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Laurindo LF, de Lima EP, Laurindo LF, Rodrigues VD, Chagas EFB, de Alvares Goulart R, Araújo AC, Guiguer EL, Pomini KT, Rici REG, Maria DA, Direito R, Barbalho SM. The therapeutic potential of bee venom-derived Apamin and Melittin conjugates in cancer treatment: A systematic review. Pharmacol Res 2024; 209:107430. [PMID: 39332751 DOI: 10.1016/j.phrs.2024.107430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/18/2024] [Accepted: 09/19/2024] [Indexed: 09/29/2024]
Abstract
The therapeutic potential of bee venom-derived peptides, particularly apamin and melittin, in cancer treatment has garnered significant attention as a promising avenue for advancing oncology. This systematic review examines preclinical studies highlighting the emerging role of these peptides in enhancing cancer therapies. Melittin and apamin, when conjugated with other therapeutic agents or formulated into novel delivery systems, have demonstrated improved efficacy in targeting tumor cells. Key findings indicate that melittin-based conjugates, such as polyethylene glycol (PEG)ylated versions, show potential in enhancing therapeutic outcomes and minimizing toxicity across various cancer models. Similarly, apamin-conjugated formulations have improved the efficacy of established anti-cancer drugs, contributing to enhanced targeting and reduced systemic toxicity. These developments underscore a growing interest in leveraging bee venom-derived peptides as adjuncts in cancer therapy. The integration of these peptides into treatment regimens offers a promising strategy to address current limitations in cancer treatment, such as drug resistance and off-target effects. However, comprehensive validation through clinical trials is essential to confirm their safety and effectiveness in human patients. This review highlights the global emergence of bee venom-derived peptides in cancer treatment, advocating for continued research and development to fully realize their therapeutic potential.
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Affiliation(s)
- Lucas Fornari Laurindo
- Department of Biochemistry and Pharmacology, School of Medicine, Faculdade de Medicina de Marília (FAMEMA), Marília, São Paulo 17519-030, Brazil; Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo 17525-902, Brazil; Department of Administration, Associate Degree in Hospital Management, Universidade de Marília (UNIMAR), Marília, São Paulo 17525-902, Brazil
| | - Enzo Pereira de Lima
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo 17525-902, Brazil
| | - Lívia Fornari Laurindo
- Department of Biochemistry and Pharmacology, School of Medicine, Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, São Paulo 15090-000, Brazil
| | - Victória Dogani Rodrigues
- Department of Biochemistry and Pharmacology, School of Medicine, Faculdade de Medicina de Marília (FAMEMA), Marília, São Paulo 17519-030, Brazil
| | - Eduardo Federighi Baisi Chagas
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo 17525-902, Brazil; Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo 17525-902, Brazil
| | - Ricardo de Alvares Goulart
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo 17525-902, Brazil; Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo 17525-902, Brazil
| | - Adriano Cressoni Araújo
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo 17525-902, Brazil; Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo 17525-902, Brazil
| | - Elen Landgraf Guiguer
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo 17525-902, Brazil; Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo 17525-902, Brazil; Department of Biochemistry and Nutrition, School of Food and Technology of Marília (FATEC), Marília, São Paulo 17500-000, Brazil
| | - Karina Torres Pomini
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo 17525-902, Brazil; Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo 17525-902, Brazil
| | - Rose Eli Grassi Rici
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo 17525-902, Brazil; Graduate Program in Anatomy of Domestic and Wild Animals, College of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo 05508-220, Brazil
| | - Durvanei Augusto Maria
- Development and innovation Laboratory, Butantan Institute, São Paulo, São Paulo 05585-000, Brazil
| | - Rosa Direito
- Laboratory of Systems Integration Pharmacology, Clinical and Regulatory Science, Research Institute for Medicines, Universidade de Lisboa (iMed.ULisboa), Av. Prof. Gama Pinto, Lisbon 1649-003, Portugal.
| | - Sandra Maria Barbalho
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo 17525-902, Brazil; Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo 17525-902, Brazil; Department of Biochemistry and Nutrition, School of Food and Technology of Marília (FATEC), Marília, São Paulo 17500-000, Brazil; UNIMAR Charity Hospital, Universidade de Marília (UNIMAR), Marília, São Paulo 17525-902, Brazil
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Duan X, Zou H, Yang J, Liu S, Xu T, Ding J. Melittin-incorporated nanomedicines for enhanced cancer immunotherapy. J Control Release 2024; 375:285-299. [PMID: 39216597 DOI: 10.1016/j.jconrel.2024.08.047] [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: 06/25/2024] [Revised: 08/23/2024] [Accepted: 08/28/2024] [Indexed: 09/04/2024]
Abstract
Immunotherapy is a rapidly developing and effective strategy for cancer therapy. Among various immunotherapy approaches, peptides have garnered significant attention due to their potent immunomodulatory effects. In particular, melittin emerged as a promising candidate to enhance cancer immunotherapy by inducing immunogenic cell death, promoting the maturation of antigen-presenting cells, activating T cells, enhancing the infiltration and cytotoxicity of effector lymphocytes, and modulating macrophage phenotypes for relieving immunosuppression. However, the clinical application of melittin is limited by poor targeting and systemic toxicity. To overcome these challenges, melittin has been incorporated into biomaterials and related nanotechnologies, resulting in extended circulation time in vivo, improved targeting, reduced adverse effects, and enhanced anti-cancer immunological action. This review provides an in-depth analysis of the immunomodulatory effects of melittin-incorporated nanomedicines and examines their development and challenges for clinical cancer immunotherapy.
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Affiliation(s)
- Xuefeng Duan
- Department of Gynecology and Obstetrics, The Second Hospital of Jilin University, 4026 Yatai Street, Changchun 130041, PR China
| | - Haoyang Zou
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, PR China
| | - Jiazhen Yang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, PR China.
| | - Shixian Liu
- Department of Orthopedics, The Second Hospital of Jilin University, 4026 Yatai Street, Changchun 130041, PR China
| | - Tianmin Xu
- Department of Gynecology and Obstetrics, The Second Hospital of Jilin University, 4026 Yatai Street, Changchun 130041, PR China.
| | - Jianxun Ding
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, PR China.
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Chahla C, Rima M, Mouawad C, Roufayel R, Kovacic H, El Obeid D, Sabatier JM, Luis J, Fajloun Z, El-Waly B. Effect of Apis mellifera syriaca Bee Venom on Glioblastoma Cancer: In Vitro and In Vivo Studies. Molecules 2024; 29:3950. [PMID: 39203027 PMCID: PMC11357583 DOI: 10.3390/molecules29163950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 08/13/2024] [Accepted: 08/17/2024] [Indexed: 09/03/2024] Open
Abstract
Glioblastoma multiforme (GBM) is a highly aggressive and fatal primary brain tumor. The resistance of GBM to conventional treatments is attributed to factors such as the blood-brain barrier, tumor heterogeneity, and treatment-resistant stem cells. Current therapeutic efforts show limited survival benefits, emphasizing the urgent need for novel treatments. In this context, natural anti-cancer extracts and especially animal venoms have garnered attention for their potential therapeutic benefits. Bee venom in general and that of the Middle Eastern bee, Apis mellifera syriaca in particular, has been shown to have cytotoxic effects on various cancer cell types, but not glioblastoma. Therefore, this study aimed to explore the potential of A. mellifera syriaca venom as a selective anti-cancer agent for glioblastoma through in vitro and in vivo studies. Our results revealed a strong cytotoxic effect of A. mellifera syriaca venom on U87 glioblastoma cells, with an IC50 of 14.32 µg/mL using the MTT test and an IC50 of 7.49 µg/mL using the LDH test. Cells treated with the bee venom became permeable to propidium iodide without showing any signs of early apoptosis, suggesting compromised membrane integrity but not early apoptosis. In these cells, poly (ADP-ribose) polymerase (PARP) underwent proteolytic cleavage similar to that seen in necrosis. Subsequent in vivo investigations demonstrated a significant reduction in the number of U87 cells in mice following bee venom injection, accompanied by a significant increase in cells expressing caspase-3, suggesting the occurrence of cellular apoptosis. These findings highlight the potential of A. mellifera syriaca venom as a therapeutically useful tool in the search for new drug candidates against glioblastoma and give insights into the molecular mechanism through which the venom acts on cancer cells.
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Affiliation(s)
- Charbel Chahla
- Inst Neurophysiopathol (INP), CNRS, Aix-Marseille Université, 13385 Marseille, France; (C.C.); (H.K.)
| | - Mohamad Rima
- Department of Natural Sciences, Lebanese American University, Byblos P.O. Box 36, Lebanon;
| | - Charbel Mouawad
- Laboratoire d’Histologie Embryologie Biologie de la Reproduction CECOS, Assistance Publique-Hôpitaux Universitaires Paris Centre, CHU Cochin, 75014 Paris, France;
| | - Rabih Roufayel
- College of Engineering and Technology, American University of the Middle East, Egaila 54200, Kuwait;
| | - Hervé Kovacic
- Inst Neurophysiopathol (INP), CNRS, Aix-Marseille Université, 13385 Marseille, France; (C.C.); (H.K.)
| | - Dany El Obeid
- Faculty of Agriculture & Veterinary Sciences, Lebanese University, Dekwaneh, Beirut 1100, Lebanon;
| | - Jean-Marc Sabatier
- Inst Neurophysiopathol (INP), CNRS, Aix-Marseille Université, 13385 Marseille, France; (C.C.); (H.K.)
| | - José Luis
- Inst Neurophysiopathol (INP), CNRS, Aix-Marseille Université, 13385 Marseille, France; (C.C.); (H.K.)
| | - Ziad Fajloun
- Laboratory of Applied Biotechnology (LBA3B), Azm Center for Research in Biotechnology and Its Applications, Department of Cell Culture, EDST, Lebanese University, Tripoli 1300, Lebanon;
- Department of Biology, Faculty of Sciences 3, Campus Michel Slayman Ras Maska, Lebanese University, Tripoli 1352, Lebanon
| | - Bilal El-Waly
- Laboratory of Applied Biotechnology (LBA3B), Azm Center for Research in Biotechnology and Its Applications, Department of Cell Culture, EDST, Lebanese University, Tripoli 1300, Lebanon;
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El-Didamony SE, Kalaba MH, Sharaf MH, El-Fakharany EM, Osman A, Sitohy M, Sitohy B. Melittin alcalase-hydrolysate: a novel chemically characterized multifunctional bioagent; antibacterial, anti-biofilm and anticancer. Front Microbiol 2024; 15:1419917. [PMID: 39091304 PMCID: PMC11293514 DOI: 10.3389/fmicb.2024.1419917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 06/27/2024] [Indexed: 08/04/2024] Open
Abstract
The prevalent life-threatening microbial and cancer diseases and lack of effective pharmaceutical therapies created the need for new molecules with antimicrobial and anticancer potential. Bee venom (BV) was collected from honeybee workers, and melittin (NM) was extracted from BV and analyzed by urea-polyacrylamide gel electrophoresis (urea-PAGE). The isolated melittin was hydrolyzed with alcalase into new bioactive peptides and evaluated for their antimicrobial and anticancer activity. Gel filtration chromatography fractionated melittin hydrolysate (HM) into three significant fractions (F1, F2, and F3), that were characterized by electrospray ionization mass spectrometry (ESI-MS) and evaluated for their antimicrobial, anti-biofilm, antitumor, and anti-migration activities. All the tested peptides showed antimicrobial and anti-biofilm activities against Gram-positive and Gram-negative bacteria. Melittin and its fractions significantly inhibited the proliferation of two types of cancer cells (Huh-7 and HCT 116). Yet, melittin and its fractions did not affect the viability of normal human lung Wi-38 cells. The IC50 and selectivity index data evidenced the superiority of melittin peptide fractions over intact melittin. Melittin enzymatic hydrolysate is a promising novel product with high potential as an antibacterial and anticancer agent.
