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Espinosa-Bustos C, Bertrand J, Villegas-Menares A, Guerrero S, Di Marcotullio L, Navacci S, Schulte G, Kozielewicz P, Bloch N, Villela V, Paulino M, Kogan MJ, Cantero J, Salas CO. New Smoothened ligands based on the purine scaffold as potential agents for treating pancreatic cancer. Bioorg Chem 2024; 151:107681. [PMID: 39106711 DOI: 10.1016/j.bioorg.2024.107681] [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: 03/28/2024] [Revised: 06/27/2024] [Accepted: 07/27/2024] [Indexed: 08/09/2024]
Abstract
Aberrant activation of the Hedgehog (Hh) signalling pathway has been associated with the development and progression of pancreatic cancer. For this reason, blockade of Hh pathway by inhibitors targeting the G protein-coupled receptor Smoothened (SMO) has been considered as a therapeutic target for the treatment of this cancer. In our previous work, we obtained a new SMO ligand based on a purine scaffold (compound I), which showed interesting antitumor activity in several cancer cell lines. In this work, we report the design and synthesis of 17 new purine derivatives, some of which showed high cytotoxic effect on Mia-PaCa-2 (Hh-dependent pancreatic cancer cell lines) and low toxicity on non-neoplastic HEK-293 cells compared with gemcitabine, such as 8f, 8g and 8h (IC50 = 4.56, 4.11 and 3.08 μM, respectively). Two of these purines also showed their ability to bind to SMO through NanoBRET assays (pKi = 5.17 for 8f and 5.01 for 8h), with higher affinities to compound I (pKi = 1.51). In addition, docking studies provided insight the purine substitution pattern is related to the affinity on SMO. Finally, studies of Hh inhibition for selected purines, using a transcriptional functional assay based on luciferase activity in NIH3T3 Shh-Light II cells, demonstrated that 8g reduced GLI activity with a IC50 = 6.4 μM as well as diminished the expression of Hh target genes in two specific Hh-dependent cell models, Med1 cells and Ptch1-/- mouse embryonic fibroblasts. Therefore, our results provide a platform for the design of SMO ligands that could be potential selective cytotoxic agents for the treatment of pancreatic cancer.
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Affiliation(s)
- Christian Espinosa-Bustos
- Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, 702843 Santiago, Chile
| | - Jeanluc Bertrand
- Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, 702843 Santiago, Chile
| | - Alondra Villegas-Menares
- Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, 702843 Santiago, Chile
| | - Simón Guerrero
- Facultad de Medicina, Universidad de Atacama, 153601 Copiapó, Chile
| | - Lucia Di Marcotullio
- Department of Molecular Medicine, Faculty Pharmacy and Medicine, Sapienza University, 00161 Rome, Italy; Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University, 00161 Rome, Italy
| | - Shirin Navacci
- Department of Molecular Medicine, Faculty Pharmacy and Medicine, Sapienza University, 00161 Rome, Italy
| | - Gunnar Schulte
- Department of Physiology and Pharmacology, Karolinska Institute, 17165 Solna, Stockholm, Sweden
| | - Pawel Kozielewicz
- Department of Physiology and Pharmacology, Karolinska Institute, 17165 Solna, Stockholm, Sweden
| | - Nicolas Bloch
- Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, 702843 Santiago, Chile
| | - Valentina Villela
- Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, 702843 Santiago, Chile
| | - Margot Paulino
- Departamento DETEMA, Facultad de Química, Universidad de la República, 11800 Montevideo, Uruguay
| | - Marcelo J Kogan
- Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, 8380492 Santiago, Chile; Advanced Center of Chronic Diseases (ACCDiS), Universidad de Chile, 8380492 Santiago, Chile
| | - Jorge Cantero
- Departamento DETEMA, Facultad de Química, Universidad de la República, 11800 Montevideo, Uruguay
| | - Cristian O Salas
- Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, 702843 Santiago, Chile.
