vitro in RS4;11 (BCL2-dependent) tumor cells, in which nimbolide induced significantly more apoptosis compared with BCL2 mutated (Jurkat BCL2Ser70-Ala) cells. Lastly, intraperitoneal administration of nimbolide in WM tumor xenografted mice, significantly reduced tumor growth and IgM secretion in vivo, while modulating the expression of several proteins as seen on immunohistochemistry. Overall, our data demonstrate that nimbolide is highly active in WM cells, as well as other B-cell cancers, and engages BCL2 to exert its cytotoxic activity.
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Affiliation(s)
- K Chitta
- Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, USA
| | - A Paulus
- Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, USA
| | - T R Caulfield
- Department of Molecular Neuroscience, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, USA
| | - S Akhtar
- Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, USA
| | - M-K K Blake
- Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, USA
| | - S Ailawadhi
- Division of Hematology and Oncology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, USA
| | - J Knight
- Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, USA
| | - M G Heckman
- Department of Health Science Research, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, USA
| | - A Pinkerton
- Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
| | - A Chanan-Khan
- Division of Hematology and Oncology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, USA
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Hao F, Kumar S, Yadav N, Chandra D. Neem components as potential agents for cancer prevention and treatment. Biochim Biophys Acta Rev Cancer 2014; 1846:247-57. [PMID: 25016141 DOI: 10.1016/j.bbcan.2014.07.002] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2014] [Revised: 06/08/2014] [Accepted: 07/03/2014] [Indexed: 02/05/2023]
Abstract
Azadirachta indica, also known as neem, is commonly found in many semi-tropical and tropical countries including India, Pakistan, and Bangladesh. The components extracted from neem plant have been used in traditional medicine for the cure of multiple diseases including cancer for centuries. The extracts of seeds, leaves, flowers, and fruits of neem have consistently shown chemopreventive and antitumor effects in different types of cancer. Azadirachtin and nimbolide are among the few bioactive components in neem that have been studied extensively, but research on a great number of additional bioactive components is warranted. The key anticancer effects of neem components on malignant cells include inhibition of cell proliferation, induction of cell death, suppression of cancer angiogenesis, restoration of cellular reduction/oxidation (redox) balance, and enhancement of the host immune responses against tumor cells. While the underlying mechanisms of these effects are mostly unclear, the suppression of NF-κB signaling pathway is, at least partially, involved in the anticancer functions of neem components. Importantly, the anti-proliferative and apoptosis-inducing effects of neem components are tumor selective as the effects on normal cells are significantly weaker. In addition, neem extracts sensitize cancer cells to immunotherapy and radiotherapy, and enhance the efficacy of certain cancer chemotherapeutic agents. This review summarizes the current updates on the anticancer effects of neem components and their possible impact on managing cancer incidence and treatment.
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Affiliation(s)
- Fang Hao
- Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA
| | - Sandeep Kumar
- Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA
| | - Neelu Yadav
- Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA
| | - Dhyan Chandra
- Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
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Essential oils and their constituents as anticancer agents: a mechanistic view. BIOMED RESEARCH INTERNATIONAL 2014; 2014:154106. [PMID: 25003106 PMCID: PMC4070586 DOI: 10.1155/2014/154106] [Citation(s) in RCA: 143] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Accepted: 04/11/2014] [Indexed: 12/31/2022]
Abstract
Exploring natural plant products as an option to find new chemical entities as anticancer agents is one of the fastest growing areas of research. Recently, in the last decade, essential oils (EOs) have been under study for their use in cancer therapy and the present review is an attempt to collect and document the available studies indicating EOs and their constituents as anticancer agents. This review enlists nearly 130 studies of EOs from various plant species and their constituents that have been studied so far for their anticancer potential and these studies have been classified as in vitro and in vivo studies for EOs and their constituents. This review also highlights in-depth various mechanisms of action of different EOs and their constituents reported in the treatment strategies for different types of cancer. The current review indicates that EOs and their constituents act by multiple pathways and mechanisms involving apoptosis, cell cycle arrest, antimetastatic and antiangiogenic, increased levels of reactive oxygen and nitrogen species (ROS/RNS), DNA repair modulation, and others to demonstrate their antiproliferative activity in the cancer cell. The effect of EOs and their constituents on tumour suppressor proteins (p53 and Akt), transcription factors (NF- κB and AP-1), MAPK-pathway, and detoxification enzymes like SOD, catalase, glutathione peroxidase, and glutathione reductase has also been discussed.