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Affiliation(s)
- Samia E. El-Didamony
- Department of Zoology and Entomology, Faculty of Science, Al-Azhar University (Girls), Nasr City, Egypt
| | - Mohamed H. Kalaba
- Department of Botany and Microbiology, Faculty of Science, Al-Azhar University (Boys), Cairo, Egypt
| | - Mohamed H. Sharaf
- Department of Botany and Microbiology, Faculty of Science, Al-Azhar University (Boys), Cairo, Egypt
| | - Esmail M. El-Fakharany
- Protein Research Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), City of Scientific Research and Technological Applications (SRTA-City), New Borg Al-Arab City, Alexandria, Egypt
- Pharmaceutical and Fermentation Industries Development Center, City of Scientific Research and Technological Applications (SRTA-City), New Borg Al-Arab City, Alexandria, Egypt
- Pharos University in Alexandria, Alexandria, Egypt
| | - Ali Osman
- Department of Biochemistry, Faculty of Agriculture, Zagazig University, Zagazig, Egypt
- Department of Clinical Microbiology, Infection, and Immunology, Umeå University, Umeå, Sweden
- Department of Diagnostics and Intervention, Oncology, Umeå University, Umeå, Sweden
| | - Mahmoud Sitohy
- Department of Biochemistry, Faculty of Agriculture, Zagazig University, Zagazig, Egypt
| | - Basel Sitohy
- Department of Clinical Microbiology, Infection, and Immunology, Umeå University, Umeå, Sweden
- Department of Diagnostics and Intervention, Oncology, Umeå University, Umeå, Sweden
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Azhamuthu T, Kathiresan S, Senkuttuvan I, Asath NAA, Ravichandran P, Vasu R. Usnic acid alleviates inflammatory responses and induces apoptotic signaling through inhibiting NF-ĸB expressions in human oral carcinoma cells. Cell Biochem Funct 2024; 42:e4074. [PMID: 38874340 DOI: 10.1002/cbf.4074] [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: 02/16/2024] [Revised: 05/08/2024] [Accepted: 06/03/2024] [Indexed: 06/15/2024]
Abstract
Usnic acid (UA) is a unique bioactive substance in lichen with potential anticancer properties. Recently, we have reported that UA can reduce 7,12-dimethylbenz[a] anthracene-induced oral carcinogenesis by inhibiting oxidative stress, inflammation, and cell proliferation in a male golden Syrian hamster in vivo model. The present study aims to explore the relevant mechanism of cell death induced by UA on human oral carcinoma (KB) cell line in an in vitro model. We found that UA can induce apoptosis (cell death) in KB cells by decreasing cell viability, increasing the production of reactive oxygen species (ROS), depolarizing mitochondrial membrane potential (MMP) levels, causing nuclear fragmentation, altering apoptotic morphology, and causing excessive DNA damage. Additionally, UA inhibits the expression of Bcl-2, a protein that promotes cell survival, while increasing the expression of p53, Bax, Cytochrome-c, Caspase-9, and 3 proteins in KB cells. UA also inhibits the expression of nuclear factor-κB (NF-κB), a protein that mediates the activation of pro-inflammatory cytokines such as TNF-α and IL-6, in KB cells. Furthermore, UA promotes apoptosis by enhancing the mitochondrial-mediated apoptotic mechanism through oxidative stress, depletion of cellular antioxidants, and an inflammatory response. Ultimately, the findings of this study suggest that UA may have potential as an anticancer therapeutic agent for oral cancer treatments.
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Affiliation(s)
- Theerthu Azhamuthu
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Tamil Nadu, India
| | - Suresh Kathiresan
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Tamil Nadu, India
| | - Ilanchitchenni Senkuttuvan
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Tamil Nadu, India
| | | | - Pugazhendhi Ravichandran
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Tamil Nadu, India
| | - Rajeswari Vasu
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Tamil Nadu, India
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Jafari Z, Sadeghi S, Dehaghi MM, Bigham A, Honarmand S, Tavasoli A, Hoseini MHM, Varma RS. Immunomodulatory activities and biomedical applications of melittin and its recent advances. Arch Pharm (Weinheim) 2024; 357:e2300569. [PMID: 38251938 DOI: 10.1002/ardp.202300569] [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: 10/06/2023] [Revised: 12/10/2023] [Accepted: 12/12/2023] [Indexed: 01/23/2024]
Abstract
Melittin (MLT), a peptide containing 26 amino acids, is a key constituent of bee venom. It comprises ∼40%-60% of the venom's dry weight and is the main pricing index for bee venom, being the causative factor of pain. The unique properties of MLT extracted from bee venom have made it a very valuable active ingredient in the pharmaceutical industry as this cationic and amphipathic peptide has propitious effects on human health in diverse biological processes. It has the ability to strongly impact the membranes of cells and display hemolytic activity with anticancer characteristics. However, the clinical application of MLT has been limited by its severe hemolytic activity, which poses a challenge for therapeutic use. By employing more efficient mechanisms, such as modifying the MLT sequence, genetic engineering, and nano-delivery systems, it is anticipated that the limitations posed by MLT can be overcome, thereby enabling its wider application in therapeutic contexts. This review has outlined recent advancements in MLT's nano-delivery systems and genetically engineered cells expressing MLT and provided an overview of where the MLTMLT's platforms are and where they will go in the future with the challenges ahead. The focus is on exploring how these approaches can overcome the limitations associated with MLT's hemolytic activity and improve its selectivity and efficacy in targeting cancer cells. These advancements hold promise for the creation of innovative and enhanced therapeutic approaches based on MLT for the treatment of cancer.
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Affiliation(s)
- Zohreh Jafari
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sahar Sadeghi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahsa Mirzarazi Dehaghi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ashkan Bigham
- Institute of Polymers, Composites and Biomaterials, National Research Council of Italy (IPCB-CNR), Naples, Italy
- Department of Chemical, Materials and Production Engineering, University of Naples Federico II, Naples, Italy
| | - Shokouh Honarmand
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Afsaneh Tavasoli
- Department of Biotechnology, Faculty of Pharmacy, Alborz University of Medical Sciences, Karaj, Iran
| | - Mostafa Haji Molla Hoseini
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Rajender S Varma
- Department of Chemistry, Centre of Excellence for Research in Sustainable Chemistry, Federal University of São Carlos, São Carlos, Brazil
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Zhang HQ, Sun C, Xu N, Liu W. The current landscape of the antimicrobial peptide melittin and its therapeutic potential. Front Immunol 2024; 15:1326033. [PMID: 38318188 PMCID: PMC10838977 DOI: 10.3389/fimmu.2024.1326033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 01/03/2024] [Indexed: 02/07/2024] Open
Abstract
Melittin, a main component of bee venom, is a cationic amphiphilic peptide with a linear α-helix structure. It has been reported that melittin can exert pharmacological effects, such as antitumor, antiviral and anti-inflammatory effects in vitro and in vivo. In particular, melittin may be beneficial for the treatment of diseases for which no specific clinical therapeutic agents exist. Melittin can effectively enhance the therapeutic properties of some first-line drugs. Elucidating the mechanism underlying melittin-mediated biological function can provide valuable insights for the application of melittin in disease intervention. However, in melittin, the positively charged amino acids enables it to directly punching holes in cell membranes. The hemolysis in red cells and the cytotoxicity triggered by melittin limit its applications. Melittin-based nanomodification, immuno-conjugation, structural regulation and gene technology strategies have been demonstrated to enhance the specificity, reduce the cytotoxicity and limit the off-target cytolysis of melittin, which suggests the potential of melittin to be used clinically. This article summarizes research progress on antiviral, antitumor and anti-inflammatory properties of melittin, and discusses the strategies of melittin-modification for its future potential clinical applications in preventing drug resistance, enhancing the selectivity to target cells and alleviating cytotoxic effects to normal cells.
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Affiliation(s)
- Hai-Qian Zhang
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Science, Changchun, Jilin, China
| | - Chengbiao Sun
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Science, Changchun, Jilin, China
| | - Na Xu
- Academic Affairs Office, Jilin Medical University, Jilin, Jilin, China
| | - Wensen Liu
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Science, Changchun, Jilin, China
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Li X, Li Z, Meng YQ, Qiao H, Zhai KR, Li ZQ, Wei SL, Li B. Melittin kills A549 cells by targeting mitochondria and blocking mitophagy flux. Redox Rep 2023; 28:2284517. [PMID: 38041592 PMCID: PMC11001274 DOI: 10.1080/13510002.2023.2284517] [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: 12/03/2023] Open
Abstract
Melittin, a naturally occurring polypeptide found in bee venom, has been recognized for its potential anti-tumor effects, particularly in the context of lung cancer. Our previous study focused on its impact on human lung adenocarcinoma cells A549, revealing that melittin induces intracellular reactive oxygen species (ROS) burst and oxidative damage, resulting in cell death. Considering the significant role of mitochondria in maintaining intracellular redox levels and ROS, we further examined the involvement of mitochondrial damage in melittin-induced apoptosis in lung cancer cells. Our findings demonstrated that melittin caused changes in mitochondrial membrane potential (MMP), triggered mitochondrial ROS burst (Figure 1), and activated the mitochondria-related apoptosis pathway Bax/Bcl-2 by directly targeting mitochondria in A549 cells (Figure 2). Further, we infected A549 cells using a lentivirus that can express melittin-Myc and confirmed that melittin can directly target binding to mitochondria, causing the biological effects described above (Figure 2). Notably, melittin induced mitochondrial damage while inhibiting autophagy, resulting in abnormal degradation of damaged mitochondria (Figure 5). To summarize, our study unveils that melittin targets mitochondria, causing mitochondrial damage, and inhibits the autophagy-lysosomal degradation pathway. This process triggers mitoROS burst and ultimately activates the mitochondria-associated Bax/Bcl-2 apoptotic signaling pathways in A549 cells.
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Affiliation(s)
- Xuan Li
- Department of Thoracic Surgery, Lanzhou University Second Hospital, Lanzhou University Second Clinical Medical College, Lanzhou, People’s Republic of China
| | - Zheng Li
- Department of Thoracic Surgery, Lanzhou University Second Hospital, Lanzhou University Second Clinical Medical College, Lanzhou, People’s Republic of China
| | - Yu-Qi Meng
- Department of Thoracic Surgery, Lanzhou University Second Hospital, Lanzhou University Second Clinical Medical College, Lanzhou, People’s Republic of China
| | - Hui Qiao
- Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, People’s Republic of China
| | - Ke-Rong Zhai
- Department of Thoracic Surgery, Lanzhou University Second Hospital, Lanzhou University Second Clinical Medical College, Lanzhou, People’s Republic of China
| | - Zhen-Qing Li
- Department of Thoracic Surgery, Lanzhou University Second Hospital, Lanzhou University Second Clinical Medical College, Lanzhou, People’s Republic of China
| | - Shi-Lin Wei
- Department of Thoracic Surgery, Lanzhou University Second Hospital, Lanzhou University Second Clinical Medical College, Lanzhou, People’s Republic of China
| | - Bin Li
- Department of Thoracic Surgery, Lanzhou University Second Hospital, Lanzhou University Second Clinical Medical College, Lanzhou, People’s Republic of China
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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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10
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Liu Q, Wang L, He D, Wu Y, Liu X, Yang Y, Chen Z, Dong Z, Luo Y, Song Y. Application Value of Antimicrobial Peptides in Gastrointestinal Tumors. Int J Mol Sci 2023; 24:16718. [PMID: 38069041 PMCID: PMC10706433 DOI: 10.3390/ijms242316718] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 11/17/2023] [Accepted: 11/22/2023] [Indexed: 12/18/2023] Open
Abstract
Gastrointestinal cancer is a common clinical malignant tumor disease that seriously endangers human health and lacks effective treatment methods. As part of the innate immune defense of many organisms, antimicrobial peptides not only have broad-spectrum antibacterial activity but also can specifically kill tumor cells. The positive charge of antimicrobial peptides under neutral conditions determines their high selectivity to tumor cells. In addition, antimicrobial peptides also have unique anticancer mechanisms, such as inducing apoptosis, autophagy, cell cycle arrest, membrane destruction, and inhibition of metastasis, which highlights the low drug resistance and high specificity of antimicrobial peptides. In this review, we summarize the related studies on antimicrobial peptides in the treatment of digestive tract tumors, mainly oral cancer, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, and colorectal cancer. This paper describes the therapeutic advantages of antimicrobial peptides due to their unique anticancer mechanisms. The length, net charge, and secondary structure of antimicrobial peptides can be modified by design or modification to further enhance their anticancer effects. In summary, as an emerging cancer treatment drug, antimicrobial peptides need to be further studied to realize their application in gastrointestinal cancer diseases.