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Stouffer M, Wandling E, Dickson L, Lin S, Duan H, Powe E, Jean‐Louis D, Tiwari AK, Amos S. Gedunin modulates cellular growth and apoptosis in glioblastoma cell lines. Cancer Rep (Hoboken) 2024; 7:e2051. [PMID: 38702989 PMCID: PMC11069102 DOI: 10.1002/cnr2.2051] [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: 11/17/2023] [Revised: 02/23/2024] [Accepted: 03/05/2024] [Indexed: 05/06/2024] Open
Abstract
BACKGROUND Glioblastomas are characterized by aggressive behavior. Surgery, radiotherapy, and alkylating agents, including temozolomide are the most common treatment options for glioblastoma. Often, conventional therapies fail to treat these tumors since they develop drug resistance. There is a need for newer agents to combat this deadly tumor. Natural products such as gedunin have shown efficacy in several human diseases. A comprehensive study of gedunin, an heat shock protein (HSP)90 inhibitor, has not been thoroughly investigated in glioblastoma cell lines with different genetic modifications. AIMS A key objective of this study was to determine how gedunin affects the biological and signaling mechanisms in glioblastoma cells, and to determine how those mechanisms affect the proliferation and apoptosis of glioblastoma cells. METHODS The viability potentials of gedunin were tested using MTT, cell counts, and wound healing assays. Gedunin's effects on glioma cells were further validated using LDH and colony formation assays. In addition, we investigated the survival and apoptotic molecular signaling targets perturbed by gedunin using Western blot analysis and flow cytometry. RESULTS Our results show that there was a reduction in cell viability and inhibition of wound healing in the cells tested. Western blot analysis of the gene expression data revealed genes such as EGFR and mTOR/Akt/NF kappa B to be associated with gedunin sensitivity. Gedunin treatment induced apoptosis by cleaving poly ADP-ribose polymerase, activating caspases, and downregulating BCL-xL. Based on these results, gedunin suppressed cell growth and HSP client proteins, resulting in apoptosis in glioblastoma cell lines. CONCLUSION Our data provide in vitro support for the anticancer activity of gedunin in glioma cells by downregulating cancer survival proteins.
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Affiliation(s)
- Michael Stouffer
- Department of Pharmaceutical SciencesCedarville University School of Pharmacy, Cedarville UniversityCedarvilleOhioUSA
| | - Elizabeth Wandling
- Department of Pharmaceutical SciencesCedarville University School of Pharmacy, Cedarville UniversityCedarvilleOhioUSA
| | - Lindsay Dickson
- Department of Pharmaceutical SciencesCedarville University School of Pharmacy, Cedarville UniversityCedarvilleOhioUSA
| | - Stacy Lin
- Department of Pharmaceutical SciencesCedarville University School of Pharmacy, Cedarville UniversityCedarvilleOhioUSA
| | - Huanyun Duan
- Department of Pharmaceutical SciencesCedarville University School of Pharmacy, Cedarville UniversityCedarvilleOhioUSA
| | - Erika Powe
- Department of Pharmaceutical SciencesCedarville University School of Pharmacy, Cedarville UniversityCedarvilleOhioUSA
| | - Denise Jean‐Louis
- Department of Pharmaceutical SciencesCedarville University School of Pharmacy, Cedarville UniversityCedarvilleOhioUSA
| | - Amit K. Tiwari
- Department of Pharmaceutical SciencesCollege of Pharmacy, University of Arkansas for Medical SciencesLittle RockArkansasUSA
| | - Samson Amos
- Department of Pharmaceutical SciencesCedarville University School of Pharmacy, Cedarville UniversityCedarvilleOhioUSA
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Zhang W, Dong Y, Sun C. Gedunin induces apoptosis and inhibits HMBG1/PI3K/AKT signaling pathways in a rat model of gastric carcinogenesis induced by methylnitronitrosoguanidine. Arch Med Sci 2024; 20:691-697. [PMID: 38757023 PMCID: PMC11094822 DOI: 10.5114/aoms/183651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 02/03/2024] [Indexed: 05/18/2024] Open
Abstract
Introduction This study aimed to evaluate the anti-cancer effects of gedunin, a natural compound, in a rat model of gastric carcinogenesis induced by MNNG. Methods Fifty-four rats were randomly assigned to six groups for a 60-day study on the effects of MNNG and gedunin. Groups 1-4 received 200 mg/kg MNNG (1, 10, or 100 mg/kg), and group 5 had only 100 mg/kg gedunin. Results Gedunin at low doses exhibited anti-cancer and protective properties against MNNG-induced damage, including reduced inflammation, and apoptosis. Conclusions Gedunin demonstrates a U-shaped dose-response, with low doses offering protection and high doses promoting tumor growth.
