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Sattayawat P, Kaewkod T, Thongyim S, Chiawpanit C, Wutti-in Y, Thepmalee C, Tragoolpua Y, Disayathanoowat T, Panya A. A Comparative Study of Melittins from Apis florea and Apis mellifera as Cytotoxic Agents Against Non-Small Cell Lung Cancer (NSCLC) Cells and Their Combination with Gefitinib. Int J Mol Sci 2025; 26:2498. [PMID: 40141140 PMCID: PMC11941996 DOI: 10.3390/ijms26062498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 03/03/2025] [Accepted: 03/04/2025] [Indexed: 03/28/2025] Open
Abstract
Lung cancer remains one of the most lethal malignancies, often diagnosed at advanced stages, leading to limited treatment options. Thus, identifying natural products with potent anti-cancer activity is crucial for improving treatment outcomes. While the melittin from Apis mellifera (Mel-AM) has been extensively studied, the melittin from Apis florea (Mel-AF), a bee species native to Southeast Asia, remains relatively underexplored. These peptides were comparatively investigated against non-small cell lung cancer (NSCLC) cell lines, A549, NCI-H460, and NCI-H1975. Mel-AF demonstrated a superior cytotoxicity (cytotoxic concentration 50% (CC50) = 2.55-5.06 µg/mL) compared to Mel-AM (CC50 = 4.32-8.48 µg/mL). While both peptides induced apoptosis via the intrinsic mitochondrial pathway, Mel-AF exhibited a more pronounced effect, significantly enhancing apoptosis induction compared to Mel-AM. Both peptides inhibited cell migration and invasion; however, when combined with gefitinib, Mel-AF more effectively enhanced the drug's inhibitory effects on the A549 and NCI-H460 cell lines compared to Mel-AM, underscoring its superior potential as a therapeutic agent. Altogether, we demonstrated that these peptides induced apoptosis in NSCLC cell lines, with Mel-AF having more pronounced effects, and the combination use of peptides with a chemotherapeutic drug showed synergistic effects against lung cancer cells, enhancing their practical use in lung cancer treatments.
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Affiliation(s)
- Pachara Sattayawat
- Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand; (P.S.); (T.K.); (S.T.); (C.C.); (Y.T.); (T.D.)
- Cell Engineering for Cancer Therapy Research Group, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand;
- Research Center of Deep Technology in Beekeeping and Bee Products for Sustainable Development Goals (SMART BEE SDGs), Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Thida Kaewkod
- Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand; (P.S.); (T.K.); (S.T.); (C.C.); (Y.T.); (T.D.)
- Cell Engineering for Cancer Therapy Research Group, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand;
- Research Center of Deep Technology in Beekeeping and Bee Products for Sustainable Development Goals (SMART BEE SDGs), Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Saruda Thongyim
- Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand; (P.S.); (T.K.); (S.T.); (C.C.); (Y.T.); (T.D.)
- Cell Engineering for Cancer Therapy Research Group, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand;
- Office of Research Administration, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Chutipa Chiawpanit
- Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand; (P.S.); (T.K.); (S.T.); (C.C.); (Y.T.); (T.D.)
- Cell Engineering for Cancer Therapy Research Group, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand;
- Office of Research Administration, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Yupanun Wutti-in
- Cell Engineering for Cancer Therapy Research Group, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand;
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Chutamas Thepmalee
- Division of Biochemistry, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand;
| | - Yingmanee Tragoolpua
- Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand; (P.S.); (T.K.); (S.T.); (C.C.); (Y.T.); (T.D.)
- Cell Engineering for Cancer Therapy Research Group, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand;
- Research Center of Deep Technology in Beekeeping and Bee Products for Sustainable Development Goals (SMART BEE SDGs), Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Terd Disayathanoowat
- Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand; (P.S.); (T.K.); (S.T.); (C.C.); (Y.T.); (T.D.)
- Research Center of Deep Technology in Beekeeping and Bee Products for Sustainable Development Goals (SMART BEE SDGs), Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Aussara Panya
- Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand; (P.S.); (T.K.); (S.T.); (C.C.); (Y.T.); (T.D.)
- Cell Engineering for Cancer Therapy Research Group, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand;
- Research Center of Deep Technology in Beekeeping and Bee Products for Sustainable Development Goals (SMART BEE SDGs), Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand
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Stela M, Cichon N, Spławska A, Szyposzynska M, Bijak M. Therapeutic Potential and Mechanisms of Bee Venom Therapy: A Comprehensive Review of Apitoxin Applications and Safety Enhancement Strategies. Pharmaceuticals (Basel) 2024; 17:1211. [PMID: 39338374 PMCID: PMC11434713 DOI: 10.3390/ph17091211] [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: 08/22/2024] [Revised: 09/06/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
Apitoxin therapy (BVT-bee venom therapy) is an emerging complementary treatment utilizing bee venom for various medical conditions. This review explores the potential and therapeutic mechanisms of bee venom, focusing on its chemical composition and the methods for its extraction and purification to enhance safety while maintaining bioactivity. Bee venom contains amphipathic peptides such as melittin and apamin, enzymes like phospholipase A2, and bioamines including histamine and catecholamines, contributing to its pleiotropic effects. The therapeutic applications of bee venom span anti-inflammatory, analgesic, antimicrobial, antiviral, neuroprotective, anti-arthritic, and anti-cancer activities. Clinical and laboratory studies have demonstrated its efficacy in treating chronic and autoimmune diseases, pain management, and improving quality of life. The immunogenic properties of bee venom necessitate ongoing research to mitigate allergic reactions, ensuring its safe and effective use in medical practice. This review summarizes the current state of research on bee venom therapy, highlighting its potential benefits and future research directions.
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Affiliation(s)
- Maksymilian Stela
- Biohazard Prevention Centre, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland
| | - Natalia Cichon
- Biohazard Prevention Centre, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland
| | - Aleksandra Spławska
- CBRN Reconnaissance and Decontamination Department, Military Institute of Chemistry and Radiometry, Antoniego Chrusciela "Montera" 105, 00-910 Warsaw, Poland
| | - Monika Szyposzynska
- CBRN Reconnaissance and Decontamination Department, Military Institute of Chemistry and Radiometry, Antoniego Chrusciela "Montera" 105, 00-910 Warsaw, Poland
| | - Michal Bijak
- Biohazard Prevention Centre, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland
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Pomella S, Melaiu O, Dri M, Martelli M, Gargari M, Barillari G. Effects of Angiogenic Factors on the Epithelial-to-Mesenchymal Transition and Their Impact on the Onset and Progression of Oral Squamous Cell Carcinoma: An Overview. Cells 2024; 13:1294. [PMID: 39120324 PMCID: PMC11311310 DOI: 10.3390/cells13151294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 07/26/2024] [Accepted: 07/29/2024] [Indexed: 08/10/2024] Open
Abstract
High levels of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)-2 and angiopoietin (ANG)-2 are found in tissues from oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs). As might be expected, VEGF, FGF-2, and ANG-2 overexpression parallels the development of new blood and lymphatic vessels that nourish the growing OPMDs or OSCCs and provide the latter with metastatic routes. Notably, VEGF, FGF-2, and ANG-2 are also linked to the epithelial-to-mesenchymal transition (EMT), a trans-differentiation process that respectively promotes or exasperates the invasiveness of normal and neoplastic oral epithelial cells. Here, we have summarized published work regarding the impact that the interplay among VEGF, FGF-2, ANG-2, vessel generation, and EMT has on oral carcinogenesis. Results from the reviewed studies indicate that VEGF, FGF-2, and ANG-2 spark either protein kinase B (AKT) or mitogen-activated protein kinases (MAPK), two signaling pathways that can promote both EMT and new vessels' formation in OPMDs and OSCCs. Since EMT and vessel generation are key to the onset and progression of OSCC, as well as to its radio- and chemo-resistance, these data encourage including AKT or MAPK inhibitors and/or antiangiogenic drugs in the treatment of this malignancy.
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Affiliation(s)
- Silvia Pomella
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Via Montpellier, 00133 Rome, Italy; (S.P.); (O.M.); (M.M.); (M.G.)
| | - Ombretta Melaiu
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Via Montpellier, 00133 Rome, Italy; (S.P.); (O.M.); (M.M.); (M.G.)
| | - Maria Dri
- Department of Surgical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy;
| | - Mirko Martelli
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Via Montpellier, 00133 Rome, Italy; (S.P.); (O.M.); (M.M.); (M.G.)
| | - Marco Gargari
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Via Montpellier, 00133 Rome, Italy; (S.P.); (O.M.); (M.M.); (M.G.)
| | - Giovanni Barillari
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Via Montpellier, 00133 Rome, Italy; (S.P.); (O.M.); (M.M.); (M.G.)
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Haque S, Hussain A, Joshi H, Sharma U, Sharma B, Aggarwal D, Rani I, Ramniwas S, Gupta M, Tuli HS. Melittin: a possible regulator of cancer proliferation in preclinical cell culture and animal models. J Cancer Res Clin Oncol 2023; 149:17709-17726. [PMID: 37919474 DOI: 10.1007/s00432-023-05458-8] [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: 07/18/2023] [Accepted: 10/03/2023] [Indexed: 11/04/2023]
Abstract
BACKGROUND Melittin is a water-soluble cationic peptide derived from bee venom that has been thoroughly studied for the cure of different cancers. However, the unwanted interactions of melittin produce hemolytic and cytotoxic effects that hinder their therapeutic applications. To overcome the shortcomings, numerous research groups have adopted different approaches, including conjugation with tumor-targeting proteins, gene therapy, and encapsulation in nanoparticles, to reduce the non-specific cytotoxic effects and potentiate their anti-cancerous activity. PURPOSE This article aims to provide mechanistic insights into the chemopreventive activity of melittin and its nanoversion in combination with standard anti-cancer drugs for the treatment of cancer. METHODS We looked over the pertinent research on melittin's chemopreventive properties in online databases such as PubMed and Scopus. CONCLUSION In the present article, the anti-cancerous effects of melittin on different cancers have been discussed very nicely, as have their possible mechanisms of action to act against different tumors. Besides, it interacts with different signal molecules that regulate the diverse pathways of cancerous cells, such as cell cycle arrest, apoptosis, metastasis, angiogenesis, and inflammation. We also discussed the recent progress in the synergistic combination of melittin with standard anti-cancer drugs and a nano-formulated version of melittin for targeted delivery to improve its anticancer potential.
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Affiliation(s)
- Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, 45142, Jazan, Saudi Arabia
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Beirut, 11022801, Lebanon
- Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, 13306, Ajman, United Arab Emirates
| | - Arif Hussain
- School of Life Sciences, Manipal Academy of Higher Education, P.O. Box 345050, Dubai, United Arab Emirates
| | - Hemant Joshi
- School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110067, India.
| | - Ujjawal Sharma
- Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, Punjab, 151401, India
| | - Bunty Sharma
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, 133207, India
| | - Diwakar Aggarwal
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, 133207, India
| | - Isha Rani
- Department of Biochemistry, Maharishi Markendashwar College of Medical Sciences and Research (MMCMSR), Sadopur, Ambala, 134007, India
| | - Seema Ramniwas
- University Centre for Research and Development, University Institute of Pharmaceutical Sciences, Chandigarh University, Gharuan, Mohali, 140413, India
| | - Madhu Gupta
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, Pushp Vihar, New Delhi, 110017, India
| | - Hardeep Singh Tuli
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, 133207, India.
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Yu X, Jia S, Yu S, Chen Y, Zhang C, Chen H, Dai Y. Recent advances in melittin-based nanoparticles for antitumor treatment: from mechanisms to targeted delivery strategies. J Nanobiotechnology 2023; 21:454. [PMID: 38017537 PMCID: PMC10685715 DOI: 10.1186/s12951-023-02223-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 11/19/2023] [Indexed: 11/30/2023] Open
Abstract
As a naturally occurring cytolytic peptide, melittin (MLT) not only exhibits a potent direct tumor cell-killing effect but also possesses various immunomodulatory functions. MLT shows minimal chances for developing resistance and has been recognized as a promising broad-spectrum antitumor drug because of this unique dual mechanism of action. However, MLT still displays obvious toxic side effects during treatment, such as nonspecific cytolytic activity, hemolytic toxicity, coagulation disorders, and allergic reactions, seriously hampering its broad clinical applications. With thorough research on antitumor mechanisms and the rapid development of nanotechnology, significant effort has been devoted to shielding against toxicity and achieving tumor-directed drug delivery to improve the therapeutic efficacy of MLT. Herein, we mainly summarize the potential antitumor mechanisms of MLT and recent progress in the targeted delivery strategies for tumor therapy, such as passive targeting, active targeting and stimulus-responsive targeting. Additionally, we also highlight the prospects and challenges of realizing the full potential of MLT in the field of tumor therapy. By exploring the antitumor molecular mechanisms and delivery strategies of MLT, this comprehensive review may inspire new ideas for tumor multimechanism synergistic therapy.