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Affiliation(s)
- Qi Liu
- College of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
| | - Lei Wang
- College of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
| | - Dongxia He
- College of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
| | - Yuewei Wu
- College of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
| | - Xian Liu
- College of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
| | - Yahan Yang
- College of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
| | - Zhizhi Chen
- College of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
| | - Zhan Dong
- College of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
| | - Ying Luo
- College of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
| | - Yuzhu Song
- College of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
- Medical College, Kunming University of Science and Technology, Kunming 650500, China
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11
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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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12
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Sun D, Li S, Huang H, Xu L. Neurotoxicity of melittin: Role of mitochondrial oxidative phosphorylation system in synaptic plasticity dysfunction. Toxicology 2023; 497-498:153628. [PMID: 37678661 DOI: 10.1016/j.tox.2023.153628] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 08/27/2023] [Accepted: 09/04/2023] [Indexed: 09/09/2023]
Abstract
Melittin (Mel), a main active peptide component of bee venom, has been proven to possess strong antitumor activity. Previous studies have shown that Mel caused severe cell membrane lysis and acted on the central nervous system (CNS). Here, this study was designed to investigate the effects of Mel on CNS and explore the potential mechanism. We confirmed the neurotoxic effect of melittin by in vivo and in vitro experiments. After subcutaneous administration of Mel (4 mg/kg, 8 mg/kg) for 14 days, the mice exhibited obvious depression-like behavior in a dose dependent manner. Besides, RNA-sequencing analysis revealed that oxidative phosphorylation (OXPHOS) signaling pathway was mostly enriched in hippocampus. Consistently, we found that Mel distinctly inhibited the activity of OXPHOS complex I and induced oxidative stress injury. Moreover, Mel significantly induced synaptic plasticity dysfunction in hippocampus via BDNF/TrkB/CREB signaling pathway. Taken together, the neurotoxic effect of Mel was involved in impairing OXPHOS system and hippocampal synaptic plasticity. These novel findings provide new insights into fully understanding the health risks of Mel and are conducive to the development of Mel related drugs.
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Affiliation(s)
- Dan Sun
- School of Pharmacy, Jiangsu Key Laboratory of Inflammation and Molecular Drug Targets, Nantong University, Nantong, Jiangsu 226001, China
| | - Shanshan Li
- School of Pharmacy, Bengbu Medical College, Bengbu, Anhui 233000, China
| | - Haiqin Huang
- School of Pharmacy, Jiangsu Key Laboratory of Inflammation and Molecular Drug Targets, Nantong University, Nantong, Jiangsu 226001, China
| | - Lixing Xu
- School of Pharmacy, Jiangsu Key Laboratory of Inflammation and Molecular Drug Targets, Nantong University, Nantong, Jiangsu 226001, China.
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13
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Pandey P, Khan F, Khan MA, Kumar R, Upadhyay TK. An Updated Review Summarizing the Anticancer Efficacy of Melittin from Bee Venom in Several Models of Human Cancers. Nutrients 2023; 15:3111. [PMID: 37513529 PMCID: PMC10385528 DOI: 10.3390/nu15143111] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 07/05/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
Apitherapy (using bee products) has gained broad recognition in cancer therapeutics globally. Honeybee venom has a broad range of biological potential, and its utilization is rapidly emerging in apitherapy. Bee products have significant potential to strengthen the immune system and improve human health. Thus, this review is targeted toward recapitulating the chemo-preventive potential of melittin (MEL), which constitutes a substantial portion of honeybee venom. Honeybee venom (apitoxin) is produced in the venom gland of the honeybee abdomen, and adult bees utilize it as a primary colony defense mechanism. Apitoxin comprises numerous biologically active compounds, including peptides, enzymes, amines, amino acids, phospholipids, minerals, carbohydrates, and volatile components. We are mainly focused on exploring the potential of melittin (a peptide component) of bee venom that has shown promising potential in the treatment of several human cancers, including breast, stomach, lung, prostate, ovary, kidney, colon, gastric, esophageal, cervical cancers, melanoma, osteosarcoma, and hepatocellular carcinoma. This review has summarized all potential studies related to the anticancerous efficacy of melittin (apitoxin), its formulations, conjugates, and nano-formulations against several human carcinomas, which would further pave the way for future researchers in developing potent drugs for cancer management.
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Affiliation(s)
- Pratibha Pandey
- Department of Biotechnology, Noida Institute of Engineering & Technology, Greater Noida 201306, Uttar Pradesh, India
| | - Fahad Khan
- Department of Biotechnology, Noida Institute of Engineering & Technology, Greater Noida 201306, Uttar Pradesh, India
| | - Minhaj Ahmad Khan
- Department of Biochemistry, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara 144411, Punjab, India
| | - Rajnish Kumar
- Department of Pharmaceutical Chemistry, Noida Institute of Engineering and Technology (Pharmacy Institute), Greater Noida 201306, Uttar Pradesh, India
| | - Tarun Kumar Upadhyay
- Department of Biotechnology, Parul Institute of Applied Sciences and Centre of Research for Development, Parul University, Vadodara 391760, Gujarat, India
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14
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Harfmann D, Florea A. Experimental envenomation with honeybee venom melittin and phospholipase A2 induced multiple ultrastructural changes in adrenocortical mitochondria. Toxicon 2023; 229:107136. [PMID: 37116588 DOI: 10.1016/j.toxicon.2023.107136] [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: 01/27/2023] [Revised: 04/25/2023] [Accepted: 04/25/2023] [Indexed: 04/30/2023]
Abstract
Bee stings represent a public health subject, but the mechanisms involved in bee venom toxicity are not yet fully understood. To evaluate the reactions of adrenocortical cells, through which organisms respond to stress, two honeybee venom components: melittin (Mlt) and phospholipase A2 (PLA2) were tested as potential chemical stressors. Modifications were investigated with transmission electron microscopy and microanalysis. A single dose of Mlt (31 mg/kg) or PLA2 (9.3 mg/kg) was injected in rats of groups ML and PL; daily doses of Mlt (350 μg/kg) or PLA2 (105 μg/kg) were injected 30 days in rats of groups M30 and P30. Adrenocortical cells in ML group showed ultrastructural degenerative alterations of nuclei, endoplasmic reticulum, and mitochondria that exhibited lipid inclusions and mitochondrial cristae (MC) re-organized into mono- or multimembrane large vesicles, and whorls of membranes. Many MC were degenerated. In the M30 group, similar ultrastructural changes, but of lower amplitude were noted; lipid cytosolic droplets were heterogenous. MC diameters in Mlt groups (melittin treated groups) were significantly higher than in control (C) group. In PL group, mitochondria contained large lipid inclusions, vesicular MC of different sizes and multiple membranes, and debris, or whorl structures. In P30 group MC were tubular with increased diameters. In both PLA2 groups (PLA2 treated groups) MC were significantly larger than in C group. We concluded that Mlt and PLA2 were powerful stressors, toxic at the tested doses, cellular reactions concerning in all groups mainly mitochondria, but also other cellular compartments. Apart from degenerative regression of MC, the rearrangement of tubular MC occurred into one or multiple large multimembrane vesicular MC. Reactions to the high doses were more pronounced, with the highest amplitude in ML group, and the lowest in P30 group.
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Affiliation(s)
- Diana Harfmann
- Department of Cell and Molecular Biology, Faculty of Medicine, "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Adrian Florea
- Department of Cell and Molecular Biology, Faculty of Medicine, "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.
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15
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Li Y, Yue X, Wang S, Li P, Zhang M, Song K, Huang X, Li Z. Protective Effect of Trillium tschonoskii Maxim Components Against Glutamate-Induced SH-SY5Y Cells Damage Through Regulating Apoptosis. Dose Response 2023; 21:15593258231169585. [PMID: 37283817 PMCID: PMC10240882 DOI: 10.1177/15593258231169585] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 03/27/2023] [Indexed: 06/08/2023] Open
Abstract
Context Among the Tujia people, the root or rhizome of Trillium tschonoskii Maxim.in Bull.Acad (TTM) is considered a miraculous herb for headaches. Previous studies have shown ethyl acetate extract (TTM1) can protect SH-SY5Y cells against glutamate injury. Objective This study clarified TTM1's mechanism against glutamate-induced cell damage, focusing on the regulation of apoptosis. The compounds were separated, identified, and performed molecular docking with pro-apoptotic proteins. Materials and Methods SH-SY5Y cells were treated with glutamate (2 mM) for 12 hour, and the effect of TTM1 (2.5, 5, 10, and 20 μg/mL) was evaluated with MTT and LDH release assays, taking EGb761(40 μg/mL) as a control. Cell apoptosis was detected with Hoechst 33258 and Annexin V-FITC and measurements of intracellular calcium and caspase-3. The major components were separated and identified by LCMS-IT-TOF and NMR, then the proapoptotic activity of TTM1 was confirmed by molecular docking method. Results TTM1 protected SH-SY5Y cells by resisting apoptosis, TTM1 (10 and 20 μg/mL) decreased apoptotic bodies and nuclear fragments, increased the proportion of normal cells to 68.38 ± 5.63% and 92.80 ± .88%, decreased VA cells to 4.30 ± .76% and 3.58 ± .45% and caspase-3 to .365 ± .034 and .344 ± .047 ng/mL.TTM1 (10 μg/mL) decreased intracellular free calcium to 2.77 ± .40. Polyphyllin VI and pennogenin 3-O-β-chacotrioside were identified in TTM1 at 15.04% and 2.84%, and had potential anti-apoptosis activities. Discussion and Conclusions Folk records of TTM for headache may be related to its anti-apoptosis of nerve cells. Identification and content determination of index components based on effective extract provides research paradigms for rare and endangered ethnic plants.
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Affiliation(s)
- Yanwen Li
- Institute of Information on Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xingnan Yue
- Shanxi University of Traditional Chinese Medicine, Taiyuan, China
| | - Shuo Wang
- School of Ethnic Medicine, Yunnan Minzu University, Kunming, China
| | - Pengyue Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Man Zhang
- School of Pharmacy, Minzu University of China, Beijing, China
| | - Kuokui Song
- School of Pharmacy, Minzu University of China, Beijing, China
| | - Xiulan Huang
- School of Pharmacy, Minzu University of China, Beijing, China
| | - Zhiyong Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
- School of Pharmacy, Minzu University of China, Beijing, China
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16
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Ertilav K, Nazıroğlu M. Honey bee venom melittin increases the oxidant activity of cisplatin and kills human glioblastoma cells by stimulating the TRPM2 channel. Toxicon 2023; 222:106993. [PMID: 36528210 DOI: 10.1016/j.toxicon.2022.106993] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 11/30/2022] [Accepted: 12/08/2022] [Indexed: 12/23/2022]
Abstract
Melittin (MLT) treatment is believed to enhance tumor cell death, apoptotic, and oxidative cytotoxic effects of cisplatin (CSP) via the modulation of Ca2+ channels in several cancer lines. The activation of TRPM2 mediated anticancer and CSP resistance actions via mitochondrial Ca2+ and Zn2+ accumulation-induced mitochondrial reactive free oxygen species (MitSOX) in the glioblastoma cells. The aim was to elucidate the effects of CSP and MLT combination via the TRPM2 stimulation on the tumor cell viability, cell number, cell death (propidium iodide/Hoechst rate), apoptosis, and MitSOX levels in the DBTRG-05MG cells. In the DBTRG-05MG cells, we induced four groups as control, MLT (2.5 μg/ml for 24 h), CSP (25 μM for 24 h), and CSP + MLT. The CSP-induced intracellular Ca2+ influxes to the TRPM2 activation were increased in the cells from coming H2O2 and ADP-Ribose. The influxes were decreased in the cells by the incubations of TRPM2 antagonists (ACA and carvacrol). The incubation of CSP increased the parameters of intracellular Ca2+ responses, mitochondria function, cytosolic free Zn2+ accumulation, apoptosis (caspase -3, -8, and -9), and MitSOX generation in the tumor cells. After the treatment of MLT with/without CSP, the parameters were further increased in the cells. In conclusion, the treatment of MLT increased the anticancer, tumor cell death, apoptotic, and oxidant effects of CSP in the glioblastoma tumor cells via activating the TRPM2. As a result, TRPM2 stimulation by MLT may be utilized as a successful agent in the CSP treatment of glioblastoma tumors.