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Affiliation(s)
- Weixiang Zhang
- Department of General Surgery, Yantai Hospital of Traditional Chinese Medicine, Yantai, Shandong, China
| | - Yongshuai Dong
- Department of General Surgery, Yantai Hospital of Traditional Chinese Medicine, Yantai, Shandong, China
| | - Chenkun Sun
- Department of General Surgery, Yantai Hospital of Traditional Chinese Medicine, Yantai, Shandong, China
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Fakhri S, Moradi SZ, Faraji F, Kooshki L, Webber K, Bishayee A. Modulation of hypoxia-inducible factor-1 signaling pathways in cancer angiogenesis, invasion, and metastasis by natural compounds: a comprehensive and critical review. Cancer Metastasis Rev 2024; 43:501-574. [PMID: 37792223 DOI: 10.1007/s10555-023-10136-9] [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: 08/17/2023] [Accepted: 09/07/2023] [Indexed: 10/05/2023]
Abstract
Tumor cells employ multiple signaling mediators to escape the hypoxic condition and trigger angiogenesis and metastasis. As a critical orchestrate of tumorigenic conditions, hypoxia-inducible factor-1 (HIF-1) is responsible for stimulating several target genes and dysregulated pathways in tumor invasion and migration. Therefore, targeting HIF-1 pathway and cross-talked mediators seems to be a novel strategy in cancer prevention and treatment. In recent decades, tremendous efforts have been made to develop multi-targeted therapies to modulate several dysregulated pathways in cancer angiogenesis, invasion, and metastasis. In this line, natural compounds have shown a bright future in combating angiogenic and metastatic conditions. Among the natural secondary metabolites, we have evaluated the critical potential of phenolic compounds, terpenes/terpenoids, alkaloids, sulfur compounds, marine- and microbe-derived agents in the attenuation of HIF-1, and interconnected pathways in fighting tumor-associated angiogenesis and invasion. This is the first comprehensive review on natural constituents as potential regulators of HIF-1 and interconnected pathways against cancer angiogenesis and metastasis. This review aims to reshape the previous strategies in cancer prevention and treatment.
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Affiliation(s)
- Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, 6734667149, Iran
| | - Seyed Zachariah Moradi
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, 6734667149, Iran
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, 6734667149, Iran
| | - Farahnaz Faraji
- Department of Pharmaceutics, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Leila Kooshki
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, 6714415153, Iran
| | - Kassidy Webber
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, 5000 Lakewood Ranch Boulevard, Bradenton, FL, 34211, USA
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, 5000 Lakewood Ranch Boulevard, Bradenton, FL, 34211, USA.