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Tundis R, Loizzo MR, Menichini F. An overview on chemical aspects and potential health benefits of limonoids and their derivatives. Crit Rev Food Sci Nutr 2014; 54:225-50. [PMID: 24188270 DOI: 10.1080/10408398.2011.581400] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
Limonoids are heavily oxygenated, modified triterpenes dominant in Meliaceae and Rutaceae plant families. The term 'limonoid' is derived from limonin, which was first identified as the bitter constituent of Citrus seeds in 1841. This group of secondary metabolites exhibits a wide range of biological properties, including anticancer, antibacterial, antifungal, antimalarial, and antiviral activities. Significant progress on the role of limonoids as promising candidates for cancer chemoprevention and/or therapy has been achieved in particular in recent years. The aim of this review article is to discuss the recent developments on limonoids chemical aspects and biological activities with the relationship between structure and activity, supporting the new possibilities for the medicinal and/or nutraceutical use of these compounds.
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Affiliation(s)
- Rosa Tundis
- a Department of Pharmacy, Health and Nutritional Sciences , University of Calabria , I-87036 Rende (CS) , Italy
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Bodduluru LN, Kasala ER, Thota N, Barua CC, Sistla R. Chemopreventive and therapeutic effects of nimbolide in cancer: the underlying mechanisms. Toxicol In Vitro 2014; 28:1026-35. [PMID: 24759803 DOI: 10.1016/j.tiv.2014.04.011] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 04/07/2014] [Accepted: 04/14/2014] [Indexed: 12/14/2022]
Abstract
Cancer chemoprevention is a strategy taken to block, reverse or retard the multistep process of carcinogenesis, including the blockage of its vital morphogenetic milestones viz. normal-preneoplasia-neoplasia-metastasis. Naturally occurring phytochemicals are becoming increasingly popular over synthetic drugs for several reasons, including safety, efficacy and easy availability. Nimbolide, a triterpene derived from the leaves and flowers of neem, is widely used in traditional medical practices for treating various human ailments. The neem limonoid exhibits multiple pharmacological effects among which its anticancer activity is the most promising. The preclinical and mechanistic studies carried over the decades have shown that nimbolide inhibits tumorigenesis and metastasis without any toxicity and unwanted side effects. Nimbolide exhibits anticancer activity through selective modulation of multiple cell signaling pathways linked to inflammation, survival, growth, invasion, angiogenesis and metastasis. The present review highlights the current knowledge on molecular targets that contribute to the observed anticancer activity of nimbolide related to (i) inhibition of carcinogenic activation and induction of antioxidant and carcinogen detoxification enzymes, (ii) induction of growth arrest and apoptosis; and (iii) suppression of proinflammatory signaling pathways related to cancer progression.
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Affiliation(s)
- Lakshmi Narendra Bodduluru
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati 781032, Assam, India.
| | - Eshvendar Reddy Kasala
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati 781032, Assam, India.
| | - Nagaraju Thota
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati 781032, Assam, India.
| | - Chandana C Barua
- Department of Pharmacology and Toxicology, College of Veterinary Science, Assam Agricultural University, Guwahati 781032, Assam, India.
| | - Ramakrishna Sistla
- Medicinal Chemistry & Pharmacology Division, Indian Institute of Chemical Technology (IICT), Hyderabad 500007, Andhra Pradesh, India.
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Takagi M, Tachi Y, Zhang J, Shinozaki T, Ishii K, Kikuchi T, Ukiya M, Banno N, Tokuda H, Akihisa T. Cytotoxic and Melanogenesis-Inhibitory Activities of Limonoids from the Leaves of Azadirachta indica
(Neem). Chem Biodivers 2014; 11:451-68. [DOI: 10.1002/cbdv.201300348] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Indexed: 11/10/2022]
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Ethanolic Neem (Azadirachta indica) Leaf Extract Prevents Growth of MCF-7 and HeLa Cells and Potentiates the Therapeutic Index of Cisplatin. JOURNAL OF ONCOLOGY 2014; 2014:321754. [PMID: 24624140 PMCID: PMC3929266 DOI: 10.1155/2014/321754] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Revised: 11/13/2013] [Accepted: 11/15/2013] [Indexed: 11/17/2022]
Abstract
The present study was designed to gain insight into the antiproliferative activity of ethanolic neem leaves extract (ENLE) alone or in combination with cisplatin by cell viability assay on human breast (MCF-7) and cervical (HeLa) cancer cells. Nuclear morphological examination and cell cycle analysis were performed to determine the mode of cell death. Further, to identify its molecular targets, the expression of genes involved in apoptosis, cell cycle progression, and drug metabolism was analyzed by RT-PCR. Treatment of MCF-7, HeLa, and normal cells with ENLE differentially suppressed the growth of cancer cells in a dose- and time-dependent manner through apoptosis. Additionally, lower dose combinations of ENLE with cisplatin resulted in synergistic growth inhibition of these cells compared to the individual drugs (combination index <1). ENLE significantly modulated the expression of bax, cyclin D1, and cytochrome P450 monooxygenases (CYP 1A1 and CYP 1A2) in a time-dependent manner in these cells. Conclusively, these results emphasize the chemopreventive ability of neem alone or in combination with chemotherapeutic treatment to reduce the cytotoxic effects on normal cells, while potentiating their efficacy at lower doses. Thus, neem may be a prospective therapeutic agent to combat gynecological cancers.