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Affiliation(s)
- Kemal Ertilav
- Department of Neurosurgery, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey
| | - Mustafa Nazıroğlu
- Neuroscience Research Center, Suleyman Demirel University, Isparta, Turkey; BSN Health, Analysis and Innovation Ltd., Goller Bolgesi Teknokenti, Isparta, Turkey.
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17
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Ullah A, Aldakheel FM, Anjum SI, Raza G, Khan SA, Tlak Gajger I. Pharmacological properties and therapeutic potential of honey bee venom. Saudi Pharm J 2023; 31:96-109. [PMID: 36685303 PMCID: PMC9845117 DOI: 10.1016/j.jsps.2022.11.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 11/09/2022] [Indexed: 11/17/2022] Open
Abstract
Honey bee venom (BV) is a valuable product, and has a wide range of biological effects, and its use is rapidly increasing in apitherapy. Therefore, the current study, we reviewed the existing knowledge about BV composition and its numerous pharmacological properties for future research and use. Honey bee venom or apitoxin is produced in the venom gland in the honey bee abdomen. Adult bees use it as a primary colony defense mechanism. It is composed of many biologically active substances including peptides, enzymes, amines, amino acids, phospholipids, minerals, carbohydrates as well as some volatile components. Melittin and phospholipase A2 are the most important components of BV, having anti-cancer, antimicrobial, anti-inflammatory, anti-arthritis, anti-nociceptive and other curative potentials. Therefore, in medicine, BV has been used for centuries against different diseases like arthritis, rheumatism, back pain, and various inflammatory infections. Nowadays, BV or its components separately, are used for the treatment of various diseases in different countries as a natural medicine with limited side effects. Consequently, scientists as well as several pharmaceutical companies are trying to get a new understanding about BV, its substances and its activity for more effective use of this natural remedy in modern medicine.
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Affiliation(s)
- Amjad Ullah
- Department of Zoology, Kohat University of Science and Technology, Kohat 26000, Khyber Pakhtunkhwa, Pakistan
| | - Fahad Mohammed Aldakheel
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 11433, Saudi Arabia,Prince Sattam bin Abdulaziz Research Chair for Epidemiology and Public Health, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia
| | - Syed Ishtiaq Anjum
- Department of Zoology, Kohat University of Science and Technology, Kohat 26000, Khyber Pakhtunkhwa, Pakistan,Corresponding author.
| | - Ghulam Raza
- Department of Biological Sciences, University of Baltistan, Skardu, Pakistan
| | - Saeed Ahmad Khan
- Department of Pharmacy, Institute of Chemical and Pharmaceutical Sciences, Kohat University of Science and Technology, Kohat, Khyber Pakhtunkhwa, Pakistan
| | - Ivana Tlak Gajger
- Department for Biology and Pathology of Fish and Bees, Faculty of Veterinary Medicine University of Zagreb, Zagreb, Croatia
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18
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Tripathi AK, Vishwanatha JK. Role of Anti-Cancer Peptides as Immunomodulatory Agents: Potential and Design Strategy. Pharmaceutics 2022; 14:pharmaceutics14122686. [PMID: 36559179 PMCID: PMC9781574 DOI: 10.3390/pharmaceutics14122686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 11/27/2022] [Accepted: 11/30/2022] [Indexed: 12/05/2022] Open
Abstract
The usage of peptide-based drugs to combat cancer is gaining significance in the pharmaceutical industry. The collateral damage caused to normal cells due to the use of chemotherapy, radiotherapy, etc. has given an impetus to the search for alternative methods of cancer treatment. For a long time, antimicrobial peptides (AMPs) have been shown to display anticancer activity. However, the immunomodulatory activity of anti-cancer peptides has not been researched very extensively. The interconnection of cancer and immune responses is well-known. Hence, a search and design of molecules that can show anti-cancer and immunomodulatory activity can be lead molecules in this field. A large number of anti-cancer peptides show good immunomodulatory activity by inhibiting the pro-inflammatory responses that assist cancer progression. Here, we thoroughly review both the naturally occurring and synthetic anti-cancer peptides that are reported to possess both anti-cancer and immunomodulatory activity. We also assess the structural and biophysical parameters that can be utilized to improve the activity. Both activities are mostly reported by different groups, however, we discuss them together to highlight their interconnection, which can be used in the future to design peptide drugs in the field of cancer therapeutics.
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19
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Fahmy UA, Badr-Eldin SM, Aldawsari HM, Alhakamy NA, Ahmed OAA, Radwan MF, Eid BG, Sayed SRM, El Sherbiny GA, Abualsunun W. Potentiality of raloxifene loaded melittin functionalized lipidic nanovesicles against pancreatic cancer cells. Drug Deliv 2022; 29:1863-1877. [PMID: 35708464 PMCID: PMC9225738 DOI: 10.1080/10717544.2022.2072544] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/25/2022] [Accepted: 04/25/2022] [Indexed: 11/09/2022] Open
Abstract
Pancreatic cancer (PC) frequency and incidence have grown rapidly in recent years. One of the most serious problems with PC is the existence of asymptotic manifestations, which frequently delays early detection, and until the diagnosis is established, tumor cells progress to the metastatic stage. Another significant concern with PC is the scarcity of well-defined pharmacotherapeutic drugs. The aim of this study was to develop an efficient nanocarrier system to augment the efficacy of raloxifene (RLX) against PC cells. As a result, the current investigation was carried out in order to give an effective treatment method, in which an optimum RLX loaded phospholipid-based vesicles with melittin (PL-MEL) was chosen using experimental design software, with particle size, zeta potential and entrapment efficiency % as dependent variables. Furthermore, anticancer activity against PANC1 cells was assessed. The optimized nanovesicle parameters were 172.5 nm for the measured size, zeta potential of -0.69 mV, and entrapment efficiency of 76.91% that were in good agreement with the expected ones. RLX-raw, plain formula, and optimized RLX-PL-MEL showed IC50 concentrations of 26.07 ± 0.98, 9.166 ± 0.34, and 1.24 ± 0.05 µg/mL, respectively. Furthermore, cell cycle analysis revealed that the nanovesicle was most effective in the G2-M phase, whereas Bax, and Bcl-2 estimates revealed that optimized RLX formula had the highest apoptotic activity among treatments investigated. However, as compared to RLX alone or plain formula alone, the optimized formula demonstrated higher expression of TNFα and Bax while a significant reduction of Bcl-2 and NF-κB expression was observed. mitochondrial membrane potential (MMP) analysis confirmed the apoptosis as well as the anticancer effect of the optimized formula. Thus, the present study results showed an improvement in the anti-PC effects of the RLX with phospholipid conjugated melittin, making it a novel treatment approach against PC.
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Affiliation(s)
- Usama A. Fahmy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Shaimaa M. Badr-Eldin
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Pharmaceutics and Industrial Pharmacy, Cairo University, Cairo, Egypt
| | - Hibah M. Aldawsari
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
- Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Nabil A. Alhakamy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
- Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah, Saudi Arabia
- Mohamed Saeed Tamer Chair for Pharmaceutical Industries, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Osama A. A. Ahmed
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
- Mohamed Saeed Tamer Chair for Pharmaceutical Industries, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohamed F. Radwan
- Department of Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Basma G. Eid
- Department of Pharmacology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Shaban R. M. Sayed
- College of Science, Electron Microscope Unit, King Saud University, Riyadh, Saudi Arabia
| | - Gamal A. El Sherbiny
- Department of Pharmacology, Faculty of Pharmacy, Cyprus International University, Nicosia, Cyprus
| | - Walaa Abualsunun
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
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20
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Alfaleh MA, Fahmy O, Al-Rabia MW, Abourehab MAS, Ahmed OAA, Fahmy UA, H Alsulimani H, Badr-Eldin SM, Aldawsari HM, Aldhabi BM, Alharbi AS, Alhakamy NA. Hybrid nanoparticulate system of Fluvastatin loaded phospholipid, alpha lipoic acid and melittin for the management of colon cancer. Sci Rep 2022; 12:19446. [PMID: 36376469 PMCID: PMC9663543 DOI: 10.1038/s41598-022-24151-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 11/10/2022] [Indexed: 11/16/2022] Open
Abstract
As a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, Fluvastatin (FLV) is used for reducing low-density lipoprotein (LDL) cholesterol as well as to prevent cardiovascular problems. FLV showed cell line cytotoxicity and antitumor effect. Melittin (MEL) exhibits antineoplastic activity and is known to be promising as a therapeutic option for cancer patients. The aim of this work was to investigate the combination of FLV with MEL loaded hybrid formula of phospholipid (PL) with alpha lipoic acid (ALA) nanoparticles to maximize anticancer tendencies. This study examines the optimization of the prepared formulation in order to minimize nanoparticles size and maximize zeta potential to potentiate cytotoxic potentialities in colon cancer cells (Caco2), cell viability, cell cycle analysis and annexin V were tested. In addition to biological markers as P53, Bax, bcl2 and Caspase 3 evaluation The combination involving FLV PL ALA MEL showed enhanced cytotoxic potentiality (IC50 = 9.242 ± 0.35 µg/mL), about twofold lower, compared to the raw FLV (IC50 = 21.74 ± 0.82 µg/mL). According to studies analyzing cell cycle, optimized FLV PL ALA MEL was found to inhibit Caco2 colon cancer cells more significantly than other therapeutic treatments, wherein a higher number of cells were found to accumulate over G2/M and pre-G1 phases, whereas G0/G1/S phases witnessed the accumulation of a lower number of cells. The optimized formulation may pave the way for a novel and more efficacious treatment for colon cancer.
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Affiliation(s)
- Mohamed A Alfaleh
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
- Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Omar Fahmy
- Department of Urology, Universiti Putra Malaysia, 43400, Selangor, Malaysia
| | - Mohammed W Al-Rabia
- Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | - Mohammed A S Abourehab
- Department of Pharmaceutics, and Industrial Pharmacy, Faculty, of Pharmacy, Minia University, Minia, Egypt
- Department of Pharmaceutics, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Osama A A Ahmed
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Usama A Fahmy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.
| | - Helal H Alsulimani
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Shaimaa M Badr-Eldin
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Pharmaceutics and Industrial Pharmacy, Cairo University, Cairo, 11562, Egypt
| | - Hibah M Aldawsari
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
- Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | - Bander M Aldhabi
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Awaad S Alharbi
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Nabil A Alhakamy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
- Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
- Mohamed Saeed Tamer Chair for Pharmaceutical Industries, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
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21
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Li X, Zhu S, Li Z, Meng Y, Huang S, Yu Q, Li B. Melittin induces ferroptosis and ER stress-CHOP-mediated apoptosis in A549 cells. Free Radic Res 2022; 56:398-410. [PMID: 36194238 DOI: 10.1080/10715762.2022.2131551] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Melittin is a natural polypeptide present in bee venom, with significant anti-tumor activity. Melittin has been reported to induce cell death in lung carcinoma cell line A549 cells, suggesting an excellent potential for treating lung cancer. However, the core mechanism underlying melittin-induced cell death in A549 cells remains unclear. This work reports that melittin induces reactive oxygen species (ROS) burst, upregulates intracellular Fe2+ levels, disrupts the glutathione-glutathione peroxidase 4 antioxidant system, and increases lipid peroxide accumulation, eventually inducing cell death, indicating that ferroptosis may be involved in the antitumor effects of melittin in A549 cells. Furthermore, A549 cells treated with the ferroptosis inhibitors ferrostatin-1 and deferoxamine demonstrated that these inhibitors could reverse the cell death induced by melittin, further confirming that melittin induces A549 cell death via ferroptosis. Furthermore, the results also illustrated that melittin activated the endoplasmic reticulum (ER) stress-CHOP (C/EBP homologous protein) apoptotic signal, closely associated with high-level intracellular ROS. The ER stress inhibitor, 4-Phenyl butyric acid, was used to confirm that ER stress-CHOP apoptotic signaling is another molecular mechanism of melittin-induced A549 cell death. Thus, our results demonstrate that ferroptosis and ER stress-CHOP signaling are key molecular mechanisms of melittin-induced cell death in lung cancer.Key policy highlightsMelittin upregulates intracellular Fe2+ levels, leading to the accumulation of lipid peroxides in A549 cells.Melittin disrupts the glutathione-glutathione peroxidase 4 antioxidant system in A549 cells.Melittin induces activation of endoplasmic reticulum stress-C/EBP homologous protein apoptosis signal.Ferroptosis and ER stress are the core molecular mechanisms underlying melittin-induced apoptosis in A549 cells.