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Nagini S, Palrasu M, Bishayee A. Limonoids from neem (Azadirachta indica A. Juss.) are potential anticancer drug candidates. Med Res Rev 2024; 44:457-496. [PMID: 37589457 DOI: 10.1002/med.21988] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 07/06/2023] [Accepted: 08/06/2023] [Indexed: 08/18/2023]
Abstract
Neem (Azadirachta indica A. Juss.), a versatile evergreen tree recognized for its ethnopharmacological value, is a rich source of limonoids of the triterpenoid class, endowed with potent medicinal properties. Extracts of neem have been documented to display anticancer effects in diverse malignant cell lines as well as in preclinical animal models that has largely been attributed to the constituent limonoids. Of late, neem limonoids have become the cynosure of research attention as potential candidate agents for cancer prevention and therapy. Among the various limonoids found in neem, azadirachtin, epoxyazadiradione, gedunin, and nimbolide, have been extensively investigated for anticancer activity. Azadirachtin, a potent biodegradable pesticide, exhibits profound antiproliferative effects by preventing mitotic spindle formation and cell division. The antiproliferative activity of gedunin has been demonstrated to be mediated primarily via inhibition of heat shock protein90 and its client proteins. Epoxyazadiradione inhibits pro-inflammatory and kinase-driven signaling pathways to block tumorigenesis. Nimbolide, the most potent cytotoxic neem limonoid, inhibits the growth of cancer cells by regulating the phosphorylation of keystone kinases that drive oncogenic signaling besides modulating the epigenome. There is overwhelming evidence to indicate that neem limonoids exert anticancer effects by preventing the acquisition of hallmark traits of cancer, such as cell proliferation, apoptosis evasion, inflammation, invasion, angiogenesis, and drug resistance. Neem limonoids are value additions to the armamentarium of natural compounds that target aberrant oncogenic signaling to inhibit cancer development and progression.
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Affiliation(s)
- Siddavaram Nagini
- Department of Biochemistry & Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, Tamil Nadu, India
| | - Manikandan Palrasu
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, USA
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, Florida, USA
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Hasan A, Khamjan N, Lohani M, Mir SS. Targeted Inhibition of Hsp90 in Combination with Metformin Modulates Programmed Cell Death Pathways in A549 Lung Cancer Cells. Appl Biochem Biotechnol 2023; 195:7338-7378. [PMID: 37000353 DOI: 10.1007/s12010-023-04424-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/14/2023] [Indexed: 04/01/2023]
Abstract
The pathophysiology of lung cancer is dependent on the dysregulation in the apoptotic and autophagic pathways. The intricate link between apoptosis and autophagy through shared signaling pathways complicates our understanding of how lung cancer pathophysiology is regulated. As drug resistance is the primary reason behind treatment failure, it is crucial to understand how cancer cells may respond to different therapies and integrate crosstalk between apoptosis and autophagy in response to them, leading to cell death or survival. Thus, in this study, we have tried to evaluate the crosstalk between autophagy and apoptosis in A549 lung cancer cell line that could be modulated by employing a combination therapy of metformin (6 mM), an anti-diabetic drug, with gedunin (12 µM), an Hsp90 inhibitor, to provide insights into the development of new cancer therapeutics. Our results demonstrated that metformin and gedunin were cytotoxic to A549 lung cancer cells. Combination of metformin and gedunin generated ROS and promoted MMP loss and DNA damage. The combination further increased the expression of AMPKα1 and promoted the nuclear localization of AMPKα1/α2. The expression of Hsp90 was downregulated, further decreasing the expression of its clients, EGFR, PIK3CA, AKT1, and AKT3. Inhibition of the EGFR/PI3K/AKT pathway upregulated TP53 and inhibited autophagy. The combination was promoting nuclear localization of p53; however, some cytoplasmic signals were also detected. Further increase in the expression of caspase 9 and caspase 3 was observed. Thus, we concluded that the combination of metformin and gedunin upregulates apoptosis by inhibiting the EGFR/PI3K/AKT pathway and autophagy in A549 lung cancer cells.
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Affiliation(s)
- Adria Hasan
- Molecular Cell Biology Laboratory, Integral Information and Research Centre-4 (IIRC-4), Integral University, Kursi Road, Lucknow, 226026, India
- Department of Bioengineering, Faculty of Engineering, Integral University, Kursi Road, Lucknow, 226026, India
- Current Address: Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Nizar Khamjan
- Department of Medical Laboratories Technology, College of Applied Medical Sciences, Jazan University, Jazan, 45142, Kingdom of Saudi Arabia
| | - Mohtashim Lohani
- Medical Research Center, Faculty of Applied Medical Sciences, Jazan University, Jazan, Kingdom of Saudi Arabia
- Emergency Medical Services, Faculty of Applied Medical Sciences, Jazan University, Jazan, Kingdom of Saudi Arabia
| | - Snober S Mir
- Molecular Cell Biology Laboratory, Integral Information and Research Centre-4 (IIRC-4), Integral University, Kursi Road, Lucknow, 226026, India.