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Affiliation(s)
- Xiang Yu
- State Key Laboratory of Digital Medical Engineering, School of Biomedical Engineering, Hainan University, Haikou, China.
- Key Laboratory of Biomedical Engineering of Hainan Province, One Health Institute, Hainan University, Haikou, China.
| | - Siyu Jia
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, China
- The First College of Clinical Medical Science, China Three Gorges University, Yichang, China
| | - Shi Yu
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, China
| | - Yaohui Chen
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, China
| | - Chengwei Zhang
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, China
| | - Haidan Chen
- The First College of Clinical Medical Science, China Three Gorges University, Yichang, China.
| | - Yanfeng Dai
- State Key Laboratory of Digital Medical Engineering, School of Biomedical Engineering, Hainan University, Haikou, China.
- Key Laboratory of Biomedical Engineering of Hainan Province, One Health Institute, Hainan University, Haikou, China.
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Yang X, Hua C, Lin L, Ganting Z. Antimicrobial peptides as potential therapy for gastrointestinal cancers. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:2831-2841. [PMID: 37249612 DOI: 10.1007/s00210-023-02536-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 05/16/2023] [Indexed: 05/31/2023]
Abstract
Since conventional therapy faces limitations in the field of different cancers as well as gastrointestinal cancers, that decrease the survival rate of patients, there is an urgent need to find new effective therapeutic approaches without the adverse effects of the traditional agents. Antimicrobial peptides (AMPs) attract much attention and are well known for their role in innate immunity. These peptides, in addition to their antimicrobial activity, exhibit strong anticancer potential against various types of malignancy. AMPs specifically target tumor cells and have selective toxicity for these cells without affecting normal cells. Here we aim to comprehensively overview the current knowledge in the field of using AMPs as novel therapeutic agents for gastrointestinal cancer.
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Affiliation(s)
- Xiaoxia Yang
- Heping Hospital Attached to Changzhi Medical College, Changzhi, 046000, China
| | - Cui Hua
- Tangshan Fengnan District Traditional Chinese Medicine Hospital, Tangshan, 063000, China.
| | - Lin Lin
- Tangshan Hongci Hospital, Tangshan, 063000, China
| | - Zhao Ganting
- Heping Hospital Attached to Changzhi Medical College, Changzhi, 046000, China
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Liu F, Chen F, Yang L, Qiu F, Zhong G, Gao S, Xi W, Lai M, He Q, Chen Y, Chen W, Zhang J, Yang L. Melittin acupoint injection in attenuating bone erosion in collagen-induced arthritis mice via inhibition of the RANKL/NF-κB signaling pathway. Quant Imaging Med Surg 2023; 13:5996-6013. [PMID: 37711782 PMCID: PMC10498218 DOI: 10.21037/qims-23-254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 07/06/2023] [Indexed: 09/16/2023]
Abstract
Background Rheumatoid arthritis (RA) is an autoimmune disease leading to chronic joint inflammation. Bone erosion is the most serious pathological condition of RA and the main cause of joint deformities and disability. Melittin acupoint injection (MAI) is an effective traditional Chinese medicine (TCM) method for RA treatment. This study aimed to investigate the effect of MAI on RA bone erosion and to elucidate the underlying mechanism. Methods A collagen-induced arthritis (CIA) mouse model was established as the experimental subject. MAI was administrated once every other day for 28 days to mice with CIA. The effects of MAI on joint diseases were assessed by body weight, arthritis index (AI) score, swollen joint count (SJC) score, and hind paw thickness. Ankle radiological changes were captured by micro-computed tomography (micro-CT) and histological changes were observed by pathological staining. Organ histological changes, spleen index, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine (Crea) levels of serum were tested to evaluate the toxicity of MAI. Cytokine expression levels were confirmed by enzyme-linked immunosorbent assay (ELISA) to evaluate the immunity of CIA mice. Results MAI administration markedly improved the clinical signs of CIA in mice, including hind paw thickness, AI, and the number of swollen paw joints (most of them P<0.05 or even <0.01). According to histopathological analysis, MAI ameliorated inflammatory cell infiltration, synovial hyperplasia, pannus formation, and bone erosion (all P<0.01). Micro-CT and tartrate-resistant acid phosphatase (TRAP) staining (P<0.01) also revealed that MAI could relieve bone erosion via reducing the formation of osteoclasts. Not only could MAI relieve the immunological boost [P<0.05 for the high-dose MAI (HM) group], but also it had no liver or kidney side effects (P>0.05). In addition, it decreased the serum levels of interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) and increased the serum levels of IL-4 and IL-10 (the majority of P<0.05 or even <0.01). Transcriptome sequencing results indicated that MAI affected the expression of osteoclast differentiation pathway genes, which was connected with the receptor activator of the nuclear factor κB ligand/nuclear factor kappa B (RANKL/NF-κB) pathway. Conclusions Based on our findings, MAI could suppress joint inflammation and inhibit RANKL/NF-κB-mediated osteoclast differentiation to rescue bone erosion in CIA mice, suggesting that MAI can be a potentially therapeutic substance for RA.
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Affiliation(s)
- Fenfang Liu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Fen Chen
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Le Yang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Fucheng Qiu
- Intensive Care Unit, Foshan Hospital of TCM, Foshan, China
| | - Guangen Zhong
- Department of Acupuncture and Rehabilitation, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Shan Gao
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Weizhe Xi
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Meilian Lai
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Qiting He
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Ying Chen
- Department of Acupuncture and Rehabilitation, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Weiming Chen
- Department of Acupuncture and Rehabilitation, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Jiping Zhang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Lu Yang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- Department of Acupuncture and Rehabilitation, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
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Małek A, Strzemski M, Kurzepa J, Kurzepa J. Can Bee Venom Be Used as Anticancer Agent in Modern Medicine? Cancers (Basel) 2023; 15:3714. [PMID: 37509375 PMCID: PMC10378503 DOI: 10.3390/cancers15143714] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 07/14/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Honey bee venom in its composition contains many biologically active peptides and enzymes that are effective in the fight against diseases of various etiologies. The history of the use of bee venom for medicinal purposes dates back thousands of years. There are many reports in the literature on the pharmacological properties of bee venom and/or its main components, e.g., anti-arthritic, anti-inflammatory, anti-microbial or neuroprotective properties. In addition, both crude venom and melittin exhibit cytotoxic activity against a wide range of tumor cells, with significant anti-metastatic activity in pre-clinical studies. Due to the constantly increasing incidence of cancer, the development of new therapeutic strategies in oncology is a particular challenge for modern medicine. A review paper discusses the various properties of bee venom with an emphasis on its anticancer properties. For this purpose, the PubMed database was searched, and publications related to "bee", "venom", "cancer" from the last 10 years were selected.
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Affiliation(s)
- Agata Małek
- Department of Medical Chemistry, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland
| | - Maciej Strzemski
- Department of Analytical Chemistry, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland
| | - Joanna Kurzepa
- 1st Department of Radiology, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland
| | - Jacek Kurzepa
- Department of Medical Chemistry, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland
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Dashevsky D, Baumann K, Undheim EAB, Nouwens A, Ikonomopoulou MP, Schmidt JO, Ge L, Kwok HF, Rodriguez J, Fry BG. Functional and Proteomic Insights into Aculeata Venoms. Toxins (Basel) 2023; 15:toxins15030224. [PMID: 36977115 PMCID: PMC10053895 DOI: 10.3390/toxins15030224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 03/07/2023] [Accepted: 03/12/2023] [Indexed: 03/19/2023] Open
Abstract
Aculeate hymenopterans use their venom for a variety of different purposes. The venom of solitary aculeates paralyze and preserve prey without killing it, whereas social aculeates utilize their venom in defence of their colony. These distinct applications of venom suggest that its components and their functions are also likely to differ. This study investigates a range of solitary and social species across Aculeata. We combined electrophoretic, mass spectrometric, and transcriptomic techniques to characterize the compositions of venoms from an incredibly diverse taxon. In addition, in vitro assays shed light on their biological activities. Although there were many common components identified in the venoms of species with different social behavior, there were also significant variations in the presence and activity of enzymes such as phospholipase A2s and serine proteases and the cytotoxicity of the venoms. Social aculeate venom showed higher presence of peptides that cause damage and pain in victims. The venom-gland transcriptome from the European honeybee (Apis mellifera) contained highly conserved toxins which match those identified by previous investigations. In contrast, venoms from less-studied taxa returned limited results from our proteomic databases, suggesting that they contain unique toxins.
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Affiliation(s)
- Daniel Dashevsky
- Australian National Insect Collection, Commonwealth Scientific & Industrial Research Organisation, Canberra, ACT 2601, Australia
- Correspondence: (D.D.); (B.G.F.)
| | - Kate Baumann
- Venom Evolution Lab, School of Biological Sciences, The University of Queensland, St. Lucia, QLD 4072, Australia
| | - Eivind A. B. Undheim
- Centre for Ecological and Evolutionary Synthesis, Department of Bioscience, University of Oslo, N-0316 Oslo, Norway
| | - Amanda Nouwens
- School of Chemistry and Molecular Biosciences, University of Queensland, St. Lucia, QLD 4072, Australia
| | - Maria P. Ikonomopoulou
- Translational Venomics Group, Madrid Institute for Advanced Studies in Food, 4075 Madrid, Spain
| | - Justin O. Schmidt
- Southwestern Biological Institute, 1961 W. Brichta Dr., Tucson, AZ 85745, USA
| | - Lilin Ge
- State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Qixia District, Nanjing 210046, China
- Institute of Translational Medicine, Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau
| | - Hang Fai Kwok
- Institute of Translational Medicine, Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau
| | - Juanita Rodriguez
- Australian National Insect Collection, Commonwealth Scientific & Industrial Research Organisation, Canberra, ACT 2601, Australia
| | - Bryan G. Fry
- Venom Evolution Lab, School of Biological Sciences, The University of Queensland, St. Lucia, QLD 4072, Australia
- Correspondence: (D.D.); (B.G.F.)
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Vakili B, Jahanian-Najafabadi A. Application of Antimicrobial Peptides in the Design and Production of Anticancer Agents. Int J Pept Res Ther 2023. [DOI: 10.1007/s10989-023-10501-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
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11
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Chen J, Liu D, Yang J, Jin C, Zhao C, Cheng J. Epidermal growth factor activates a hypoxia-inducible factor 1α-microRNA-21 axis to inhibit aquaporin 4 in chronic rhinosinusitis. Ann N Y Acad Sci 2022; 1518:299-314. [PMID: 36303271 DOI: 10.1111/nyas.14914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The pathogenesis of chronic rhinosinusitis (CRS) is largely unknown, but accumulating evidence supports the role of the airway epithelium in its pathophysiology. In our study here, we evaluated whether epidermal growth factor (EGF) regulates a hypoxia-inducible factor 1α (HIF-1α)-microRNA-21 (miR-21)-aquaporin 4 (AQP4) axis in nasal epithelial cells from CRS patients. We found that, compared with normal sinus mucosa, EGF, HIF-1α, and miR-21 were upregulated and AQP4 was downregulated in sinus mucosa from patients with CRS and in a CRS mouse model. It was established that EGF upregulated HIF-1α and miR-21 expression, that HIF-1α regulated miR-21 transcription, and that the AQP4 gene was a target of miR-21. Knockdown of EGF and HIF-1α mRNAs and of miR-21, or overexpression of AQP4 mRNA, inhibited proliferation and promoted apoptosis of hypoxia-exposed human nasal epithelial cells, effects that were associated with reduced levels of α-SMA, fibronectin, and vimentin, as well as promoted caspase-3 activity and E-cadherin levels. In the mouse CRS model, EGF elevation increased in vivo production of inflammatory IL-4 and IFN-γ to promote CRS, which was reversed by AQP4 elevation. Collectively, EGF upregulates HIF-1α and miR-21 expression to inhibit AQP4 expression, thereby promoting the proliferation of nasal epithelial cells and the development of CRS.