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Affiliation(s)
- Xuan Li
- Department of Thoracic Surgery, Lanzhou University Second Hospital, Lanzhou University Second Clinical Medical College, Lanzhou University 730030, Lanzhou, China
| | - Sen Zhu
- School of Life Sciences, Lanzhou University, 730030, Lanzhou, China
| | - Zheng Li
- Department of Thoracic Surgery, Lanzhou University Second Hospital, Lanzhou University Second Clinical Medical College, Lanzhou University 730030, Lanzhou, China
| | - Yuqi Meng
- Department of Thoracic Surgery, Lanzhou University Second Hospital, Lanzhou University Second Clinical Medical College, Lanzhou University 730030, Lanzhou, China
| | - Sujie Huang
- School of Basic Medical Sciences, Lanzhou University, 730030, Lanzhou, China
| | - Qiyao Yu
- Department of Thoracic Surgery, Lanzhou University Second Hospital, Lanzhou University Second Clinical Medical College, Lanzhou University 730030, Lanzhou, China
| | - Bin Li
- Department of Thoracic Surgery, Lanzhou University Second Hospital, Lanzhou University Second Clinical Medical College, Lanzhou University 730030, Lanzhou, China
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22
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Varol A, Sezen S, Evcimen D, Zarepour A, Ulus G, Zarrabi A, Badr G, Daştan SD, Orbayoğlu AG, Selamoğlu Z, Varol M. Cellular targets and molecular activity mechanisms of bee venom in cancer: recent trends and developments. TOXIN REV 2022; 41:1382-1395. [DOI: 10.1080/15569543.2021.2024576] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 12/27/2021] [Accepted: 12/27/2021] [Indexed: 12/24/2022]
Affiliation(s)
- Ayşegül Varol
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Serap Sezen
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Istanbul, Turkey
- Faculty of Engineering and Natural Science, Sabanci University, Istanbul, Turkey
| | - Dilhan Evcimen
- Department of Molecular Biology and Genetics, Faculty of Science, Kotekli Campus, Mugla Sitki Kocman University, Mugla, Turkey
| | - Atefeh Zarepour
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, Turkey
| | - Gönül Ulus
- Department of Biology, Faculty of Science, Ege University, Izmir, Turkey
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, Turkey
| | - Gamal Badr
- Department of Zoology, Faculty of Science, Laboratory of Immunology, Assiut University, Assiut, Egypt
| | - Sevgi Durna Daştan
- Department of Biology, Faculty of Science, Sivas Cumhuriyet University, Sivas, Turkey
| | - Asya Gülistan Orbayoğlu
- Department of Molecular Biology and Genetics, Faculty of Science, Kotekli Campus, Mugla Sitki Kocman University, Mugla, Turkey
| | - Zeliha Selamoğlu
- Department Medical Biology, Faculty of Medicine, Nigde Ömer Halisdemir University, Nigde, Turkey
| | - Mehmet Varol
- Department of Molecular Biology and Genetics, Faculty of Science, Kotekli Campus, Mugla Sitki Kocman University, Mugla, Turkey
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23
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Hou G, Li Y, Wang Q, Zhang H, Liang S, Liu B, Shi W. iRGD-grafted N-trimethyl chitosan-coated protein nanotubes enhanced the anticancer efficacy of curcumin and melittin. Int J Biol Macromol 2022; 222:348-359. [PMID: 36150572 DOI: 10.1016/j.ijbiomac.2022.09.171] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 08/30/2022] [Accepted: 09/19/2022] [Indexed: 11/28/2022]
Abstract
Curcumin (Cur) and Melittin (Mel) are two natural extracts that have been shown anti-tumor effects. However, their applications are limited due to poor oral bioavailability and the lack of tumor-targeting property. Here, we developed a novel nanocomposite that enabled the co-delivery of Cur and Mel, which consists of α-lactalbumin protein nanotubes (NTs), positively charged N,N,N-trimethyl chitosan (TMC), and a tumor-targeting cyclic peptide iRGD. The results showed that NTs/Cur-TMC-Mel-iRGD incorporated the advantages of each component, for instance, effective compounds loading by NTs, improved cellular uptake by TMC, prolonged accumulation in tumors by iRGD as well as synergistic anti-tumor effects of Cur and Mel. In the tumor-bearing mice, NTs/Cur-TMC-Mel-iRGD treatment remarkably induced cancer cell apoptosis while inhibiting cell proliferation, leading to suppressed tumor growth. Besides, no obvious adverse effects were observed in the blood physiology and tissue histology. Overall, our study provided an effective strategy for co-delivering Cur and Mel, which has a potential for translational clinical research aiming to treat solid tumors.
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Affiliation(s)
- Guohua Hou
- Research Center of Food Colloids and Delivery of Functionality, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, PR China
| | - Yuan Li
- Research Center of Food Colloids and Delivery of Functionality, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, PR China
| | - Qimeng Wang
- Research Center of Food Colloids and Delivery of Functionality, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, PR China
| | - Huijuan Zhang
- Department of Nutrition and Health, China Agricultural University, Beijing 100091, PR China
| | - Shuang Liang
- Department of Nutrition and Health, China Agricultural University, Beijing 100091, PR China
| | - Bin Liu
- Department of Nutrition and Health, China Agricultural University, Beijing 100091, PR China.
| | - Wenbiao Shi
- Department of Nutrition and Health, China Agricultural University, Beijing 100091, PR China.
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24
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The Strong Anti-Tumor Effect of Smp24 in Lung Adenocarcinoma A549 Cells Depends on Its Induction of Mitochondrial Dysfunctions and ROS Accumulation. Toxins (Basel) 2022; 14:toxins14090590. [PMID: 36136528 PMCID: PMC9502404 DOI: 10.3390/toxins14090590] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 08/16/2022] [Accepted: 08/25/2022] [Indexed: 12/14/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of death in lung cancer due to its aggressiveness and rapid migration. The potent antitumor effect of Smp24, an antimicrobial peptide derived from Egyptian scorpion Scorpio maurus palmatus via damaging the membrane and cytoskeleton have been reported earlier. However, its effects on mitochondrial functions and ROS accumulation in human lung cancer cells remain unknown. In the current study, we discovered that Smp24 can interact with the cell membrane and be internalized into A549 cells via endocytosis, followed by targeting mitochondria and affect mitochondrial function, which significantly causes ROS overproduction, altering mitochondrial membrane potential and the expression of cell cycle distribution-related proteins, mitochondrial apoptotic pathway, MAPK, as well as PI3K/Akt/mTOR/FAK signaling pathways. In summary, the antitumor effect of Smp24 against A549 cells is related to the induction of apoptosis, autophagy plus cell cycle arrest via mitochondrial dysfunction, and ROS accumulation. Accordingly, our findings shed light on the anticancer mechanism of Smp24, which may contribute to its further development as a potential agent in the treatment of lung cancer cells.
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25
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Antitumoral potential of Chartergellus-CP1 peptide from Chartergellus communis wasp venom in two different breast cancer cell lines (HR+ and triple-negative). Toxicon 2022; 216:148-156. [PMID: 35839869 DOI: 10.1016/j.toxicon.2022.07.004] [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: 03/18/2022] [Revised: 06/20/2022] [Accepted: 07/08/2022] [Indexed: 02/07/2023]
Abstract
Breast cancer represents the most incident cancer in women. Surgery, chemotherapy, radiation therapy, and hormone therapy remain the main treatment for this type of cancer. However, increasing resistance to anti-cancer drugs through poor response for some types of breast cancer to treatments highlights the need to develop new therapeutic agents to fight the disease. In this study, we evaluated the anti-tumor potential of the Chartergellus-CP1 peptide isolated from the wasp venom of Chartergellus communis in human breast cancer cell lines MCF-7 (HR+) and MDA-MB-231 (triple-negative). Cells viability, morphology, cell cycle dynamics, reactive oxygen species (ROS) production, and apoptosis were assessed for both cell lines after exposure to Chartergellus-CP1 during 24 and 48h. The results showed that Chartergellus-CP1 led to a significant increase of cells in the S phase in addition to a high generation of ROS (being more evident in the MCF-7 cell line) associated with apoptotic cell death. This work demonstrates, for the first time, the cytotoxic effects of Chatergellus-CP1 on human breast cancer cell lines including cell cycle profile, oxidative stress generation, and cell death mechanisms.
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26
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Soltan-Alinejad P, Alipour H, Meharabani D, Azizi K. Therapeutic Potential of Bee and Scorpion Venom Phospholipase A2 (PLA2): A Narrative Review. IRANIAN JOURNAL OF MEDICAL SCIENCES 2022; 47:300-313. [PMID: 35919080 PMCID: PMC9339116 DOI: 10.30476/ijms.2021.88511.1927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 12/07/2020] [Accepted: 01/23/2021] [Indexed: 11/19/2022]
Abstract
Venomous arthropods such as scorpions and bees form one of the important groups with an essential role in medical entomology. Their venom possesses a mixture of diverse compounds, such as peptides, some of which have toxic effects, and enzymatic peptide Phospholipase A2 (PLA2) with a pharmacological potential in the treatment of a wide range of diseases. Bee and scorpion venom PLA2 group III has been used in immunotherapy, the treatment of neurodegenerative and inflammatory diseases. They were assessed for antinociceptive, wound healing, anti-cancer, anti-viral, anti-bacterial, anti-parasitic, and anti-angiogenesis effects. PLA2 has been identified in different species of scorpions and bees. The anti-leishmania, anti-bacterial, anti-viral, and anti-malarial activities of scorpion PLA2 still need further investigation. Many pieces of research have been stopped in the laboratory stage, and several studies need vast investigation in the clinical phase to show the pharmacological potential of PLA2. In this review, the medical significance of PLA2 from the venom of two arthropods, namely bees and scorpions, is discussed.
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Affiliation(s)
- Parisa Soltan-Alinejad
- Research Center for Health Sciences, Institute of Health, Department of Medical Entomology and Vector Control, School of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hamzeh Alipour
- Research Center for Health Sciences, Institute of Health, Department of Medical Entomology and Vector Control, School of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Davood Meharabani
- Li Ka Shing Center for Health Research and Innovation, University of Alberta, Edmonton, AB, Canada,
Stem Cell Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Kourosh Azizi
- Research Center for Health Sciences, Institute of Health, Department of Medical Entomology and Vector Control, School of Health, Shiraz University of Medical Sciences, Shiraz, Iran
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27
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Akbarzadeh-Khiavi M, Torabi M, Olfati AH, Rahbarnia L, Safary A. Bio-nano scale modifications of melittin for improving therapeutic efficacy. Expert Opin Biol Ther 2022; 22:895-909. [PMID: 35687355 DOI: 10.1080/14712598.2022.2088277] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Melittin (MLT), a natural membrane-active component, is the most prominent cytolytic peptide from bee venom. Remarkable biological properties of MLT, including anti-inflammatory, antimicrobial, anticancer, anti-protozoan, and antiarthritic activities, make it an up-and-coming therapeutic candidate for a wide variety of human diseases. Therapeutic applications of MLT may be hindered due to low stability, high toxicity, and weak tissue penetration. Different bio-nano scale modifications hold promise for improving its functionality and therapeutic efficacy. AREAS COVERED In the current review, we aimed to provide a comprehensive insight into strategies used for MLT conjugations and modifications, cellular delivery of modified forms, and their clinical perspectives by reviewing the published literature on PubMed, Scopus, and Google Scholar databases. We also emphasized the MLT structure modifications, mechanism of action, and cellular toxicity. EXPERT OPINION Developing new analogs and conjugates of MLT as a natural drug with improved functions and fewer side effects is crucial for the clinical translation of this approach worldwide, especially where the chemicals and synthetic drugs are more expensive or unavailable in the healthcare system. MLT-nanoconjugation may be one of the best-optimized strategies for improving peptide delivery, increasing its therapeutic efficacy, and providing minimal nonspecific cellular lytic activity. [Figure: see text].