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Abstract
Neem (Azadirachta indica A. Juss) is one of the most versatile medicinal plants, widely distributed in the Indian subcontinent. Neem is a rich source of limonoids that are endowed with potent medicinal properties predominantly antioxidant, anti-inflammatory, and anticancer activities. Azadirachtin, gedunin, and nimbolide are more extensively investigated relative to other neem limonoids. Accumulating evidence indicates that the anticancer effects of neem limonoids are mediated through the inhibition of hallmark capabilities of cancer such as cell proliferation, apoptosis evasion, inflammation, invasion, and angiogenesis. The neem limonoids have been demonstrated to target oncogenic signaling kinases and transcription factors chiefly, NF-κB, Wnt/β-catenin, PI3K/Akt, MAPK, and JAK/STAT signaling pathways. Neem limonoids that target multiple pathways that are aberrant in cancer are ideal candidates for cancer chemoprevention and therapy.
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Affiliation(s)
- Siddavaram Nagini
- Faculty of Science, Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar, Tamil Nadu, India.
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45
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Deng S, May BH, Zhang AL, Lu C, Xue CCL. Phytotherapy in the management of psoriasis: a review of the efficacy and safety of oral interventions and the pharmacological actions of the main plants. Arch Dermatol Res 2013; 306:211-29. [DOI: 10.1007/s00403-013-1428-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Revised: 10/14/2013] [Accepted: 10/31/2013] [Indexed: 01/11/2023]
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Rout KK, Mishra SK. Development of a Sensitive HPTLC Method for Quantification of Nimbolide in Azadirachta indica and Its Dosage Form. J Chromatogr Sci 2013; 52:1089-94. [DOI: 10.1093/chromsci/bmt151] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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Chitta KS, Khan ANH, Ersing N, Swaika A, Masood A, Paulus A, Qadeer A, Advani P, Sher T, Miller KC, Lee K, Chanan-Khan AA. Neem leaf extract induces cell death by apoptosis and autophagy in B-chronic lymphocytic leukemia cells. Leuk Lymphoma 2013; 55:652-61. [PMID: 23721511 DOI: 10.3109/10428194.2013.807927] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and is currently incurable. To expand the therapeutic armamentarium, we investigated neem leaf extract (NLE) after a patient with CLL demonstrated disease regression upon taking oral NLE. NLE-mediated apoptosis was examined in peripheral blood mononuclear cells (PBMCs) from 41 patients with CLL. NLE induced a dose-dependent reduction in CLL cell viability with significant apoptosis observed at 0.06% (w/v) by 24 h. Annexin-V staining and poly(ADP-ribose) polymerase 1 (PARP-1) and caspase 3 cleavage were observed after NLE treatment. However, a pan-caspase inhibitor only partially blocked NLE-mediated cell death. NLE also caused loss of mitochondrial outer membrane permeability and nuclear translocation of apoptosis-inducing factor. Furthermore, NLE treatment resulted in LC3-I cleavage. Biochemical analyses revealed that NLE also inhibits Bcl-2 and p53 proteins. In summary, NLE exhibits anti-leukemic properties in patient primary CLL cells and demonstrates clinical efficacy, warranting further investigation as a potential therapy for CLL.