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Affiliation(s)
- Junjun Chen
- Department of Pharmacy, The Second Hospital of Jilin University, Changchun, P. R. China
| | - Dong Liu
- Department of Radiology, The Second Hospital of Jilin University, Changchun, P. R. China
| | - Jingpu Yang
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Hospital of Jilin University, Changchun, P. R. China
| | - Chengxun Jin
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Hospital of Jilin University, Changchun, P. R. China
| | - Chang Zhao
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Hospital of Jilin University, Changchun, P. R. China
| | - Jinzhang Cheng
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Hospital of Jilin University, Changchun, P. R. China
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12
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Zhou J, Wang L, Peng C, Peng F. Co-Targeting Tumor Angiogenesis and Immunosuppressive Tumor Microenvironment: A Perspective in Ethnopharmacology. Front Pharmacol 2022; 13:886198. [PMID: 35784750 PMCID: PMC9242535 DOI: 10.3389/fphar.2022.886198] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 05/04/2022] [Indexed: 11/13/2022] Open
Abstract
Tumor angiogenesis is one of the most important processes of cancer deterioration via nurturing an immunosuppressive tumor environment (TME). Targeting tumor angiogenesis has been widely accepted as a cancer intervention approach, which is also synergistically associated with immune therapy. However, drug resistance is the biggest challenge of anti-angiogenesis therapy, which affects the outcomes of anti-angiogeneic agents, and even combined with immunotherapy. Here, emerging targets and representative candidate molecules from ethnopharmacology (including traditional Chinese medicine, TCM) have been focused, and they have been proved to regulate tumor angiogenesis. Further investigations on derivatives and delivery systems of these molecules will provide a comprehensive landscape in preclinical studies. More importantly, the molecule library of ethnopharmacology meets the viability for targeting angiogenesis and TME simultaneously, which is attributed to the pleiotropy of pro-angiogenic factors (such as VEGF) toward cancer cells, endothelial cells, and immune cells. We primarily shed light on the potentiality of ethnopharmacology against tumor angiogenesis, particularly TCM. More research studies concerning the crosstalk between angiogenesis and TME remodeling from the perspective of botanical medicine are awaited.
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Affiliation(s)
- Jianbo Zhou
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Li Wang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Fu Peng, ; Cheng Peng,
| | - Fu Peng
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
- *Correspondence: Fu Peng, ; Cheng Peng,
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13
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de Keijzer MJ, de Klerk DJ, de Haan LR, van Kooten RT, Franchi LP, Dias LM, Kleijn TG, van Doorn DJ, Heger M. Inhibition of the HIF-1 Survival Pathway as a Strategy to Augment Photodynamic Therapy Efficacy. Methods Mol Biol 2022; 2451:285-403. [PMID: 35505024 DOI: 10.1007/978-1-0716-2099-1_19] [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] [Indexed: 06/14/2023]
Abstract
Photodynamic therapy (PDT) is a non-to-minimally invasive treatment modality that utilizes photoactivatable drugs called photosensitizers to disrupt tumors with locally photoproduced reactive oxygen species (ROS). Photosensitizer activation by light results in hyperoxidative stress and subsequent tumor cell death, vascular shutdown and hypoxia, and an antitumor immune response. However, sublethally afflicted tumor cells initiate several survival mechanisms that account for decreased PDT efficacy. The hypoxia inducible factor 1 (HIF-1) pathway is one of the most effective cell survival pathways that contributes to cell recovery from PDT-induced damage. Several hundred target genes of the HIF-1 heterodimeric complex collectively mediate processes that are involved in tumor cell survival directly and indirectly (e.g., vascularization, glucose metabolism, proliferation, and metastasis). The broad spectrum of biological ramifications culminating from the activation of HIF-1 target genes reflects the importance of HIF-1 in the context of therapeutic recalcitrance. This chapter elaborates on the involvement of HIF-1 in cancer biology, the hypoxic response mechanisms, and the role of HIF-1 in PDT. An overview of inhibitors that either directly or indirectly impede HIF-1-mediated survival signaling is provided. The inhibitors may be used as pharmacological adjuvants in combination with PDT to augment therapeutic efficacy.
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Affiliation(s)
- Mark J de Keijzer
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
- Department of Pharmaceutics, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Daniel J de Klerk
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
- Laboratory of Experimental Oncology, Department of Pathology, Erasmus MC, Rotterdam, The Netherlands
| | - Lianne R de Haan
- Laboratory of Experimental Oncology, Department of Pathology, Erasmus MC, Rotterdam, The Netherlands
| | - Robert T van Kooten
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - Leonardo P Franchi
- Departamento de Bioquímica e Biologia Molecular, Instituto de Ciências Biológicas (ICB) 2, Universidade Federal de Goiás (UFG), Goiânia, GO, Brazil
- Faculty of Philosophy, Sciences, and Letters of Ribeirão Preto, epartment of Chemistry, Center of Nanotechnology and Tissue Engineering-Photobiology and Photomedicine Research Group,University of São Paulo, São Paulo, Brazil
| | - Lionel M Dias
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
- Laboratory of Experimental Oncology, Department of Pathology, Erasmus MC, Rotterdam, The Netherlands
| | - Tony G Kleijn
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
- Laboratory of Experimental Oncology, Department of Pathology, Erasmus MC, Rotterdam, The Netherlands
| | - Diederick J van Doorn
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Location AMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Michal Heger
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, People's Republic of China.
- Department of Pharmaceutics, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
- Laboratory of Experimental Oncology, Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
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14
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Guha S, Ferrie RP, Ghimire J, Ventura CR, Wu E, Sun L, Kim SY, Wiedman GR, Hristova K, Wimley WC. Applications and evolution of melittin, the quintessential membrane active peptide. Biochem Pharmacol 2021; 193:114769. [PMID: 34543656 DOI: 10.1016/j.bcp.2021.114769] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 09/14/2021] [Accepted: 09/15/2021] [Indexed: 12/12/2022]
Abstract
Melittin, the main venom component of the European Honeybee, is a cationic linear peptide-amide of 26 amino acid residues with the sequence: GIGAVLKVLTTGLPALISWIKRKRQQ-NH2. Melittin binds to lipid bilayer membranes, folds into amphipathic α-helical secondary structure and disrupts the permeability barrier. Since melittin was first described, a remarkable array of activities and potential applications in biology and medicine have been described. Melittin is also a favorite model system for biophysicists to study the structure, folding and function of peptides and proteins in membranes. Melittin has also been used as a template for the evolution of new activities in membranes. Here we overview the rich history of scientific research into the many activities of melittin and outline exciting future applications.
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Affiliation(s)
- Shantanu Guha
- University of Texas Health Science Center at Houston, Department of Microbiology and Molecular Genetics, Houston, TX, USA
| | - Ryan P Ferrie
- Tulane University School of Medicine, Department of Biochemistry and Molecular Biology, New Orleans, LA, USA
| | - Jenisha Ghimire
- Tulane University School of Medicine, Department of Biochemistry and Molecular Biology, New Orleans, LA, USA
| | - Cristina R Ventura
- Seton Hall University, Department of Chemistry and Biochemistry, South Orange, NJ, USA
| | - Eric Wu
- Tulane University School of Medicine, Department of Biochemistry and Molecular Biology, New Orleans, LA, USA
| | - Leisheng Sun
- Tulane University School of Medicine, Department of Biochemistry and Molecular Biology, New Orleans, LA, USA
| | - Sarah Y Kim
- Duke University, Department of Biomedical Engineering, Durham, NC, USA
| | - Gregory R Wiedman
- Seton Hall University, Department of Chemistry and Biochemistry, South Orange, NJ, USA
| | - Kalina Hristova
- Johns Hopkins University, Department of Materials Science and Engineering, Baltimore, MD, USA.
| | - Wimley C Wimley
- University of Texas Health Science Center at Houston, Department of Microbiology and Molecular Genetics, Houston, TX, USA.
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15
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El Bakary NM, Alsharkawy AZ, Shouaib ZA, Barakat EMS. Role of Bee Venom and Melittin on Restraining Angiogenesis and Metastasis in γ-Irradiated Solid Ehrlich Carcinoma-Bearing Mice. Integr Cancer Ther 2021; 19:1534735420944476. [PMID: 32735464 PMCID: PMC7401046 DOI: 10.1177/1534735420944476] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Pathological angiogenesis and apoptosis evasion are common hallmarks of cancer. The present work was an endeavor to evaluate the influence of bee venom (BV) or its major constituent melittin (MEL) as antiapoptotic and angiogenic regulator modifier on the tumor growth and the cell sensitivity to ionizing radiation targeting the improvement of cancer therapeutic protocols. BV (0.56 mg/kg/day) and MEL (500 µg/kg body weight/day) were injected intraperitoneally to mice bearing 1 cm3 solid tumor of Ehrlich ascites carcinoma (EAC) for 21 consecutive days. Mice were whole-body exposed to 1 Gray (Gy) of γ-radiation (2 fractionated doses). Treatment with BV or MEL markedly suppresses the proliferation of tumor in EAC mice. The concentrations of m-RNA for angiogenic factors (TNF-α, VEGF) as well as MMPs 2 and 9 activities and NO concentration were significantly decreased, combined with improvements in apoptotic regulators (caspase-3 activity) and normal cells redox tone (catalase and free radicals content) compared with EAC mice. Moreover, the histopathological investigation confirms the improvement exerted by BV or MEL in the EAC mice group or EAC + R group. Exposure to γ-radiation sustained the modulatory effect of BV on tumor when compared with EAC + BV mice. Convincingly, the role of BV or MEL as a natural antiangiogenic in the biological sequelae after radiation exposure is verified. Hence, BV and its major constituent MEL might represent a potential therapeutic strategy for increasing the radiation response of solid tumors.
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Affiliation(s)
- Nermeen M El Bakary
- National Centre for Radiation Research and Technology, Atomic Energy Authority, Cairo, Egypt
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16
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Dabbagh Moghaddam F, Akbarzadeh I, Marzbankia E, Farid M, khaledi L, Reihani AH, Javidfar M, Mortazavi P. Delivery of melittin-loaded niosomes for breast cancer treatment: an in vitro and in vivo evaluation of anti-cancer effect. Cancer Nanotechnol 2021. [DOI: 10.1186/s12645-021-00085-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Abstract
Background
Melittin, a peptide component of honey bee venom, is an appealing candidate for cancer therapy. In the current study, melittin, melittin-loaded niosome, and empty niosome had been optimized and the anticancer effect assessed in vitro on 4T1 and SKBR3 breast cell lines and in vivo on BALB/C inbred mice. "Thin-layer hydration method" was used for preparing the niosomes; different niosomal formulations of melittin were prepared and characterized in terms of morphology, size, polydispersity index, encapsulation efficiency, release kinetics, and stability. A niosome was formulated and loaded with melittin as a promising drug carrier system for chemotherapy of the breast cancer cells. Hemolysis, apoptosis, cell cytotoxicity, invasion and migration of selected concentrations of melittin, and melittin-loaded niosome were evaluated on 4T1 and SKBR3 cells using hemolytic activity assay, flow cytometry, MTT assay, soft agar colony assay, and wound healing assay. Real-time PCR was used to determine the gene expression. 40 BALB/c inbred mice were used; then, the histopathology, P53 immunohistochemical assay and estimate of renal and liver enzyme activity for all groups had been done.
Results
This study showed melittin-loaded niosome is an excellent substitute in breast cancer treatment due to enhanced targeting, encapsulation efficiency, PDI, and release rate and shows a high anticancer effect on cell lines. The melittin-loaded niosome affects the genes expression by studied cells were higher than other samples; down-regulates the expression of Bcl2, MMP2, and MMP9 genes while they up-regulate the expression of Bax, Caspase3 and Caspase9 genes. They have also enhanced the apoptosis rate and inhibited cell migration, invasion in both cell lines compared to the melittin samples. Results of histopathology showed reduce mitosis index, invasion and pleomorphism in melittin-loaded niosome. Renal and hepatic biomarker activity did not significantly differ in melittin-loaded niosome and melittin compared to healthy control. In immunohistochemistry, P53 expression did not show a significant change in all groups.
Conclusions
Our study successfully declares that melittin-loaded niosome had more anti-cancer effects than free melittin. This project has demonstrated that niosomes are suitable vesicle carriers for melittin, compare to the free form.