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Affiliation(s)
- Mostafa Akbarzadeh-Khiavi
- Liver and Gastrointestinal Diseases Research Center Tabriz University of Medical Sciences, Tabriz, Iran.,Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mitra Torabi
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir-Hossein Olfati
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Rahbarnia
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Azam Safary
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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28
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Qi J, Liu Y, Xu H, Xue T, Su Y, Lin Z. Anti-cancer effect of melittin-Au25(MHA)18 complexes on human cervical cancer HeLa cells. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2021.103078] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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29
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Zhao Q, Feng H, Yang Z, Liang J, Jin Z, Chen L, Zhan L, Xuan M, Yan J, Kuang J, Cheng X, Zhao R, Qiu W. The central role of a two-way positive feedback pathway in molecular targeted therapies-mediated pyroptosis in anaplastic thyroid cancer. Clin Transl Med 2022; 12:e727. [PMID: 35184413 PMCID: PMC8858618 DOI: 10.1002/ctm2.727] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 01/17/2022] [Accepted: 01/24/2022] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Anaplastic thyroid carcinoma (ATC) is one of the most aggressive tumours. We previously confirmed that apatinib has potential therapeutic effects on ATC via regulated cell death (RCD). As a newly identified RCD, pyroptosis demonstrates direct antitumour activity different from apoptosis or autophagy. Therefore, the clinical significance, regulatory role and underlying mechanisms of pyroptosis in ATC were focused on in this study. METHODS In a phase II trial, patients with anaplastic or poorly differentiated thyroid carcinoma received apatinib 500 mg once daily. Multiple assays were implemented to evaluate the antitumour efficacy of apatinib and/or melittin in vitro and in vivo. High-throughput sequencing was applied to analyse differential mRNAs expression in ATC cells treated by apatinib with or without melittin. In situ Hoechst 33342/PI double-staining, LDH release assay and enzyme-linked immunosorbent assay (ELISA) were employed to determine pyroptosis. In mechanism exploration, quantitative RT-PCR, Western blotting and si-RNA knocking down were executed. RESULTS Seventeen patients were evaluable. Apatinib showed a promising therapeutic effect by a disease control rate (DCR) of 88.2%; however, treatment was terminated in 23.5% of patients due to intolerable toxicity. To reduce adverse events, a pyroptosis-mediated synergistic antitumour effect of apatinib and melittin was identified in treatment of ATC in vitro and in vivo. The caspase-1-gasdermin D (GSDMD) axis-mediated pyroptosis was the key to extra antitumour effect of the combination of apatinib and melittin. Moreover, caspase-3-gasdermin E (GSDME) pyroptosis pathway also functioned importantly in addition to caspase-1-GSDMD pathway. Evidenced by in vitro and in vivo study, a two-way positive feedback interaction was innovatively confirmed between caspase-1-GSDMD and caspase-3-GSDME axes. CONCLUSIONS Through pyroptosis mediated by caspase-1-GSDMD and caspase-3-GSDME axes synchronically, low-dosage apatinib and melittin could synergistically achieve a comparable therapeutic potential with reduced AEs. More importantly, a two-way positive feedback interaction is innovatively proposed between these two axes, which provide a new prospect of targeted therapy.
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Affiliation(s)
- Qiwu Zhao
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Haoran Feng
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Zheyu Yang
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Juyong Liang
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Zhijian Jin
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Lingxie Chen
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Ling Zhan
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Ming Xuan
- Department of General SurgeryRuijin Hospital Gubei CampusShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Jiqi Yan
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Jie Kuang
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xi Cheng
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Ren Zhao
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Weihua Qiu
- Department of General SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
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30
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Tanprasert P, Limpakan Yamada S, Chattipakorn SC, Chattipakorn N, Shinlapawittayatorn K. Targeting mitochondria as a therapeutic anti-gastric cancer approach. Apoptosis 2022; 27:163-183. [PMID: 35089473 DOI: 10.1007/s10495-022-01709-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/01/2022] [Indexed: 11/29/2022]
Abstract
Gastric cancer is regarded as the fifth most common cancer globally but the third most common cancer death. Although systemic chemotherapy is the primary treatment for advanced gastric cancer patients, the outcome of chemotherapy is unsatisfactory. Novel therapeutic strategies and potential alternative treatments are therefore needed to overcome the impact of this disease. At a cellular level, mitochondria play an important role in cell survival and apoptosis. A growing body of studies have shown that mitochondria play a central role in the regulation of cellular function, metabolism, and cell death during carcinogenesis. Interestingly, the impact of mitochondrial dynamics, including fission/fusion and mitophagy, on carcinogenesis and cancer progression has also been reported, suggesting the potential targeting of mitochondrial dynamics for the treatment of cancer. This review not only comprehensively summarizes the homeostasis of gastric cancer cells, but the potential therapeutic interventions for the targeting of mitochondria for gastric cancer therapy are also highlighted and discussed.
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Affiliation(s)
- Peticha Tanprasert
- Division of Gastrointestinal Surgery and Endoscopy, Department of Surgery, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Sirikan Limpakan Yamada
- Division of Gastrointestinal Surgery and Endoscopy, Department of Surgery, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Siriporn C Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Nipon Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand.,Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Krekwit Shinlapawittayatorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand. .,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand. .,Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
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31
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Chai J, Yang W, Gao Y, Guo R, Peng Q, Abdel-Rahman MA, Xu X. Antitumor Effects of Scorpion Peptide Smp43 through Mitochondrial Dysfunction and Membrane Disruption on Hepatocellular Carcinoma. JOURNAL OF NATURAL PRODUCTS 2021; 84:3147-3160. [PMID: 34866381 DOI: 10.1021/acs.jnatprod.1c00963] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Smp43, a cationic antimicrobial peptide identified from the venom gland of the Egyptian scorpion Scorpio maurus palmatus, shows cytotoxicity toward hepatoma cell line HepG2 by membrane disruption. However, its underlying detailed mechanisms still remain to be further clarified. In the present study, we evaluated the cellular internalization of Smp43 and explored its effects on cell viability, cell cycle, apoptosis, autophagy, necrosis, and factor expression related to these cellular processes in human HepG2. Smp43 was found to suppress the growth of HepG2, Huh7, and human primary hepatocellular carcinoma cells while showing low toxicity to normal LO2 cells. Furthermore, Smp43 could interact with the cell membrane and be internalized into HepG2 cells via endocytosis and pore formation, which caused a ROS production increase, mitochondrial membrane potential decline, cytoskeleton disorganization, dysregulation of cyclin expression, mitochondrial apoptotic pathway activation, and alteration of MAPK as well as PI3K/Akt/mTOR signaling pathways. Finally, Smp43 showed effective antitumor protection in the HepG2 xenograft mice model. Overall, these findings indicate that Smp43 significantly exerts antitumor effects via induction of apoptosis, autophagy, necrosis, and cell cycle arrest due to its induction of mitochondrial dysfunction and membrane disruption. This discovery will extend the antitumor mechanisms of antimicrobial peptides and contribute to the development of antitumor agents against hepatocellular carcinoma.
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Affiliation(s)
- Jinwei Chai
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Wanren Yang
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Yahua Gao
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Ruiyin Guo
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Qing Peng
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | | | - Xueqing Xu
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
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32
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Chang SN, Kim SH, Kim HJ, Jeong YJ, Lee KC. In Vitro and In Vivo Investigation of the Radiation-Sensitizing Effects of Melittin in Breast Cancer Cells. Int J Pept Res Ther 2021. [DOI: 10.1007/s10989-021-10313-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Huang JY, Peng SF, Chueh FS, Chen PY, Huang YP, Huang WW, Chung JG. Melittin suppresses epithelial-mesenchymal transition and metastasis in human gastric cancer AGS cells via regulating Wnt/BMP associated pathway. Biosci Biotechnol Biochem 2021; 85:2250-2262. [PMID: 34482401 DOI: 10.1093/bbb/zbab153] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 08/25/2021] [Indexed: 12/21/2022]
Abstract
Gastric cancer has a poor prognosis; once cancer has metastasized, it can easily lead to patient death. Melittin is one of the major components extracted from the bee venom. It has been shown that melittin emerges antitumor activities against many human cancer cell lines. Our results indicated that melittin at 0.2-0.5 µm significantly reduced total cell viability in human gastric cancer AGS cells. At low concentrations (0.05-0.15 µm), melittin displayed antimetastasis effects and inhibited cell adhesion and colony formation. Besides, it inhibited cell motility and suppressed cell migration and invasion. Melittin inhibited the activities of MMP-2 and MMP-9 and the integrity of cell membrane in AGS cells. Furthermore, Western blotting results showed that melittin decreased the protein expressions of Wnt/BMP and MMP-2 signaling pathways. Based on these observations, melittin inhibited cell migration and invasion of AGS cells through multiple signaling pathways. It may be used to treat metastasized gastric cancers in the future.
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Affiliation(s)
- Jye-Yu Huang
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
| | - Shu-Fen Peng
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
- Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Fu-Shin Chueh
- Department of Food Nutrition and Health Biotechnology, Asia University, Wufeng, Taichung, Taiwan
| | - Po-Yuan Chen
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
| | - Yi-Ping Huang
- Department of Physiology, China Medical University, Taichung, Taiwan
| | - Wen-Wen Huang
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
| | - Jing-Gung Chung
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
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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: 79] [Impact Index Per Article: 19.8] [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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Kang SY, Hwang D, Shin S, Park J, Kim M, Rahman MDH, Rahman MA, Ko SG, Kim B. Potential of Bioactive Food Components against Gastric Cancer: Insights into Molecular Mechanism and Therapeutic Targets. Cancers (Basel) 2021; 13:cancers13184502. [PMID: 34572730 PMCID: PMC8469857 DOI: 10.3390/cancers13184502] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 09/02/2021] [Accepted: 09/03/2021] [Indexed: 12/18/2022] Open
Abstract
Gastric cancer, also known as stomach cancer, is a cancer that develops from the lining of the stomach. Accumulated evidence and epidemiological studies have indicated that bioactive food components from natural products play an important role in gastric cancer prevention and treatment, although its mechanism of action has not yet been elucidated. Particularly, experimental studies have shown that natural bioactive food products display a protective effect against gastric cancer via numerous molecular mechanisms, such as suppression of cell metastasis, anti-angiogenesis, inhibition of cell proliferation, induction of apoptosis, and modulation of autophagy. Chemotherapy remains the standard treatment for advanced gastric cancer along with surgery, radiation therapy, hormone therapy, as well as immunotherapy, and its adverse side effects including neutropenia, stomatitis, mucositis, diarrhea, nausea, and emesis are well documented. However, administration of naturally occurring bioactive phytochemical food components could increase the efficacy of gastric chemotherapy and other chemotherapeutic resistance. Additionally, several studies have suggested that bioactive food components with structural stability, potential bioavailability, and powerful bioactivity are important to develop novel treatment strategies for gastric cancer management, which may minimize the adverse effects. Therefore, the purpose of this review is to summarize the potential therapeutic effects of natural bioactive food products on the prevention and treatment of gastric cancer with intensive molecular mechanisms of action, bioavailability, and safety efficacy.
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Affiliation(s)
- Seog Young Kang
- College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea; (S.Y.K.); (D.H.); (S.S.); (J.P.); (M.A.R.)
| | - Dongwon Hwang
- College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea; (S.Y.K.); (D.H.); (S.S.); (J.P.); (M.A.R.)
| | - Soyoung Shin
- College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea; (S.Y.K.); (D.H.); (S.S.); (J.P.); (M.A.R.)
| | - Jinju Park
- College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea; (S.Y.K.); (D.H.); (S.S.); (J.P.); (M.A.R.)
| | - Myoungchan Kim
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea;
| | - MD. Hasanur Rahman
- Department of Biotechnology and Genetic Engineering, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh;
| | - Md. Ataur Rahman
- College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea; (S.Y.K.); (D.H.); (S.S.); (J.P.); (M.A.R.)
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea;
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea;
| | - Seong-Gyu Ko
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea;
| | - Bonglee Kim
- College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea; (S.Y.K.); (D.H.); (S.S.); (J.P.); (M.A.R.)