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Gupta SC, Prasad S, Sethumadhavan DR, Nair MS, Mo YY, Aggarwal BB. Nimbolide, a limonoid triterpene, inhibits growth of human colorectal cancer xenografts by suppressing the proinflammatory microenvironment. Clin Cancer Res 2013; 19:4465-76. [PMID: 23766363 DOI: 10.1158/1078-0432.ccr-13-0080] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE Extensive research over the past decade has revealed that the proinflammatory microenvironment plays a critical role in the development of colorectal cancer. Whether nimbolide, a limonoid triterpene, can inhibit the growth of colorectal cancer was investigated in the present study. EXPERIMENTAL DESIGN The effect of nimbolide on proliferation of colorectal cancer cell lines was examined by MTT assay, apoptosis by caspase activation and poly-ADP ribose polymerase cleavage, NF-κB activation by DNA-binding assay, and protein expression by Western blotting. The effect of nimbolide on the tumor growth in vivo was examined in colorectal cancer xenografts in a nude mouse model. RESULTS Nimbolide inhibited proliferation, induced apoptosis, and suppressed NF-κB activation and NF-κB-regulated tumorigenic proteins in colorectal cancer cells. The suppression of NF-κB activation by nimbolide was caused by sequential inhibition of IκB kinase (IKK) activation, IκBα phosphorylation, and p65 nuclear translocation. Furthermore, the effect of nimbolide on IKK activity was found to be direct. In vivo, nimbolide (at 5 and 20 mg/kg body weight), injected intraperitoneally after tumor inoculation, significantly decreased the volume of colorectal cancer xenografts. The limonoid-treated xenografts exhibited significant downregulation in the expression of proteins involved in tumor cell survival (Bcl-2, Bcl-xL, c-IAP-1, survivin, and Mcl-1), proliferation (c-Myc and cyclin D1), invasion (MMP-9, ICAM-1), metastasis (CXCR4), and angiogenesis (VEGF). The limonoid was found to be bioavailable in the blood plasma and tumor tissues of treated mice. CONCLUSIONS Our studies provide evidence that nimbolide can suppress the growth of human colorectal cancer through modulation of the proinflammatory microenvironment.
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Affiliation(s)
- Subash C Gupta
- Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
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Huang J, Lv C, Hu M, Zhong G. The mitochondria-mediate apoptosis of Lepidopteran cells induced by azadirachtin. PLoS One 2013; 8:e58499. [PMID: 23516491 PMCID: PMC3596413 DOI: 10.1371/journal.pone.0058499] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2011] [Accepted: 02/07/2013] [Indexed: 01/31/2023] Open
Abstract
Mitochondria have been shown to play an important role in apoptosis using mammalian cell lines. However, this seems not to be the case in Drosophila, an insect model organism; thus more in-depth studies of insect cell apoptosis are necessary. In the present study, mitochondrial involvement during azadirachtin- and camptothecin-induced apoptosis in Spodoptera frugiperda Sf9 cells (isolated from Spodoptera frugiperda pupal ovarian tissue) was investigated. The results showed that both azadirachtin and camptothecin could induce apoptosis in Sf9 cells. Reactive oxygen species (ROS) generation, activation of mitochondrial permeability transition pores (MPTPs) and loss of mitochondrial membrane potential (MMP) were observed very early during apoptosis and were followed subsequently by the release of cytochrome-c from the mitochondria. Furthermore, the results also revealed that the opening of MPTPs and the loss of MMP induced by azadirachtin could be significantly inhibited by the permeability transition pore (PTP) inhibitor cyclosporin A (CsA), which was used to identify the key role of mitochondria in the apoptosis of Sf9 cells. However, in camptothecin-treated Sf9 cells, CsA could not suppress the opening of MPTPs and the loss of MMP when apoptosis was induced. The data from caspase-3 and caspase-9 activity assays and detection of apoptosis by morphological observation and flow cytometry also uncovered the different effect of CsA on the two botanical apoptosis inducers. Although different mechanisms of apoptosis induction exist, our study revealed that mitochondria play a crucial role in insect cell line apoptosis.
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Affiliation(s)
- Jingfei Huang
- Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, Laboratory of Insect Toxicology, South China Agricultural University, Guangzhou, P.R. China
| | - Chaojun Lv
- Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, Laboratory of Insect Toxicology, South China Agricultural University, Guangzhou, P.R. China
- Institute of Coconut, Chinese Academy of Tropical Agricultural Sciences, Wenchang, Hainan Province, China
| | - Meiying Hu
- Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, Laboratory of Insect Toxicology, South China Agricultural University, Guangzhou, P.R. China
| | - Guohua Zhong
- Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, Laboratory of Insect Toxicology, South China Agricultural University, Guangzhou, P.R. China
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Manoharan S, Wani SA, Vasudevan K, Manimaran A, Prabhakar MM, Karthikeyan S, Rajasekaran D. Saffron Reduction of 7,12-Dimethylbenz[a]anthracene-induced Hamster Buccal Pouch Carcinogenesis. Asian Pac J Cancer Prev 2013; 14:951-7. [DOI: 10.7314/apjcp.2013.14.2.951] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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