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Mir Hassani Z, Nabiuni M, Parivar K, Abdirad S, Karimzadeh L. Melittin inhibits the expression of key genes involved in tumor microenvironment formation by suppressing HIF-1α signaling in breast cancer cells. Med Oncol 2021; 38:77. [PMID: 34076777 DOI: 10.1007/s12032-021-01526-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 05/21/2021] [Indexed: 11/29/2022]
Abstract
HIF-1α has critical roles in the formation of tumor microenvironment by regulating genes involved in angiogenesis and anaerobic respiration. TME fuels tumors' growth and metastasis and presents therapy with several challenges. Therefore, we aimed to investigate if Melittin disrupts HIF-1α signaling pathway in breast adenocarcinoma cell line MDA-MB-231. Breast adenocarcinoma cell line MDA-MB-231 was cultured in the presence of different doses of Melittin, and MTT assay was carried out to measure Melittin's cytotoxic effects. Cells were exposed to 5% O2 to mimic hypoxic conditions and Melittin. Western blot was used to measure HIF-1α protein levels. Gene expression analysis was performed using real-time PCR to measure relative mRNA abundance of genes involved in tumor microenvironment formation. Our results revealed that Melittin effectively inhibits HIF-1α at transcriptional and translational/post-translational level. HIF-1α protein and mRNA level were significantly decreased in Melittin-treated groups. It is found that inhibition of HIF-1α by Melittin is through downregulation of NFκB gene expression. Furthermore, gene expression analysis showed a downregulation in VEGFA and LDHA expression due to inhibition of HIF-1α protein by Melittin. In addition, cell toxicity assay showed that Melittin inhibits the growth of MDA-MB-231 cell line through activation of extrinsic and intrinsic apoptotic pathways by upregulating TNFA and BAX expression. Melittin suppresses the expression of genes responsible for formation of TME physiological hallmarks by suppressing HIF-1α signaling pathway. Our results suggest that Melittin can modulate tumor microenvironment by inhibition of VEGFA and LDHA.
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Affiliation(s)
- Zabih Mir Hassani
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, 31979-37551, Tehran, Iran
| | - Mohammad Nabiuni
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, 31979-37551, Tehran, Iran.
| | - Kazem Parivar
- Department of Biology, Faculty of Life Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Somayeh Abdirad
- Department of Plant Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Latifeh Karimzadeh
- Department of Animal Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran
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18
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Zhou J, Wan C, Cheng J, Huang H, Lovell JF, Jin H. Delivery Strategies for Melittin-Based Cancer Therapy. ACS APPLIED MATERIALS & INTERFACES 2021; 13:17158-17173. [PMID: 33847113 DOI: 10.1021/acsami.1c03640] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Melittin (MLT) has been studied preclinically as an anticancer agent based on its broad lytic effects in multiple tumor types. However, unsatisfactory tissue distribution, hemolysis, rapid metabolism, and limited specificity are critical obstacles that limit the translation of MLT. Emerging drug delivery strategies hold promise for targeting, controlled drug release, reduced side effects, and ultimately improved treatment efficiency. In this review, we discuss recent advances in the use of diverse carriers to deliver MLT, with an emphasis on the design and mechanisms of action. We further outline the opportunities for MLT-based cancer immunotherapy.
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Affiliation(s)
- Jie Zhou
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, P. R. China
| | - Chao Wan
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, P. R. China
| | - Jing Cheng
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, P. R. China
| | - Hao Huang
- Guo Life Science Center, Wuhan Shengrun Biotechnology Co. Ltd, Wuhan 430075, P.R. China
| | - Jonathan F Lovell
- Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, New York 14260, United States
| | - Honglin Jin
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, P. R. China
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19
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Yu R, Wang M, Wang M, Han L. Melittin suppresses growth and induces apoptosis of non-small-cell lung cancer cells via down-regulation of TGF-β-mediated ERK signal pathway. ACTA ACUST UNITED AC 2020; 54:e9017. [PMID: 33331417 PMCID: PMC7747877 DOI: 10.1590/1414-431x20209017] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 09/15/2020] [Indexed: 02/06/2023]
Abstract
The purpose of this study was to investigate the anti-cancer effect of melittin on growth, migration, invasion, and apoptosis of non-small-cell lung cancer (NSCLC) cells. This study also explored the potential anti-cancer mechanism of melittin in NSCLC cells. The results demonstrated that melittin suppressed growth, migration, and invasion, and induced apoptosis of NSCLC cells in vitro. Melittin increased pro-apoptotic caspase-3 and Apaf-1 gene expression. Melittin inhibited tumor growth factor (TGF)-β expression and phosphorylated ERK/total ERK (pERK/tERK) in NSCLC cells. However, TGF-β overexpression (pTGF-β) abolished melittin-decreased TGF-β expression and pERK/tERK in NSCLC cells. Treatment with melittin suppressed tumor growth and prolonged mouse survival during the 120-day observation in vivo. Treatment with melittin increased TUNEL-positive cells and decreased expression levels of TGF-β and ERK in tumor tissue compared to the control group. In conclusion, the findings of this study indicated that melittin inhibited growth, migration, and invasion, and induced apoptosis of NSCLC cells through down-regulation of TGF-β-mediated ERK signaling pathway, suggesting melittin may be a promising anti-cancer agent for NSCLC therapy.
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Affiliation(s)
- Renzhi Yu
- Department of Respiratory Medicine, Mudanjiang Medical University Affiliated Hongqi Hospital, Mudanjiang, China
| | - Miao Wang
- Department of Respiratory Medicine, Mudanjiang Medical University Affiliated Hongqi Hospital, Mudanjiang, China
| | - Minghuan Wang
- Community Health Service Center, Mudanjiang Medical University Affiliated Hongqi Hospital, Mudanjiang, China
| | - Lei Han
- Department of Respiratory Medicine, Mudanjiang Medical University Affiliated Hongqi Hospital, Mudanjiang, China
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20
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Su X, Yang Y, Ma L, Luo P, Shen K, Dai H, Jiang Y, Shuai L, Liu Z, You J, Min K, Shi C, Chen Z. Human Positive Coactivator 4 Affects the Progression and Prognosis of Pancreatic Ductal Adenocarcinoma via the mTOR/P70s6k Signaling Pathway. Onco Targets Ther 2020; 13:12213-12223. [PMID: 33273827 PMCID: PMC7705283 DOI: 10.2147/ott.s284219] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 11/17/2020] [Indexed: 12/13/2022] Open
Abstract
Introduction Pancreatic cancer is one of the deadliest cancers in the world, and pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all cases. Human positive coactivator 4 (PC4) is a transcriptional coactivator that has been associated with the development and progression of several tumors. However, no studies investigated the potential role of PC4 in PDAC. Methods We investigated PC4 expression in 81 PDAC tissue samples using immunohistochemistry and studied the impact of PC4 expression and the molecular mechanisms of this altered expression on PDAC tumorigenesis and proliferation both in vitro and in vivo. Results PC4 overexpression was correlated with a poor outcome in PDAC patients. The RNAi-mediated knockdown of PC4 expression in CFPAC-1 and AsPC-1 cell lines reduced cell proliferation and tumor growth. The loss of PC4 in PDAC inhibits cell growth by inducing cell cycle arrest at the G1/S transition and suppressing the mTOR/p70s6k pathway. Discussion/Conclusion Our findings reveal for the first time that PC4 exerts oncogenic functions by activating mTOR/p70s6k signaling pathway-mediated cell proliferation, implying that PC4 is a promising therapeutic target for PDAC.
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Affiliation(s)
- Xingxing Su
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, People's Republic of China
| | - Yishi Yang
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, People's Republic of China
| | - Le Ma
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing 400038, People's Republic of China
| | - Peng Luo
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing 400038, People's Republic of China
| | - Kaicheng Shen
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, People's Republic of China
| | - Haisu Dai
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, People's Republic of China
| | - Yan Jiang
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, People's Republic of China
| | - Ling Shuai
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, People's Republic of China
| | - Zhipeng Liu
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, People's Republic of China
| | - Jinshan You
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, People's Republic of China
| | - Ke Min
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, People's Republic of China
| | - Chunmeng Shi
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing 400038, People's Republic of China
| | - Zhiyu Chen
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, People's Republic of China
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21
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Carpena M, Nuñez-Estevez B, Soria-Lopez A, Simal-Gandara J. Bee Venom: An Updating Review of Its Bioactive Molecules and Its Health Applications. Nutrients 2020; 12:nu12113360. [PMID: 33142794 PMCID: PMC7693387 DOI: 10.3390/nu12113360] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 10/27/2020] [Accepted: 10/29/2020] [Indexed: 02/07/2023] Open
Abstract
Bee venom (BV) is usually associated with pain since, when humans are stung by bees, local inflammation and even an allergic reaction can be produced. BV has been traditionally used in ancient medicine and in acupuncture. It consists of a mixture of substances, principally of proteins and peptides, including enzymes as well as other types of molecules in a very low concentration. Melittin and phospholipase A2 (PLA2) are the most abundant and studied compounds of BV. Literature of the main biological activities exerted by BV shows that most studies focuses on the comprehension and test of anti-inflammatory effects and its mechanisms of action. Other properties such as antioxidant, antimicrobial, neuroprotective or antitumor effects have also been assessed, both in vitro and in vivo. Moreover, human trials are necessary to confirm those clinical applications. However, notwithstanding the therapeutic potential of BV, there are certain problems regarding its safety and the possible appearance of adverse effects. On this perspective, new approaches have been developed to avoid these complications. This manuscript is aimed at reviewing the actual knowledge on BV components and its associated biological activities as well as the latest advances on this subject.
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Tang Q, Lim T, Wei XJ, Wang QY, Xu JC, Shen LY, Zhu ZZ, Zhang CQ. A free-standing multilayer film as a novel delivery carrier of platelet lysates for potential wound-dressing applications. Biomaterials 2020; 255:120138. [DOI: 10.1016/j.biomaterials.2020.120138] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 05/03/2020] [Accepted: 05/19/2020] [Indexed: 12/16/2022]
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Trac NT, Chung EJ. Peptide-based targeting of immunosuppressive cells in cancer. Bioact Mater 2020; 5:92-101. [PMID: 31956738 PMCID: PMC6962647 DOI: 10.1016/j.bioactmat.2020.01.006] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 01/06/2020] [Accepted: 01/09/2020] [Indexed: 02/07/2023] Open
Abstract
Cancer progression is marked by the infiltration of immunosuppressive cells, such as tumor-associated macrophages (TAMs), regulatory T lymphocytes (Tregs), and myeloid-derived suppressor cells (MDSCs). These cells play a key role in abrogating the cytotoxic T lymphocyte-mediated (CTL) immune response, allowing tumor growth to proceed unabated. Furthermore, targeting these immunosuppressive cells through the use of peptides and peptide-based nanomedicine has shown promising results. Here we review the origins and functions of immunosuppressive cells in cancer progression, peptide-based systems used in their targeting, and explore future avenues of research regarding cancer immunotherapy. The success of these studies demonstrates the importance of the tumor immune microenvironment in the propagation of cancer and the potential of peptide-based nanomaterials as immunomodulatory agents.
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Affiliation(s)
- Noah T. Trac
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
| | - Eun Ji Chung
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
- Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA
- Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Vascular Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA, USA
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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Melittin-A Natural Peptide from Bee Venom Which Induces Apoptosis in Human Leukaemia Cells. Biomolecules 2020; 10:biom10020247. [PMID: 32041197 PMCID: PMC7072249 DOI: 10.3390/biom10020247] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 01/29/2020] [Accepted: 02/04/2020] [Indexed: 12/11/2022] Open
Abstract
Bee venom is a very complex mixture produced and secreted by the honeybee (Apis mellifera). Melittin is a major component of bee venom that accounts for about 52% of its dry mass. A vast number of studies have been dedicated to the effects of melittin’s regulation of apoptosis and to the factors that induce apoptosis in various types of cancer such as breast, ovarian, prostate, lung. The latest evidence indicates its potential as a therapeutic agent in the treatment of leukaemia. The aim of our present study is to evaluate melittin’s ability to induce apoptosis in leukaemia cell lines of different origin acute lymphoblastic leukaemia (CCRF-CEM) and chronic myelogenous leukaemia (K-562). We demonstrated that melittin strongly reduced cell viability in both leukaemia cell lines but not in physiological peripheral blood mononuclear cells (PMBCs). Subsequent estimated parameters (mitochondrial membrane potential, Annexin V binding and Caspases 3/7 activity) clearly demonstrated that melittin induced apoptosis in leukaemia cells. This is a very important step for research into the development of new potential anti-leukaemia as well as anticancer therapies. Further analyses on the molecular level have been also planned (analysis of proapoptotic genes expression and DNA damages) for our next research project, which will also focus on melittin.