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea;
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Korea;
- Correspondence:
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Li Y, Ruan S, Wang Z, Feng N, Zhang Y. Hyaluronic Acid Coating Reduces the Leakage of Melittin Encapsulated in Liposomes and Increases Targeted Delivery to Melanoma Cells. Pharmaceutics 2021; 13:pharmaceutics13081235. [PMID: 34452196 PMCID: PMC8398362 DOI: 10.3390/pharmaceutics13081235] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 07/25/2021] [Accepted: 08/06/2021] [Indexed: 12/31/2022] Open
Abstract
Melittin is a promising antitumor substance; however, it is a nonspecific cytolytic peptide, which limits its clinical application. In this study, melittin liposomes (Mel-Lip) and hyaluronic acid (HA)-modified Mel-Lip (Mel-HA-Lip) were designed to reduce the toxicity and increase the anti-tumor effects of melittin. The optimal preparation procedure was evaluated using a uniform design based on the single factor method, and the concentration of HA was determined based on the cellular uptake of coumarin 6 labeled HA-Lip. Liposomes and HA-modified liposomes were evaluated in vitro by assessing cytotoxicity, cellular uptake, and release behavior. Liposomes prepared in the optimum formulation improved stability, with a particle size of 132.7 ± 1.55 nm, zeta potential of −11.5 ± 1.51 mV, entrapment efficiency of 86.25 ± 1.28%, and drug-loading efficiency of 3.91 ± 0.49%. Cellular uptake tests revealed that the uptake of nanoparticles significantly increased with HA modification, suggesting that HA modification enhanced the internalization of liposomes within cells, which was consistent with the results of the cytotoxicity analysis. Furthermore, in vitro release experiments showed that Mel-HA-Lip possessed a stronger sustained-release effect compared with Mel-Lip. The results of this experiment provide insight into the potential tumor-targeting effects of melittin.
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Affiliation(s)
| | | | | | - Nianping Feng
- Correspondence: (N.F.); (Y.Z.); Tel.: +86-21-51322198 (Y.Z.)
| | - Yongtai Zhang
- Correspondence: (N.F.); (Y.Z.); Tel.: +86-21-51322198 (Y.Z.)
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Lv L, Yang N, Cao Y, Dang J, Cheng L, El-Sheikh MA, Zhang Y. d-Carvone inhibits the JAK/STAT3 signaling pathway and induced the apoptotic cell death in the human gastric cancer AGS cells. J Biochem Mol Toxicol 2021; 35:e22746. [PMID: 33661530 DOI: 10.1002/jbt.22746] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 01/21/2021] [Accepted: 02/10/2021] [Indexed: 11/09/2022]
Abstract
Globally, gastric cancer is one of the leading cause of death. Surgical and chemotherapy constitute an important treatment regimen. Unfortunately, less than 20 persons out of 100 patients are live on almost 5 years. Hence, a nontoxic, effective and significantly enhancing novel therapeutic agent is required. d-Carvone is a natural terpenoid present in the essential oils and abundant in the seeds of caraway, as well as known folk medication for diarrhea, acidity, and other gastric disorders. Nevertheless, the role of d-carvone on gastric cancer and its underlying molecular mechanism resides enigmatic. Cells were treated with d-carvone to find out the IC50 by MTT assay. This study shows that 20 and 25 μM d-carvone has induced the reactive oxygen species production and mitochondrial membrane potential in gastric cancer AGS cells, which were evaluated by 2,7-dichlorofluoresceindiacetate and Rh123 staining methods, respectively. The effect of d-carvone against the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway was studied through immunoblotting. Then, we found that it effectively inhibited the proliferation of cell, and the induction of cell apoptosis was scrutinized by dual, 4',6-diamidino-2-phenylindole, and also propidium iodide staining methods. We also explored the fundamental molecular signaling mechanism of the d-carvone and our data depicts that d-carvone induced apoptosis cell death by mitochondrial reactive oxygen species production and downregulation of the and JAK and STAT3 signaling molecules. These overall findings support that the d-carvone inhibits the JAK/STAT3 signaling pathway and induces cell death in the gastric cancer AGS cells.
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Affiliation(s)
- Long Lv
- Department of General Surgery, Nanjing Gaochun People's Hospital, Nanjing, Jiangsu, China
| | - Nan Yang
- Day Observation Ward of The First Hospital of Jilin University, Changchun, Jilin, China
| | - Youhong Cao
- Department of Gastroenterology, Nanjing Gaochun People's Hospital, Nanjing, Jiangsu, China
| | - Junqiang Dang
- First Division of Surgery, People's Hospital of Tongchuan, Tongchuan, Shaanxi, China
| | - Likun Cheng
- Department of Internal Medicine, Tangshan Third Hospital, Tangshan, Hebei, China
| | - Mohamed A El-Sheikh
- Department of Botany & Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Yun Zhang
- Department of Gastroenterology, The First People's Hospital of Taizhou, Taizhou, Zhejiang, China
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Colella F, Scillitani G, Pierri CL. Sweet as honey, bitter as bile: Mitochondriotoxic peptides and other therapeutic proteins isolated from animal tissues, for dealing with mitochondrial apoptosis. Toxicology 2020; 447:152612. [PMID: 33171268 DOI: 10.1016/j.tox.2020.152612] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 10/02/2020] [Accepted: 10/06/2020] [Indexed: 02/06/2023]
Abstract
Mitochondria are subcellular organelles involved in cell metabolism and cell life-cycle. Their role in apoptosis regulation makes them an interesting target of new drugs for dealing with cancer or rare diseases. Several peptides and proteins isolated from animal and plant sources are known for their therapeutic properties and have been tested on cancer cell-lines and xenograft murine models, highlighting their ability in inducing cell-death by triggering mitochondrial apoptosis. Some of those molecules have been even approved as drugs. Conversely, many other bioactive compounds are still under investigation for their proapoptotic properties. In this review we report about a group of peptides, isolated from animal venoms, with potential therapeutic properties related to their ability in triggering mitochondrial apoptosis. This class of compounds is known with different names, such as mitochondriotoxins or mitocans.
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Affiliation(s)
- Francesco Colella
- Laboratory of Biochemistry, Molecular and Structural Biology, Department of Biosciences, Biotechnologies, Biopharmaceutics, University of Bari, Via E. Orabona, 4, 70125, Bari, Italy
| | | | - Ciro Leonardo Pierri
- Laboratory of Biochemistry, Molecular and Structural Biology, Department of Biosciences, Biotechnologies, Biopharmaceutics, University of Bari, Via E. Orabona, 4, 70125, Bari, Italy; BROWSer S.r.l. (https://browser-bioinf.com/) c/o Department of Biosciences, Biotechnologies, Biopharmaceutics, University "Aldo Moro" of Bari, Via E. Orabona, 4, 70126, Bari, Italy.
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Zhou C, Ma J, Lu Y, Zhao W, Xu B, Lin J, Ma Y, Tian Y, Zhang Q, Wang W, Yan W, Jiao P. TERT promoter regulating melittin expression induces apoptosis and G 0/G 1 cell cycle arrest in esophageal carcinoma cells. Oncol Lett 2020; 21:16. [PMID: 33240422 PMCID: PMC7681202 DOI: 10.3892/ol.2020.12277] [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: 03/04/2020] [Accepted: 07/15/2020] [Indexed: 12/14/2022] Open
Abstract
Esophageal squamous cell carcinoma accounts for a large proportion of cancer-associated mortalities in both men and women. Melittin is the major active component of bee venom, which has been reported to possess anti-inflammatory, antibacterial and anti-cancer properties. The aim of the present study was to construct a tumor targeted recombinant plasmid [pc-telomerase reverse transcriptase (TERT)-melittin] containing a human TERT promoter followed by a melittin coding sequence and to explore the effects of this plasmid in esophageal cell carcinoma and investigate preliminarily the underlying mechanisms of this effect. TE1 cells were transfected with pcTERT-melittin and the resulting apoptosis was subsequently examined. The viability of TE1 cells transfected with pcTERT-melittin was measured using a Cell Counting Kit-8 assay, which indicated inhibited proliferation. The disruption of mitochondrial membranes and the concomitant production of reactive oxygen species demonstrated an inducible apoptotic effect of melittin in TE1 cells. Apoptotic cells were also counted using an Annexin V-FITC and PI double-staining assay. The upregulation of cleaved caspase-9, cleaved caspase-3, Bax and poly(ADP-ribose) polymerase 1 in pcTERT-melittin transfected TE1 cells, suggested that pcTERT-melittin-induced apoptosis was associated with the mitochondrial pathway. TE1 cells were also arrested in the G0/G1 phase when transfected with pcTERT-melittin, followed by the decline of CDK4, CDK6 and cyclin D1 expression levels. As cell invasion and metastasis are common in patients with esophageal cancer, a cell migration assay was conducted and it was found that pcTERT-melittin transfection reduced the migratory and invasive abilities of TE1 cells. The findings of the present study demonstrated that pcTERT-melittin may induce apoptosis of esophageal carcinoma cells and inhibit tumor metastasis.
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Affiliation(s)
- Chao Zhou
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Jie Ma
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yuanhua Lu
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Wan Zhao
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Bingxue Xu
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Jian Lin
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yongjun Ma
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yafei Tian
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Qi Zhang
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Wei Wang
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Weiqun Yan
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Ping Jiao
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
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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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Melittin from Apis florea Venom as a Promising Therapeutic Agent for Skin Cancer Treatment. Antibiotics (Basel) 2020; 9:antibiotics9080517. [PMID: 32823904 PMCID: PMC7460526 DOI: 10.3390/antibiotics9080517] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 08/11/2020] [Accepted: 08/12/2020] [Indexed: 02/02/2023] Open
Abstract
Melittin, a major component found in bee venom, is produced by the Apis species of the honey bee. In this study, the effect of melittin derived from Apis florea (Mel-AF), which is a wild honey bee species that is indigenous to Thailand, was investigated against human malignant melanoma (A375) cells. In this study, Mel-AF exhibited considerable potential in the anti-proliferative action of A375 cells. Subsequently, the cellular mechanism of Mel-AF that induced cell death was investigated in terms of apoptosis. As a result, gene and protein expression levels, which indicated the activation of cytochrome-c release and caspase-9 expression, eventually triggered the release of the caspase-3 executioner upon Mel-AF. We then determined that apoptosis-mediated cell death was carried out through the intrinsic mitochondrial pathway. Moreover, advanced abilities, including cell motility and invasion, were significantly suppressed. Mel-AF manipulated the actin arrangement via the trapping of stress fibers that were found underneath the membrane, which resulted in the defective actin cytoskeleton organization. Consequently, the expression of EGFR, a binding protein to F-actin, was also found to be suppressed. This outcome strongly supports the effects of Mel-AF in the inhibition of progressive malignant activity through the disruption of actin cytoskeleton-EGFR interaction and the EGFR signaling system. Thus, the findings of our current study indicate the potential usefulness of Mel-AF in cancer treatments as an apoptosis inducer and a potential actin-targeting agent.
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Kim A, Lee SY, Kim BY, Chung SK. Elimination of Teratogenic Human Induced Pluripotent Stem Cells by Bee Venom via Calcium-Calpain Pathway. Int J Mol Sci 2020; 21:ijms21093265. [PMID: 32380745 PMCID: PMC7246707 DOI: 10.3390/ijms21093265] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 04/29/2020] [Accepted: 05/02/2020] [Indexed: 12/14/2022] Open
Abstract
Induced pluripotent stem cells (iPSCs) are regarded as a promising option for cell-based regenerative medicine. To obtain safe and efficient iPSC-based cell products, it is necessary to selectively eliminate the residual iPSCs prior to in vivo implantation due to the risk of teratoma formation. Bee venom (BV) has long been used in traditional Chinese medicine to treat inflammatory diseases and relieve pain, and has been shown to exhibit anti-cancer, anti-mutagenic, anti-nociceptive, and radioprotective activities. However, the potential benefits of BV in iPSC therapy, particularly its anti-teratoma activity, have not been examined. In this study, we found that BV selectively induced cell death in iPSCs, but not in iPSC-derived differentiated cells (iPSCs-Diff). BV rapidly disrupted cell membrane integrity and focal adhesions, followed by induction of apoptosis and necroptosis in iPSCs. We also found that BV remarkably enhanced intracellular calcium levels, calpain activation, and reactive oxygen speciesgeneration in iPSCs. BV treatment before in ovo grafting efficiently prevented iPSC-derived teratoma formation. In contrast, no DNA damage was observed in iPSCs-Diff following BV treatment, further demonstrating the safety of BV for use with iPSCs-Diff. Taken together, these findings show that BV has potent anti-teratoma activity by eliminating residual iPSCs, and can be used for the development of effective and safe iPSC-based cell therapies.