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An overview of the bioactive compounds, therapeutic properties and toxic effects of apitoxin. Food Chem Toxicol 2019; 134:110864. [PMID: 31574265 DOI: 10.1016/j.fct.2019.110864] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Revised: 09/26/2019] [Accepted: 09/27/2019] [Indexed: 12/15/2022]
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Lyu C, Fang F, Li B. Anti-Tumor Effects of Melittin and Its Potential Applications in Clinic. Curr Protein Pept Sci 2019; 20:240-250. [PMID: 29895240 DOI: 10.2174/1389203719666180612084615] [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: 01/01/2018] [Revised: 04/10/2018] [Accepted: 05/21/2018] [Indexed: 02/08/2023]
Abstract
Melittin, a major component of bee venom, is a water-soluble toxic peptide of which a various biological effects have been identified to be useful in anti-tumor therapy. In addition, Melittin also has anti-parasitic, anti-bacterial, anti-viral, and anti-inflammatory activities. Therefore, it is a very attractive therapeutic candidate for human diseases. However, melittin induces extensive hemolysis, a severe side effect that dampens its future development and clinical application. Thus, studies of melittin derivatives and new drug delivery systems have been conducted to explore approaches for optimizing the efficacy of this compound, while reducing its toxicity. A number of reviews have focused on each side, respectively. In this review, we summarize the research progress on the anti-tumor effects of melittin and its derivatives, and discuss its future potential clinical applications.
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Affiliation(s)
- Can Lyu
- Changhai Hospital of Traditional Chinese Medicine, Second Military Medical University, Shanghai, China
| | - Fanfu Fang
- Changhai Hospital of Traditional Chinese Medicine, Second Military Medical University, Shanghai, China
| | - Bai Li
- Changhai Hospital of Traditional Chinese Medicine, Second Military Medical University, Shanghai, China
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Lim HN, Baek SB, Jung HJ. Bee Venom and Its Peptide Component Melittin Suppress Growth and Migration of Melanoma Cells via Inhibition of PI3K/AKT/mTOR and MAPK Pathways. Molecules 2019; 24:molecules24050929. [PMID: 30866426 PMCID: PMC6429308 DOI: 10.3390/molecules24050929] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Revised: 02/28/2019] [Accepted: 03/03/2019] [Indexed: 01/28/2023] Open
Abstract
Malignant melanoma is the deadliest form of skin cancer and highly chemoresistant. Melittin, an amphiphilic peptide containing 26 amino acid residues, is the major active ingredient from bee venom (BV). Although melittin is known to have several biological activities such as anti-inflammatory, antibacterial and anticancer effects, its antimelanoma effect and underlying molecular mechanism have not been fully elucidated. In the current study, we investigated the inhibitory effect and action mechanism of BV and melittin against various melanoma cells including B16F10, A375SM and SK-MEL-28. BV and melittin potently suppressed the growth, clonogenic survival, migration and invasion of melanoma cells. They also reduced the melanin formation in α-melanocyte-stimulating hormone (MSH)-stimulated melanoma cells. Furthermore, BV and melittin induced the apoptosis of melanoma cells by enhancing the activities of caspase-3 and -9. In addition, we demonstrated that the antimelanoma effect of BV and melittin is associated with the downregulation of PI3K/AKT/mTOR and MAPK signaling pathways. We also found that the combination of melittin with the chemotherapeutic agent temozolomide (TMZ) significantly increases the inhibition of growth as well as invasion in melanoma cells compared to melittin or TMZ alone. Taken together, these results suggest that melittin could be potentially applied for the prevention and treatment of malignant melanoma.
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Affiliation(s)
- Haet Nim Lim
- Department of Pharmaceutical Engineering & Biotechnology, Sun Moon University, 70, Sunmoon-ro 221, Tangjeong-myeon, Asan-si, Chungnam 31460, Korea.
| | - Seung Bae Baek
- Eco system Lab., LOCORICO, Sun Moon University, 70, Sunmoon-ro 221, Tangjeong-myeon, Asan-si, Chungnam 31460, Korea.
| | - Hye Jin Jung
- Department of Pharmaceutical Engineering & Biotechnology, Sun Moon University, 70, Sunmoon-ro 221, Tangjeong-myeon, Asan-si, Chungnam 31460, Korea.
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Melittin Constrains the Expression of Identified Key Genes Associated with Bladder Cancer. J Immunol Res 2018; 2018:5038172. [PMID: 29854840 PMCID: PMC5960535 DOI: 10.1155/2018/5038172] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 03/02/2018] [Accepted: 04/02/2018] [Indexed: 12/25/2022] Open
Abstract
This work is aimed at investigating the effect of melittin on identified key genes in bladder cancer (BC) and further providing a theoretical basis for BC treatment. GSE35014 downloaded from the Gene Expression Omnibus (GEO) database was used to screen differentially expressed genes (DEGs) in BC cells and control. Results showed that a total of 389 upregulated and 169 downregulated genes were identified. Subsequently, GO analysis, KEGG pathway enrichment analysis, and PPI network analysis were employed to disclose the crucial genes and signaling pathways involved in BC. Fifteen module-related DEGs and their associated signaling pathways were obtained according to the PPI network and modular analyses. Based on the analysis of articles retrieved in the PubMed database, we found that melittin could induce apoptosis and constrain the progression of tumor cells as a result of regulating critical cancer-related signaling pathways, such as PI3K-Akt and TNF signaling pathways. Furthermore, PI3K-Akt and TNF signaling pathways were also found to be associated with module-related DEGs according to biological analyses. At last, qRT-PCR analysis demonstrated that melittin could constrain the expression of module-related DEGs (LPAR1, COL5A1, COL6A2, CXCL1, CXCL2, and CXCL3) associated with PI3K-Akt and TNF signaling pathways in BC cells. Functional assays revealed that melittin could constrain the proliferative and migrated abilities of BC cells. Conjointly, these findings provide a theoretical basis for these six genes as drug-sensitive markers of melittin in BC treatment.
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Shin SH, Ye MK, Choi SY, Park KK. Anti-inflammatory effect of bee venom in an allergic chronic rhinosinusitis mouse model. Mol Med Rep 2018. [PMID: 29532888 DOI: 10.3892/mmr.2018.8720] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Bee venom (BV) has long been used as anti-inflammatory agent in traditional oriental medicine; however, the effect of BV on chronic rhinosinusitis (CRS) is not commonly studied. The aim of the present study was to determine the anti-inflammatory effect of BV on an allergic CRS mouse model. An allergic CRS mouse model was established following the administration of ovalbumin with Staphylococcus aureus enterotoxin B (SEB) into the nose. A total of 0.5 or 5 ng/ml of BV were intranasally applied 3 times a week for 8 weeks. Histopathological alterations were observed using hematoxylin and eosin, and Periodic acid Schiff staining. The levels of inflammatory cell infiltration, interleukin (IL)‑4, IL‑10 and interferon (INF)‑γ in nasal lavage fluid (NLF) were measured. Nuclear factor (NF)‑κB and activator protein (AP)‑1 expressions were also determined by immunohistochemical staining. The group treated with BV had significantly decreased inflammatory cell infiltration and PAS‑positive cells. The levels of INF‑γ, and neutrophil and eosinophil counts in NLF were significantly decreased, and the SEB‑induced NF‑κB and AP‑1 expressions in mouse nasal mucosa were significantly suppressed by 0.5 and 5 ng/ml BV. Thus, BV exerted significant anti‑inflammatory effects in an allergic CRS mouse model and may have potential value for the treatment of CRS.
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Affiliation(s)
- Seung-Heon Shin
- Department of Otolaryngology‑Head and Neck Surgery, School of Medicine, Catholic University of Daegu, Daegu 42472, Republic of Korea
| | - Mi-Kyung Ye
- Department of Otolaryngology‑Head and Neck Surgery, School of Medicine, Catholic University of Daegu, Daegu 42472, Republic of Korea
| | - Sung-Yong Choi
- Department of Otolaryngology‑Head and Neck Surgery, School of Medicine, Catholic University of Daegu, Daegu 42472, Republic of Korea
| | - Kwan-Kyu Park
- Department of Pathology, School of Medicine, Catholic University of Daegu, Daegu 42472, Republic of Korea
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Socarras KM, Theophilus PAS, Torres JP, Gupta K, Sapi E. Antimicrobial Activity of Bee Venom and Melittin against Borrelia burgdorferi. Antibiotics (Basel) 2017; 6:antibiotics6040031. [PMID: 29186026 PMCID: PMC5745474 DOI: 10.3390/antibiotics6040031] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 11/21/2017] [Accepted: 11/22/2017] [Indexed: 01/12/2023] Open
Abstract
Lyme disease is a tick-borne, multi-systemic disease, caused by the bacterium Borrelia burgdorferi. Though antibiotics are used as a primary treatment, relapse often occurs after the discontinuation of antimicrobial agents. The reason for relapse remains unknown, however previous studies suggest the possible presence of antibiotic resistant Borrelia round bodies, persisters and attached biofilm forms. Thus, there is an urgent need to find antimicrobial agents suitable to eliminate all known forms of B. burgdorferi. In this study, natural antimicrobial agents such as Apis mellifera venom and a known component, melittin, were tested using SYBR Green I/PI, direct cell counting, biofilm assays combined with LIVE/DEAD and atomic force microscopy methods. The obtained results were compared to standalone and combinations of antibiotics such as Doxycycline, Cefoperazone, Daptomycin, which were recently found to be effective against Borrelia persisters. Our findings showed that both bee venom and melittin had significant effects on all the tested forms of B. burgdorferi. In contrast, the control antibiotics when used individually or even in combinations had limited effects on the attached biofilm form. These findings strongly suggest that whole bee venom or melittin could be effective antimicrobial agents for B. burgdorferi; however, further research is necessary to evaluate their effectiveness in vivo, as well as their safe and effective delivery method for their therapeutic use.
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Affiliation(s)
- Kayla M Socarras
- Lyme Disease Research Group, Department of Biology and Environmental Science, University of New Haven, West Haven, CT 06519, USA.
| | - Priyanka A S Theophilus
- Lyme Disease Research Group, Department of Biology and Environmental Science, University of New Haven, West Haven, CT 06519, USA.
| | - Jason P Torres
- Lyme Disease Research Group, Department of Biology and Environmental Science, University of New Haven, West Haven, CT 06519, USA.
| | - Khusali Gupta
- Lyme Disease Research Group, Department of Biology and Environmental Science, University of New Haven, West Haven, CT 06519, USA.
| | - Eva Sapi
- Lyme Disease Research Group, Department of Biology and Environmental Science, University of New Haven, West Haven, CT 06519, USA.
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Zhang SF, Chen Z. Melittin exerts an antitumor effect on non-small cell lung cancer cells. Mol Med Rep 2017; 16:3581-3586. [DOI: 10.3892/mmr.2017.6970] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 05/08/2017] [Indexed: 11/05/2022] Open
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Liu Y, Wang X, Jia Y, Liu Y. Effects of bufalin on the mTOR/p70S6K pathway and apoptosis in esophageal squamous cell carcinoma in nude mice. Int J Mol Med 2017; 40:357-366. [PMID: 28656204 PMCID: PMC5504976 DOI: 10.3892/ijmm.2017.3039] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 06/15/2017] [Indexed: 12/20/2022] Open
Abstract
The aim of this study was to investigate the effects of bufalin on the mammalian target of rapamycin (mTOR/p70S6 kinase (p70S6K) signaling pathway and cell apoptosis in orthotopically transplanted tumors in nude mice. The mice were inoculated with human esophageal squamous cell carcinoma (ESCC) ECA109 cells in order to establish a model of orthotopicall transplanted ESCC tumors. The mice are administered low, medium and high doses of bufalin (0.5, 1.0 and 1.5 mg/kg) or rapamycin, or a combination of both. After the tumors were removed, the mRNA expression levels of mTOR, p70S6K, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), cellular inhibitor of apoptosis protein 1 (cIAP1) and caspase-3 were detected by RT-PCR. In addition, we performed western blot analysis and immunohistochemical analysis to determine the protein expression of mTOR, p70S6K, 4EBP1, cIAP1, active caspase-3, Bcl-2 and Bad in the tumor tissue. The results revealed that bufalin exerted a significant anti-tumor effect in the nude mice with ESCC orthotopically transplanted tumors. This was shown by the decrease in the expression of mTOR, p70S6K and 4EBP1, which suggested that bufalin may possibly be used to inhibit tumor growth via the inhibition of the activation of p70S6K and 4EBP1. We also found that bufalin decreased the expression of cIAP1 and Bcl-2, and increased that of active caspase-3 and Bad, thus indicating that bufalin promoted apoptosis. Thus, our findings suggest that bufalin promotes tumor cell apoptosis, and this may be one of the important anti-tumor mechanisms of action of bufalin.