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Affiliation(s)
- Aeyung Kim
- Clinical Medicine Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea
- Correspondence: (A.K.); (S.-K.C.); Tel.: +82-42-868-9674 (A.K.); +82-42-868-9634 (S.-K.C.)
| | - Seo-Young Lee
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea; (S.-Y.L.); (B.-Y.K.)
| | - Bu-Yeo Kim
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea; (S.-Y.L.); (B.-Y.K.)
| | - Sun-Ku Chung
- Clinical Medicine Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea
- Correspondence: (A.K.); (S.-K.C.); Tel.: +82-42-868-9674 (A.K.); +82-42-868-9634 (S.-K.C.)
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Qi J, Chen Y, Xue T, Lin Y, Huang S, Cao S, Wang X, Su Y, Lin Z. Graphene oxide-based magnetic nanocomposites for the delivery of melittin to cervical cancer HeLa cells. NANOTECHNOLOGY 2020; 31:065102. [PMID: 31645027 DOI: 10.1088/1361-6528/ab5084] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Melittin (MEL), the primary active component of bee venom, has recently emerged as a promising cancer chemotherapeutic agent. However, the instability and rapid degradation of MEL is a significant challenge in practical therapeutic applications. In the present study, graphene oxide (GO)-based magnetic nanocomposites (PEG-GO-Fe3O4) were prepared and adopted as the drug delivery vehicles of MEL, and the anticancer effects of PEG-GO-Fe3O4/MEL complexes on human cervical cancer HeLa cells were studied. PEG-GO-Fe3O4 exhibited a series of unique physical and chemical properties resulting in multiple interactions with MEL, and ultimately the release of MEL. In vitro experiments showed that PEG-GO-Fe3O4/MEL not only distinctly enhanced the inhibition effect on HeLa cells, but also induced pore formation in the cell membrane that ultimately led to cell lysis. In this newly developed drug delivery system, PEGylated GO plays the role of a MEL protector while Fe3O4 nanoparticles act as magnetic responders; therefore active MEL can be released over a long period of time (up to 72 h) and maintain its inhibition effect on HeLa cells.
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Affiliation(s)
- Jinxia Qi
- Center of Scientific Research, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, People's Republic of China
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Yao J, Zhang Z, Li S, Li B, Wang XH. Melittin inhibits proliferation, migration and invasion of bladder cancer cells by regulating key genes based on bioinformatics and experimental assays. J Cell Mol Med 2019; 24:655-670. [PMID: 31691530 PMCID: PMC6933335 DOI: 10.1111/jcmm.14775] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 09/05/2019] [Accepted: 09/30/2019] [Indexed: 12/12/2022] Open
Abstract
The antitumour effect of melittin (MEL) has recently attracted considerable attention. Nonetheless, information regarding the functional role of MEL in bladder cancer (BC) is currently limited. Herein, we investigated the effect of MEL on critical module genes identified in BC. In total, 2015 and 4679 differentially expressed genes (DEGs) associated with BC were identified from the GSE31189 set and The Cancer Genome Atlas database, respectively. GSE‐identified DEGs were mapped and analysed using Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes analyses to determine BC‐involved crucial genes and signal pathways. Coupled with protein–protein interaction network and Molecular Complex Detection analyses, Modules 2 and 4 were highlighted in the progression of BC. In in‐vitro experiments, MEL inhibited the proliferation, migration, and invasion of UM‐UC‐3 and 5637 cells. The expression of NRAS, PAK2, EGFR and PAK1 in Module 4—enriched in the MAPK signalling pathway—was significantly reduced after treatment with MEL at concentrations of 4 or 6 μg/mL. Finally, quantitative reverse transcription‐polymerase chain reaction and Western blotting analyses revealed MEL inhibited the expression of genes at the mRNA (ERK1/2, ERK5, JNK and MEK5), protein (ERK5, MEK5, JNK and ERK1/2) and phosphorylation (p‐ERK1/2, p‐JNK, and p‐38) levels. This novel evidence indicates MEL exerts effects on the ERK5‐MAK pathway—a branch of MAPK signalling pathway. Collectively, these findings provide a theoretical basis for MEL application in BC treatment.
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Affiliation(s)
- Jie Yao
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zhan Zhang
- Department of Rehabilitation Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Sheng Li
- Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Bai Li
- Department of Rehabilitation Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Xing-Huan Wang
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China
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Tao W, Li Y, Zhu M, Li C, Li P. LncRNA NORAD Promotes Proliferation And Inhibits Apoptosis Of Gastric Cancer By Regulating miR-214/Akt/mTOR Axis. Onco Targets Ther 2019; 12:8841-8851. [PMID: 31802897 PMCID: PMC6826994 DOI: 10.2147/ott.s216862] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 09/20/2019] [Indexed: 12/14/2022] Open
Abstract
PURPOSE In previous studies, we confirmed that the overexpression of lncRNA NORAD was associated with the occurrence and development of gastric cancer (GC). The aim of the present study was to explore the molecular mechanism of lncRNA NORAD on GC cell proliferation and apoptosis in vitro and in vivo. PATIENTS AND METHODS The quantitative Real-Time PCR (qRT-PCR) was used to determine the expression levels of lncRNA NORAD and miR-214 in GC tissues and cells. The interaction between lncRNA NORAD and miR-214 was investigated by biological information and Dual-Luciferase gene reporter assay. Effect of lncRNA NORAD on GC tumor growth in vivo was studied in tumor xenograft model mice. The apoptosis of GC cells was determined by flow cytometry. The proliferation of GC cells was determined by 5-ethynyl-2´-deoxyuridine (EDU) and colony formation assays. Western Blot was used to determine the expressions of caspase-3, Akt and mTOR in GC tissues and cells. RESULTS The qRT-PCR results showed that lncRNA NORAD was highly expressed in human GC tissues and cell lines, while miR-214 was significantly down-regulated. Meanwhile, there was a direct interaction between lncRNA NORAD and miR-214. In addition, lncRNA NORAD could promote the growth and proliferation of GC cells both in vivo and in vitro. NOARD could also inhibit the apoptosis of GC cells by down-regulating caspase-3; however, miR-214 overexpression attenuated this effect. Moreover, lncRNA NORAD promoted the phosphorylation of Akt and mTOR in mouse GC tissues and GC cell lines, while miR-214 mimics inhibited that promotion. CONCLUSION These results suggested that NORAD could promote the development of GC by inhibiting miR-214 expression and activating the Akt/mTOR signaling pathway.
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Affiliation(s)
- Wei Tao
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan City, Ningxia750004, People’s Republic of China
| | - Yajun Li
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan City, Ningxia750004, People’s Republic of China
| | - Meng Zhu
- Department of Gastroenterology, Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi710049, People’s Republic of China
| | - Cheng Li
- Department of Gastroenterology, Pingluo County People’s Hospital, Shizuishan City, Ningxia753400, People’s Republic of China
| | - Peng Li
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan City, Ningxia750004, People’s Republic of China
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Soliman C, Eastwood S, Truong VK, Ramsland PA, Elbourne A. The membrane effects of melittin on gastric and colorectal cancer. PLoS One 2019; 14:e0224028. [PMID: 31622415 PMCID: PMC6797111 DOI: 10.1371/journal.pone.0224028] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 10/03/2019] [Indexed: 01/30/2023] Open
Abstract
The cytotoxic effects of melittin, a bee-venom peptide, have been widely studied towards cancer cells. Typically, these studies have examined the effect of melittin over extended-time courses (6-24 hours), meaning that immediate cellular interactions have been overlooked. In this work, we demonstrate the rapid effects of melittin on both gastric and colorectal cancer, specifically AGS, COLO205 and HCT-15 cell lines, over a period of 15 minutes. Melittin exhibited a dose dependent effect at 4 hours of treatment, with complete cellular death occurring at the highest dose of 20 μg/mL. Interestingly, when observed at shorter time points, melittin induced cellular changes within seconds; membrane damage was observed as swelling, breakage or blebbing. High-resolution imaging revealed treated cells to be compromised, showing clear change in cellular morphology. After 1 minute of melittin treatment, membrane changes were observed, and intracellular material could be seen expelled from the cells. Overall, these results enhance our understanding of the fast acting anti-cancer effects of melittin.
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Affiliation(s)
- Caroline Soliman
- School of Science, RMIT University, Bundoora West Campusm Bundoora, Victoria, Australia
| | - Sarah Eastwood
- School of Science, RMIT University, Bundoora West Campusm Bundoora, Victoria, Australia
| | - Vi Khanh Truong
- School of Science, RMIT University, Bundoora West Campusm Bundoora, Victoria, Australia
- Nanobiotechnology Laboratory, RMIT University, Melbourne City Campus, Melbourne, Victoria, Australia
| | - Paul A. Ramsland
- School of Science, RMIT University, Bundoora West Campusm Bundoora, Victoria, Australia
- Department of Immunology, Central Clinical School (Monash University), Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia
- Department of Surgery Austin Health (University of Melbourne), Austin Health, Heidelberg, Victoria, Australia
| | - Aaron Elbourne
- School of Science, RMIT University, Bundoora West Campusm Bundoora, Victoria, Australia
- Nanobiotechnology Laboratory, RMIT University, Melbourne City Campus, Melbourne, Victoria, Australia
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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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Combination of Sodium Selenite and Doxorubicin Prodrug Ac-Phe-Lys-PABC-ADM Affects Gastric Cancer Cell Apoptosis in Xenografted Mice. BIOMED RESEARCH INTERNATIONAL 2019; 2019:2486783. [PMID: 31531348 PMCID: PMC6720824 DOI: 10.1155/2019/2486783] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 07/11/2019] [Indexed: 01/17/2023]
Abstract
The incidence of gastric cancer is extremely high in China, prompting the development of effective therapeutic strategies. Sodium selenite (SS) affects the proliferation and redifferentiation of gastric cancer cells and the Adriamycin prodrug Ac-Phe-Lys-PABC-ADM (PADM) reduces toxicity in gastric cancer treatment. However, the mechanisms involved therein remain unclear. In this study, nude mice were transplanted with SGC-7901 gastric cancer cells to construct a tumor xenograft model. After administration of SS and PADM, tumor weight and size were reduced. In addition, the levels of alanine aminotransferase, aspartate transaminase, creatinine, and lactate dehydrogenase were decreased, indicating improved hepatic and renal function and inhibited cancer cell metabolism. Furthermore, combined treatment of SS and PADM downregulated the expression of cell cycle-related proteins (cyclin-dependent kinase 4, Ki67, cyclin E, and cyclin D1), elevated that of proapoptosis proteins (Bax, cleaved caspase-3, cleaved caspase-9, and P53), and upregulated that of mitochondrial apoptosis-associated proteins (apoptotic protease activating factor 1 and second mitochondria-derived activator of caspases). In conclusion, combined treatment of SS and PADM effectively promoted apoptosis in gastric cancer xenografts via the mitochondrial apoptosis pathway.
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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: 56] [Impact Index Per Article: 9.3] [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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Ramírez-Rivera S, Bernal G. Music Is Capable of Inducing Changes in Gene Expression in Gastric Cancer Cells. J Gastrointest Cancer 2019; 50:175-180. [PMID: 30632030 DOI: 10.1007/s12029-019-00203-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE Music has recognized beneficial effects on cancer patients; however, very little is known about the molecular processes which produce these benefits. The aim of this work was to evaluate the effect of music on proliferation and gene expression in gastric cancer cells. METHODS AGS gastric cancer cells were exposed to metal and classical music, and subsequently cell proliferation and expression of genes associated with apoptosis and cell-cycle control were evaluated. RESULTS Proliferation of AGS cells increased when exposed to metal music, but not when exposed to classical music. Gene expression of caspase-3 and 8 and cyclin B1 increased in response to both musical genres; classical music repressed the expression of p53, and metal music repressed the expression of PUMA. CONCLUSIONS This is the first study to demonstrate music as a modulator of gene expression in a cancer cell line. Additional experiments are required to better understand the mechanisms of how different musical genres can induce changes in gene expression.
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Affiliation(s)
- Sebastián Ramírez-Rivera
- Laboratory of Molecular and Cellular Biology of Cancer, Department of Biomedical Sciences, Faculty of Medicine, Universidad Católica del Norte, Coquimbo, Chile
| | - Giuliano Bernal
- Laboratory of Molecular and Cellular Biology of Cancer, Department of Biomedical Sciences, Faculty of Medicine, Universidad Católica del Norte, Coquimbo, Chile.
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