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Affiliation(s)
- Yao Liu
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Xu Wang
- Department of Pathology, The First Central Hospital of Baoding, Baoding, Hebei 071000, P.R. China
| | - Ying Jia
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Yueping Liu
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
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Rady I, Siddiqui IA, Rady M, Mukhtar H. Melittin, a major peptide component of bee venom, and its conjugates in cancer therapy. Cancer Lett 2017; 402:16-31. [PMID: 28536009 DOI: 10.1016/j.canlet.2017.05.010] [Citation(s) in RCA: 226] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 05/11/2017] [Accepted: 05/12/2017] [Indexed: 02/07/2023]
Abstract
Melittin (MEL), a major peptide component of bee venom, is an attractive candidate for cancer therapy. This agent has shown a variety of anti-cancer effects in preclinical cell culture and animal model systems. Despite a convincing efficacy data against variety of cancers, its applicability to humans has met with challenges due to several issues including its non-specific cytotoxicity, degradation and hemolytic activity. Several optimization approaches including utilization of nanoparticle based delivery of MEL have been utilized to circumvent the issues. Here, we summarize the current understanding of the anticancer effects of bee venom and MEL on different kinds of cancers. Further, we also present the available information for the possible mechanism of action of bee venom and/or MEL.
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Affiliation(s)
- Islam Rady
- School of Medicine and Public Health, Department of Dermatology, University of Wisconsin-Madison, WI 53706, USA; Department of Zoology, Faculty of Science, Al-Azhar University, Cairo, Egypt
| | - Imtiaz A Siddiqui
- School of Medicine and Public Health, Department of Dermatology, University of Wisconsin-Madison, WI 53706, USA
| | - Mohamad Rady
- Department of Zoology, Faculty of Science, Al-Azhar University, Cairo, Egypt
| | - Hasan Mukhtar
- School of Medicine and Public Health, Department of Dermatology, University of Wisconsin-Madison, WI 53706, USA.
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Adiponectin promotes VEGF-A-dependent angiogenesis in human chondrosarcoma through PI3K, Akt, mTOR, and HIF-α pathway. Oncotarget 2017; 6:36746-61. [PMID: 26468982 PMCID: PMC4742208 DOI: 10.18632/oncotarget.5479] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 10/02/2015] [Indexed: 01/16/2023] Open
Abstract
Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Adiponectin is a protein hormone secreted predominantly by differentiated adipocytes. On the other hand, angiogenesis is a critical step in tumor growth and metastasis. However, the relationship of adiponectin with vascular endothelial growth factor-A (VEGF-A) expression and angiogenesis in human chondrosarcoma is mostly unknown. In this study we first demonstrated that the expression of adiponectin was correlated with tumor stage of human chondrosarcoma tissues. In addition, we also found that adiponectin increased VEGF-A expression in human chondrosarcoma cells and subsequently induced migration and tube formation in human endothelial progenitor cells (EPCs). Adiponectin promoted VEGF-A expression through adiponectin receptor (AdipoR), phosphoinositide 3 kinase (PI3K), Akt, mammalian target of rapamycin (mTOR), and hypoxia-inducible factor-1α (HIF)-1α signaling cascades. Knockdown of adiponectin decreased VEGF-A expression and also abolished chondrosarcoma conditional medium-mediated tube formation in EPCs in vitro as well as angiogenesis effects in the chick chorioallantoic membrane and Matrigel plug nude mice model in vivo. Therefore, adiponectin is crucial for tumor angiogenesis and growth, which may represent a novel target for anti-angiogenic therapy in human chondrosarcoma.
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Kim MH, Jeong YJ, Cho HJ, Hoe HS, Park KK, Park YY, Choi YH, Kim CH, Chang HW, Park YJ, Chung IK, Chang YC. Delphinidin inhibits angiogenesis through the suppression of HIF-1α and VEGF expression in A549 lung cancer cells. Oncol Rep 2016; 37:777-784. [PMID: 27959445 DOI: 10.3892/or.2016.5296] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 08/09/2016] [Indexed: 11/05/2022] Open
Abstract
Delphinidin, a polyphenol that belongs to the group of anthocyanidins and is abundant in many pigmented fruits and vegetables, possesses important antioxidant, anti‑inflammatory, anti-mutagenic and anticancer properties. In the present study, we investigated the inhibitory effects of delphinidin on vascular endothelial growth factor (VEGF) expression, an important factor involved in angiogenesis and tumor progression, in A549 human lung cancer cells. Delphinidin inhibited CoCl2- and epidermal growth factor (EGF)-induced VEGF mRNA expression and VEGF protein production. Delphinidin also decreased CoCl2- and EGF-stimulated expression of hypoxia‑inducible factor (HIF)‑1α, which is a transcription factor of VEGF. Delphinidin suppressed CoCl2- and EGF-induced hypoxia‑response element (HRE) promoter activity, suggesting that the inhibitory effects of delphinidin on VEGF expression are caused by the suppression of the binding of HIF-1 to the HRE promoter. We also found that delphinidin specifically decreased the CoCl2- and EGF-induced HIF-1α protein expression by blocking the ERK and PI3K/Akt/mTOR/p70S6K signaling pathways, whereas the p38-mediated pathways were not involved. In animal models, EGF-induced new blood vessel formation was significantly inhibited by delphinidin. Therefore, our results indicate that delphinidin has a potentially new role in anti‑angiogenic action by inhibiting HIF-1α and VEGF expression.
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Affiliation(s)
- Mun-Hyeon Kim
- Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea
| | - Yun-Jeong Jeong
- Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea
| | - Hyun-Ji Cho
- Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea
| | - Hyang-Sook Hoe
- Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu 701-300, Republic of Korea
| | - Kwan-Kyu Park
- Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea
| | - Yoon-Yub Park
- Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea
| | - Yung Hyun Choi
- Department of Biochemistry, College of Oriental Medicine, Dongeui University, Busan 614-052, Republic of Korea
| | - Cheorl-Ho Kim
- Department of Biological Sciences, Sungkyunkwan University, Suwon, Gyeonggi 440-746, Republic of Korea
| | - Hyeun-Wook Chang
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 701-947, Republic of Korea
| | - Young-Ja Park
- Department of Clinical Pathology, Sorabol College, Gyeongju, Gyeongbuk 780-711, Republic of Korea
| | - Il-Kyung Chung
- Department of Biotechnology, Catholic University of Daegu, Gyeongsan, Gyeongbuk 712-702, Republic of Korea
| | - Young-Chae Chang
- Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea
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Mengke NS, Hu B, Han QP, Deng YY, Fang M, Xie D, Li A, Zeng HK. Rapamycin inhibits lipopolysaccharide-induced neuroinflammation in vitro and in vivo. Mol Med Rep 2016; 14:4957-4966. [PMID: 27779711 PMCID: PMC5355655 DOI: 10.3892/mmr.2016.5883] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 07/08/2016] [Indexed: 01/05/2023] Open
Abstract
Alzheimer's disease (AD) is the most common type of progressive neurodegenerative disorder, and is responsible for the most common form of dementia in the elderly. Inflammation occurs in the brains of patients with AD, and is critical for disease progression. In the present study, the effects of rapamycin (RAPA) on neuroinflammation lipopolysaccharide (LPS)-induced were investigated. SH-SY5Y human neuroblastoma cells were treated with 20 µg/ml LPS and 0.1, 1 or 10 nmol/l RAPA, and were analyzed at various time points (6, 12 and 24 h). The mRNA expression levels of interleukin (IL) 1β, IL6 and hypoxia-inducible factor 1α (HIF1α) were determined using reverse transcription-quantitative polymerase chain reaction. The protein expression levels of phosphorylated (p-)S6, p-nuclear factor κB (NFκB), p-inhibitor of NFκB kinase subunit β (IKKβ) and p-tau protein were measured by western blot analysis. p-IKKβ, p-NFκB, p-S6 and p-tau were significantly decreased at 6, 12 and 24 h when cells were treated with ≥0.1 nmol/ml RAPA. In addition, female Sprague Dawley rats were intracranially injected with a single dose of 100 µg/kg LPS in the absence or presence of 1 mg/kg RAPA pretreatment. Brain tissues were subjected to immunohistochemical analysis 6–24 h later, which revealed that the expression levels of HIF1α and p-S6 in rat cerebral cortex were increased following LPS injection; however, this increase was abrogated by RAPA treatment. RAPA may therefore be considered a potential therapeutic agent for the early or emergency treatment of neuroinflammation.
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Affiliation(s)
- Na-Shun Mengke
- Faculty of Graduate Studies, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Bei Hu
- Faculty of Graduate Studies, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Qian-Peng Han
- Faculty of Graduate Studies, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Yi-Yu Deng
- Department of Emergency and Critical Care Medicine, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China
| | - Ming Fang
- Department of Emergency and Critical Care Medicine, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China
| | - Di Xie
- Faculty of Graduate Studies, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Ang Li
- Department of Histoembryology, Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Hong-Ke Zeng
- Faculty of Graduate Studies, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
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Alonezi S, Tusiimire J, Wallace J, Dufton MJ, Parkinson JA, Young LC, Clements CJ, Park JK, Jeon JW, Ferro VA, Watson DG. Metabolomic Profiling of the Effects of Melittin on Cisplatin Resistant and Cisplatin Sensitive Ovarian Cancer Cells Using Mass Spectrometry and Biolog Microarray Technology. Metabolites 2016; 6:metabo6040035. [PMID: 27754384 PMCID: PMC5192441 DOI: 10.3390/metabo6040035] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 10/10/2016] [Accepted: 10/11/2016] [Indexed: 12/30/2022] Open
Abstract
In the present study, liquid chromatography-mass spectrometry (LC-MS) was employed to characterise the metabolic profiles of two human ovarian cancer cell lines A2780 (cisplatin-sensitive) and A2780CR (cisplatin-resistant) in response to their exposure to melittin, a cytotoxic peptide from bee venom. In addition, the metabolomics data were supported by application of Biolog microarray technology to examine the utilisation of carbon sources by the two cell lines. Data extraction with MZmine 2.14 and database searching were applied to provide metabolite lists. Principal component analysis (PCA) gave clear separation between the cisplatin-sensitive and resistant strains and their respective controls. The cisplatin-resistant cells were slightly more sensitive to melittin than the sensitive cells with IC50 values of 4.5 and 6.8 μg/mL respectively, although the latter cell line exhibited the greatest metabolic perturbation upon treatment. The changes induced by melittin in the cisplatin-sensitive cells led mostly to reduced levels of amino acids in the proline/glutamine/arginine pathway, as well as to decreased levels of carnitines, polyamines, adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD+). The effects on energy metabolism were supported by the data from the Biolog assays. The lipid compositions of the two cell lines were quite different with the A2780 cells having higher levels of several ether lipids than the A2780CR cells. Melittin also had some effect on the lipid composition of the cells. Overall, this study suggests that melittin might have some potential as an adjuvant therapy in cancer treatment.
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Affiliation(s)
- Sanad Alonezi
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.
| | - Jonans Tusiimire
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.
| | - Jennifer Wallace
- WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, UK.
| | - Mark J Dufton
- WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, UK.
| | - John A Parkinson
- WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, UK.
| | - Louise C Young
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.
| | - Carol J Clements
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.
| | - Jin Kyu Park
- Beesen Co. Ltd., Bio Venture Town, Yuseong Daero 1662, Dae Jeon 34054, Korea.
| | - Jong Woon Jeon
- Beesen Co. Ltd., Bio Venture Town, Yuseong Daero 1662, Dae Jeon 34054, Korea.
| | - Valerie A Ferro
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.
| | - David G Watson
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.
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Tanideh N, Abdordideh E, Yousefabad SLA, Daneshi S, Hosseinabadi OK, Samani SM, Derakhshan far A. Evaluation of the healing effect of honey and colostrum in treatment of cutaneous wound in rat. ACTA ACUST UNITED AC 2016. [DOI: 10.1007/s00580-016-2347-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Vétillard A, Bouzid W. [Ants: a chemical library of anticancer molecules]. Biol Aujourdhui 2016; 210:119-25. [PMID: 27687602 DOI: 10.1051/jbio/2016021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Indexed: 11/14/2022]
Abstract
Animal venoms are complex mixtures containing simple organic molecules, proteins, peptides, and other bioactive elements with extraordinary biological properties associated with their ability to act on a number of molecular receptors in the process of incapacitating their target organisms. In such a context, arthropod venoms are invaluable sources of bioactive substances, with therapeutic interest but the limited availability of some venom such as those from ants, has restricted the potential that these biomolecules could represent. We investigated for the first time transcriptomic expression from the ant species Tetramorium bicarinatum. Four hundred randomly selected clones from cDNA libraries were sequenced and a total of 374 expressed sequence tags (ESTs) were generated. Based on the results of BLAST searches, these sequences were clustered and assembled into 269 contigs. About 72% (269) of these matched BLASTx hits with an interesting diversity and unusual abundance of cellular transcripts (48%) related to gene and protein expression reflecting the specialization of this tissue. In addition, transcripts encoding transposases were relatively highly expressed (14%). It may be that transposable elements are present and that their presence accounts for some of the variation in venom toxins. About twenty per cent of the ESTs were categorized as putative toxins, the major part represented by allergens (48% of the total venom toxins) such as pilosulin 5, sol i 3 and Myp p I and II. Several contigs encoding enzymes, including zinc-metalloproteases (17%) that are likely involved in the processing and activation of venom proteins/peptides, were also identified from the library. In addition, a number of sequences (8%) had no significant similarity to any known sequence which indicates a potential source of for the discovery of new toxins. In order to provide a global insight on the transcripts expressed in the venom gland of the Brazilian ant species Tetramorium bicarinatum and to unveil the potential of their products, high-throughput expressed sequence tags were generated using Illumina paired-end sequencing technology. A total of 212 371 758 pairs of quality-filtered, 100-base-pair Illumina reads were obtained. The de novo assemblies yielded 36 042 contigs for which 27 873 have at least one predicted ORF among which 59.77% produce significant hits in the available databases. The investigation of the read mapping toxin class revealed and confirmed a high diversification with the major part consistent with the classical hymenopteran venom protein signature represented by venom allergen (33.3%) followed by a diverse toxin-expression profile including several distinct isoforms of phospholipase A1 and A2, venom serine protease, hyaluronidase, protease inhibitor and secapin. Moreover, our results revealed for the first time the presence of toxin-like peptides that have been previously identified from unrelated venomous animals such as waprin-like (snakes) and agatoxins (spiders and conus). These studies provide a first insight of the gene expression scenario of the venom gland of T. bicarinatum which might contribute to acquiring a more comprehensive view about the origin and functional diversity of venom proteins of this ant. Based on such results, we conducted cytotoxic tests from the crude venom of T.bicarinatum ant and reported toxic effect on tumoral cells lines from one of the fifth of the most frequently occurring cancers with a 3-year survival rate of only 30%. In such a context, new therapeutic strategies are essential and the discovery of new molecules in ant venom could be one possible avenue. Thus our project aims to characterize, from the crude venom of T.bicarinatum, the molecule(s) which have potential anti-cancerous toxicity as well as their mechanisms of action.
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Application of bee venom and its main constituent melittin for cancer treatment. Cancer Chemother Pharmacol 2016; 78:1113-1130. [DOI: 10.1007/s00280-016-3160-1] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 09/20/2016] [Indexed: 01/29/2023]
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Assad DX, Elias ST, Melo AC, Ferreira CG, De Luca Canto G, Guerra ENS. Potential impact of mTOR inhibitors on cervical squamous cell carcinoma: A systematic review. Oncol Lett 2016; 12:4107-4116. [PMID: 27895779 DOI: 10.3892/ol.2016.5157] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 05/10/2016] [Indexed: 12/30/2022] Open
Abstract
The aim of the present systematic review was to analyze the potential impact of mammalian target of rapamycin (mTOR) inhibitors on the treatment of cervical squamous cell carcinoma (CSCC). A systematic literature search was conducted in PubMed, PMC, Scopus, Cochrane Library, LILACS, Web of Science, Google Scholar and ScienceDirect on January 19, 2015, without time and language restrictions. Studies that evaluated women of any age with CSCC and who received mTOR inhibitors alone or in association with other treatments were considered. Randomized and non-randomized clinical trials were included, and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist was followed. Selected studies were methodologically appraised according to the Grades of Recommendation, Assessment, Development and Evaluation method to assess the quality of evidence. Of 642 identified citations, 43 studies were fully reviewed; however, only 3 studies met the inclusion criteria and were used for qualitative analysis. Of these, two studies were phase 1 and one was a phase 2 clinical trial. The studies included were not conclusive with regard to the association between mTOR inhibitor treatment and cervical cancer. The main analysis of secondary endpoints revealed that individuals treated with other drugs in association with mTOR inhibitors achieved partial responses (15.4-33.3%) or stable disease (17.6-28%). Treatment with mTOR inhibitors in general was well tolerated in patients with metastatic disease. The predominant toxicities were grade 1 and 2. The phase 1 trials included in this review demonstrated that mTOR inhibitor treatments are feasible and safe. However, the currently available evidence is insufficient to determine the effect of mTOR inhibitors on CSCC, and further investigation in high-quality, randomized clinical trials is required.
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Affiliation(s)
- Daniele Xavier Assad
- Oral Histopathology Laboratory, School of Health Sciences, University of Brasília, Brasília, Federal District 70910-900, Brazil; Oncology Center, Hospital Sírio-Libanês, Brasília, Federal District 71635-610, Brazil
| | - Silvia Taveira Elias
- Oral Histopathology Laboratory, School of Health Sciences, University of Brasília, Brasília, Federal District 70910-900, Brazil
| | - Andréia Cristina Melo
- Department of Clinical Research, National Institute of Cancer, Rio de Janeiro 20220-410, Brazil
| | - Carlos Gil Ferreira
- Department of Clinical Research, National Institute of Cancer, Rio de Janeiro 20220-410, Brazil; National Clinical Cancer Research Network, Ministry of Health, Brasília, Federal District 70058-900, Brazil; Department of Clinical Research, D'or Institute for Research, Rio de Janeiro 22281-100, Brazil
| | - Graziela De Luca Canto
- Department of Dentistry, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88036-800, Brazil; Department of Dentistry, University of Alberta, Edmonton, Alberta T6G 1C9, Canada
| | - Eliete Neves Silva Guerra
- Oral Histopathology Laboratory, School of Health Sciences, University of Brasília, Brasília, Federal District 70910-900, Brazil
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Park JH, Cho YY, Yoon SW, Park B. Suppression of MMP-9 and FAK expression by pomolic acid via blocking of NF-κB/ERK/mTOR signaling pathways in growth factor-stimulated human breast cancer cells. Int J Oncol 2016; 49:1230-40. [PMID: 27573547 DOI: 10.3892/ijo.2016.3585] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 06/14/2016] [Indexed: 11/06/2022] Open
Abstract
The expression of matrix metalloproteinase-9 (MMP-9) and the phosphorylation of focal adhesion kinase (FAK) have been implicated in the invasion, metastasis and cell motility of cancer cells. It is considered that epidermal growth factor (EGF) may increase cell motility, an event involved in cancer cell invasion and metastasis. Pomolic acid (PA), an active triterpenoid from Euscaphis japonica, is known to inhibit the proliferation of a variety of cancer cells, but the effect of PA on the invasiveness of cancer cells is largely unknown. In this study, we first determined the molecular mechanism by which PA inhibits the migratory and invasive abilities of highly metastatic MDA-MB‑231 cells. Transwell invasion, wound-healing assay and F-actin reorganization showed that PA significantly inhibits the EGF-induced invasion, migration and cell motility by reducing expression of MMP-9 and FAK phosphorylation. In particular, PA potently suppressed the phosphorylation of nuclear factor (NF)-κB, extraceullar signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway. Furthermore, PA treatment inhibited the DNA binding activity of NF-κB and activator protein (AP)-1, which is known to mediate the expression of EGFR and MMP-9. These results suggest that PA may be a potential therapeutic candidate for treatment of breast cancer metastasis.
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Affiliation(s)
- Ji-Hyun Park
- College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea
| | - Yoon Young Cho
- Department of Oncology/Hematology, Daegu Catholic University Medical Center, Daegu 42472, Republic of Korea
| | - Seong Woo Yoon
- Department of Korean Internal Medicine, Korean Medicine Cancer Center, Kyung Hee University Hospital at Gangdong, Seoul 05278, Republic of Korea
| | - Byoungduck Park
- College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea
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Kong GM, Tao WH, Diao YL, Fang PH, Wang JJ, Bo P, Qian F. Melittin induces human gastric cancer cell apoptosis via activation of mitochondrial pathway. World J Gastroenterol 2016; 22:3186-3195. [PMID: 27003995 PMCID: PMC4789993 DOI: 10.3748/wjg.v22.i11.3186] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2015] [Revised: 11/17/2015] [Accepted: 12/14/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the apoptotic effects of melittin on SGC-7901 cells via activation of the mitochondrial signaling pathway in vitro.
METHODS: SGC-7901 cells were stimulated by melittin, and its effect on proliferation and apoptosis of was investigated by methyl thiazolyl tetrazolium assay, morphologic structure with transmission electron microscopy, annexin-V/propidium iodide double-staining assay, measuring mitochondrial membrane potential (MMP) levels, and analyzing reactive oxygen species (ROS) concentrations were analyzed by flow cytometry. Cytochrome C (Cyt C), apoptosis-inducing factor (AIF), endonuclease G (Endo G), second mitochondria-derived activator of caspases (Smac)/direct IAP binding protein with low isoelectric point (Diablo), and FAS were analyzed by western blot. The expression of caspase-3 and caspase-8 was measured using activity assay kits.
RESULTS: Melittin was incubated at 1.0, 2.0, 4.0, or 6.0 μg/mL for 1, 2, 4, 6, or 8 h and showed a time- and concentration-dependent inhibition of SGC-7901 cell growth. Melittin induced SGC-7901 cell apoptosis, which was confirmed by typical morphological changes. Treatment with 4 μg/mL melittin induced early apoptosis of SGC-7901 cells, and the early apoptosis rates were 39.97% ± 3.19%, 59.27% ± 3.94%, and 71.50% ± 2.87% vs 32.63% ± 2.75% for 1, 2, and 4 h vs 0 h (n = 3, P < 0.05); the ROS levels were 616.53% ± 79.78%, 974.81% ± 102.40%, and 1330.94% ± 93.09% vs 603.74% ± 71.99% (n = 3, P < 0.05); the MMP values were 2.07 ± 0.05, 1.78 ± 0.29, and 1.16 ± 0.25 vs 2.55 ± 0.42 (n = 3, P < 0.05); caspase-3 activity was significantly higher compared to the control (5492.3 ± 321.1, 6562.0 ± 381.3, and 8695.7 ± 449.1 vs 2330.0 ± 121.9), but the caspase activity of the non-tumor cell line L-O2 was not different from that of the control. With the addition of the caspase-3 inhibitor (Ac-DEVD-CHO), caspase-3 activity was significantly decreased compared to the control group (1067.0 ± 132.5 U/g vs 8695.7 ± 449.1 U/g). The expression of the Cyt C, Endo G, and AIF proteins in SGC-7901 cells was significantly higher than those in the control (P < 0.05), while the expression of the Smac/Diablo protein was significantly lower than the control group after melittin exposure (P < 0.01). Ac-DEVD-CHO did not, however, have any effect on the expression of caspase-8 and FAS in the SGC-7901 cells.
CONCLUSION: Melittin can induce apoptosis of human gastric cancer (GC) cells through the mitochondria pathways, and it may be a potent agent in the treatment of human GC.
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Kim MH, Kim MH, Park YJ, Chang YC, Park YY, Song HO. Delphinidin Suppresses Angiogenesis via the Inhibition of HIF-1α and STAT3 Expressions in PC3M Cells. ACTA ACUST UNITED AC 2016. [DOI: 10.9721/kjfst.2016.48.1.66] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Lee HL, Park SH, Kim TM, Jung YY, Park MH, Oh SH, Yun HS, Jun HO, Yoo HS, Han SB, Lee US, Yoon JH, Song MJ, Hong JT. Bee venom inhibits growth of human cervical tumors in mice. Oncotarget 2016; 6:7280-92. [PMID: 25730901 PMCID: PMC4466684 DOI: 10.18632/oncotarget.3110] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Accepted: 01/08/2015] [Indexed: 11/25/2022] Open
Abstract
We studied whether bee venom (BV) inhibits cervical tumor growth through enhancement of death receptor (DR) expressions and inactivation of nuclear factor kappa B (NF-κB) in mice. In vivo study showed that BV (1 mg/kg) inhibited tumor growth. Similar inhibitory effects of BV on cancer growth in primary human cervical cancer cells were also found. BV (1–5 μg/ml) also inhibited the growth of cancer cells, Ca Ski and C33Aby the induction of apoptotic cell death in a dose dependent manner. Agreed with cancer cell growth inhibition, expression of death receptors; FAS, DR3 and DR6, and DR downstream pro-apoptotic proteins including caspase-3 and Bax was concomitantly increased, but the NF-κB activity and the expression of Bcl-2 were inhibited by treatment with BV in tumor mice, human cancer cell and human tumor samples as well as cultured cancer cells. In addition, deletion of FAS, DR3 and DR6 by small interfering RNA significantly reversed BV-induced cell growth inhibitory effects as well as NF-κB inactivation. These results suggest that BV inhibits cervical tumor growth through enhancement of FAS, DR3 and DR6 expression via inhibition of NF-κB pathway.
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Affiliation(s)
- Hye Lim Lee
- College of Pharmacy and Medical Research Center, Heungduk, Cheongju, Chungbuk, Republic of Korea
| | - Sang Ho Park
- Clinical Research Laboratory, Uijeonbu St. Mary's Hospital, The Catholic University of Korea College of Medicine, Uijeongbu, Republic of Korea
| | - Tae Myoung Kim
- College of Veterinary Medicine, Chungbuk National University, Heungduk, Cheongju, Chungbuk, Republic of Korea
| | - Yu Yeon Jung
- College of Pharmacy and Medical Research Center, Heungduk, Cheongju, Chungbuk, Republic of Korea
| | - Mi Hee Park
- College of Pharmacy and Medical Research Center, Heungduk, Cheongju, Chungbuk, Republic of Korea
| | - Sang Hyun Oh
- College of Pharmacy and Medical Research Center, Heungduk, Cheongju, Chungbuk, Republic of Korea
| | - Hye Seok Yun
- College of Pharmacy and Medical Research Center, Heungduk, Cheongju, Chungbuk, Republic of Korea
| | - Hyung Ok Jun
- College of Pharmacy and Medical Research Center, Heungduk, Cheongju, Chungbuk, Republic of Korea
| | - Hwan Soo Yoo
- College of Pharmacy and Medical Research Center, Heungduk, Cheongju, Chungbuk, Republic of Korea
| | - Sang-Bae Han
- College of Pharmacy and Medical Research Center, Heungduk, Cheongju, Chungbuk, Republic of Korea
| | - Ung Soo Lee
- Department of Food Science & Technology, Korea National University of Transportation, Jeungpyeong, Republic of Korea
| | - Joo Hee Yoon
- Department of Obstetrics and Gynecology, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Paldal-gu, Suwon, Gyeonggi-do, Republic of Korea
| | - Min Jong Song
- Department of Obstetrics and Gynecology, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Jung-gu, Daejeon, Republic of Korea
| | - Jin Tae Hong
- College of Pharmacy and Medical Research Center, Heungduk, Cheongju, Chungbuk, Republic of Korea
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Lee EJ, Kim BJ, Jeong JE, Chung HL, Yang EK, Kim WT. Bee Venom Exerts Neuroprotective Effects on Neuronal Cells and Astrocytes under Hypoxic Conditions Through MAPK Signaling Pathways. NEONATAL MEDICINE 2016. [DOI: 10.5385/nm.2016.23.1.43] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Affiliation(s)
- Eun Joo Lee
- Department of Pediatrics, Catholic University of Daegu School of Medicine, Daegu, Korea
| | - Bong Jae Kim
- Department of Pediatrics, Catholic University of Daegu School of Medicine, Daegu, Korea
| | - Ji Eun Jeong
- Department of Pediatrics, Catholic University of Daegu School of Medicine, Daegu, Korea
| | - Hai Lee Chung
- Department of Pediatrics, Catholic University of Daegu School of Medicine, Daegu, Korea
| | - Eun Kyoung Yang
- Department of Physiology, Kyungpook National University School of Medicine, Daegu, Korea
| | - Woo Taek Kim
- Department of Pediatrics, Catholic University of Daegu School of Medicine, Daegu, Korea
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47
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The protective effect of bee venom on fibrosis causing inflammatory diseases. Toxins (Basel) 2015; 7:4758-72. [PMID: 26580653 PMCID: PMC4663532 DOI: 10.3390/toxins7114758] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Revised: 10/24/2015] [Accepted: 11/05/2015] [Indexed: 02/06/2023] Open
Abstract
Bee venom therapy is a treatment modality that may be thousands of years old and involves the application of live bee stings to the patient’s skin or, in more recent years, the injection of bee venom into the skin with a hypodermic needle. Studies have proven the effectiveness of bee venom in treating pathological conditions such as arthritis, pain and cancerous tumors. However, there has not been sufficient review to fully elucidate the cellular mechanisms of the anti-inflammatory effects of bee venom and its components. In this respect, the present study reviews current understanding of the mechanisms of the anti-inflammatory properties of bee venom and its components in the treatment of liver fibrosis, atherosclerosis and skin disease.
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48
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Qian CY, Wang KL, Fang FF, Gu W, Huang F, Wang FZ, Li B, Wang LN. Triple-controlled oncolytic adenovirus expressing melittin to exert inhibitory efficacy on hepatocellular carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:10403-10411. [PMID: 26617748 PMCID: PMC4637563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Accepted: 07/27/2015] [Indexed: 06/05/2023]
Abstract
Hepatocellular carcinoma (HCC) is a highly malignant disease, and its outcome of routine therapies is poor. Comprehensive treatment including gene therapy is an important way to improve patients' prognosis and survival. In this study, we successfully constructed a triple-controlled cancer-selective oncolytic adenovirus, QG511-HA-Melittin, carrying melittin gene, in which the hybrid promoter, hypoxia-response element (HRE)-AFP promoter, was used to control viral E1a expression targeting AFP-positive cancer cells in hypoxia microenviroment, and the E1b-55 kDa gene was deleted in cancer cells with p53-deficiency. The cytological experiments found that the viral replication of QG511-HA-Melittin was increased to 12800-folds in Hep3B cells within 48 h, and 130-folds in SMMC-7721, but the virus did not replicate in L-02 cells. QG511-HA-Melittin had a strong inhibition effect on AFP-positive HCC cell proliferation, such as Hep3B and HepG2, whereas, there was low or no inhibition effect of QG511-HA-Melittin on AFP-negative cancer cells SMMC-7721 and normal cells L-02. In the in vivo experiment, compared with the blank control group, QG511-HA-Melittin can significantly inhibit the growth of HCC xenografts (P<0.05). The survival of mice in QG511-HA-Melittin group was much longer than that of the blank control group. Both in vitro and in vivo experiments manifested that QG511-HA-Melittin exerts an inhibitory effect on HCC cells, which may provide a new strategy for HCC biotherapy.
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Affiliation(s)
- Chun-Yu Qian
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University Shanghai 200433, China
| | - Kai-Li Wang
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University Shanghai 200433, China
| | - Fan-Fu Fang
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University Shanghai 200433, China
| | - Wei Gu
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University Shanghai 200433, China
| | - Feng Huang
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University Shanghai 200433, China
| | - Fu-Zhe Wang
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University Shanghai 200433, China
| | - Bai Li
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University Shanghai 200433, China
| | - Li-Na Wang
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University Shanghai 200433, China
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Wang D, Hu L, Su M, Wang J, Xu T. Preparation and functional characterization of human vascular endothelial growth factor-melittin fusion protein with analysis of the antitumor activity in vitro and in vivo. Int J Oncol 2015; 47:1160-8. [PMID: 26166416 DOI: 10.3892/ijo.2015.3078] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2015] [Accepted: 06/22/2015] [Indexed: 11/06/2022] Open
Abstract
Vascular endothelial growth factor and its tyrosine kinase receptors have been identified as key mediators of the regulation of pathologic blood vessel growth and maintenance in the promotion of angiogenesis and tumor growth. Therefore, an alternative approach to destroying tumor endothelium would be to make this tissue particularly sensitive to VEGF-mediated drug delivery. To verify this hypothesis, we generated a protein containing VEGF165 fused to melittin. Melittin is a small linear peptide composed of 26 amino acid residues that can exert toxic or inhibitory effects on many types of tumor cells. This protein is a cytolytic peptide that attacks lipid membranes, leading to significant toxicity. In the present study, the Pichia pastoris expression system was used to express the fusion protein. Under optimal conditions, stable VEGF165-melittin production was achieved using a series of purification steps. The activity of VEGF165-melittin fusion protein was compared with melittin for its ability to suppress the growth of tumor cell line in vitro. The fusion toxin selectively inhibited growth of human hepatocellular carcinoma HepG-2 cell line with high expression of VEGFR-2. We found that sensitivity of VEGFR-2 transfected 293 cells to VEGF165-melittin enhanced as the cellular VEGFR-2 density increased. In an in vivo initial experiment, the fusion protein inhibited tumor growth in xenografts assays. Furthermore, successful expression and characterization of the fusion protein demonstrated its efficacy for use as a novel treatment strategy for cancer.
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Affiliation(s)
- Dingding Wang
- Department of Biotechnology, College of Life Science and Bio-pharmaceuticals, Guangdong Pharmaceutical University, Guangzhou, Guangdong, P.R. China
| | - Lili Hu
- Department of Biotechnology, College of Life Science and Bio-pharmaceuticals, Guangdong Pharmaceutical University, Guangzhou, Guangdong, P.R. China
| | - Manman Su
- Department of Regenerative Medicine, College of Pharmacy, Jilin University, Changchun, Jilin, P.R. China
| | - Ju Wang
- Guangdong Provincial Key Laboratory of Bio-engineering Medicine (National Engineering Research Centre of Genetic Medicine), Guangzhou, Guangdong, P.R. China
| | - Tianmin Xu
- Department of Obstetrics and Gynecology, The Second Clinical Hospital, Jilin University, Changchun, Jilin, P.R. China
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Moreno M, Giralt E. Three valuable peptides from bee and wasp venoms for therapeutic and biotechnological use: melittin, apamin and mastoparan. Toxins (Basel) 2015; 7:1126-50. [PMID: 25835385 PMCID: PMC4417959 DOI: 10.3390/toxins7041126] [Citation(s) in RCA: 215] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 03/18/2015] [Accepted: 03/25/2015] [Indexed: 12/14/2022] Open
Abstract
While knowledge of the composition and mode of action of bee and wasp venoms dates back 50 years, the therapeutic value of these toxins remains relatively unexploded. The properties of these venoms are now being studied with the aim to design and develop new therapeutic drugs. Far from evaluating the extensive number of monographs, journals and books related to bee and wasp venoms and the therapeutic effect of these toxins in numerous diseases, the following review focuses on the three most characterized peptides, namely melittin, apamin, and mastoparan. Here, we update information related to these compounds from the perspective of applied science and discuss their potential therapeutic and biotechnological applications in biomedicine.
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Affiliation(s)
- Miguel Moreno
- Chemistry and Molecular Pharmacology, Institute for Research in Biomedicine (IRB Barcelona), Baldiri i Reixac, 10, Barcelona 08028, Spain.
| | - Ernest Giralt
- Chemistry and Molecular Pharmacology, Institute for Research in Biomedicine (IRB Barcelona), Baldiri i Reixac, 10, Barcelona 08028, Spain.
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