- Department of Biosciences, Faculty of Science, Integral University, Kursi Road, Lucknow, 226026, India.
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Wang X, Li M, Yin J, Fang J, Ying Y, Ye T, Zhang F, Ma S, Qin H, Liu X. Emetine dihydrochloride alleviated radiation-induced lung injury through inhibiting EMT. J Cell Mol Med 2023; 27:3839-3850. [PMID: 37723905 PMCID: PMC10718159 DOI: 10.1111/jcmm.17959] [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: 06/10/2023] [Revised: 08/22/2023] [Accepted: 09/01/2023] [Indexed: 09/20/2023] Open
Abstract
Radiation-induced lung injury (RILI), divided into early radiation pneumonia (RP) and late radiation-induced pulmonary fibrosis (RIPF), is a common serious disease after clinical chest radiotherapy or nuclear accident, which seriously threatens the life safety of patients. There has been no effective prevention or treatment strategy till now. Epithelial-mesenchymal transition (EMT) is a key step in the occurrence and development of RILI. In this study, we demonstrated that emetine dihydrochloride (EDD) alleviated RILI through inhibiting EMT. We found that EDD significantly attenuated EMT-related markers, reduced Smad3 phosphorylation expression after radiation. Then, for the first time, we observed EDD alleviated lung hyperaemia and reduced collagen deposit induced by irradiation, providing protection against RILI. Finally, it was found that EDD inhibited radiation-induced EMT in lung tissues. Our study suggested that EDD alleviated RILI through inhibiting EMT by blocking Smad3 signalling pathways. In summary, our results indicated that EDD is a novel potential radioprotector for RILI.
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Affiliation(s)
- Xin Wang
- Key Laboratory of Radiobiology (Ministry of Health), School of Public HealthJilin UniversityChangchunChina
- Department of NeurologyThe Third Hospital of Jilin UniversityChangchunChina
| | - Mo Li
- Department of Thyroid SurgeryThe Second Hospital of Jilin UniversityChangchunChina
| | - Jizhong Yin
- Department of Radiation Medicine, Faculty of Naval MedicineNaval Medical UniversityShanghaiChina
| | - Jiayan Fang
- School of Public Health and ManagementWenzhou Medical UniversityWenzhouChina
| | - Yimeng Ying
- School of Public Health and ManagementWenzhou Medical UniversityWenzhouChina
| | - Tianxia Ye
- School of Public Health and ManagementWenzhou Medical UniversityWenzhouChina
| | - Fangxiao Zhang
- School of Public Health and ManagementWenzhou Medical UniversityWenzhouChina
| | - Shumei Ma
- School of Public Health and ManagementWenzhou Medical UniversityWenzhouChina
| | - Hongran Qin
- Department of Nuclear Radiation, Shanghai Pulmonary Hospital, School of MedicineTongji UniversityShanghaiChina
| | - Xiaodong Liu
- Key Laboratory of Radiobiology (Ministry of Health), School of Public HealthJilin UniversityChangchunChina
- School of Public Health and ManagementWenzhou Medical UniversityWenzhouChina
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Mehmetoglu-Gurbuz T, Lakshmanaswamy R, Perez K, Sandoval M, Jimenez CA, Rocha J, Goldfarb RM, Perry C, Bencomo A, Neela N, Barragan JA, Sanchez R, Swain RM, Subramani R. Nimbolide Inhibits SOD2 to Control Pancreatic Ductal Adenocarcinoma Growth and Metastasis. Antioxidants (Basel) 2023; 12:1791. [PMID: 37891871 PMCID: PMC10604165 DOI: 10.3390/antiox12101791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 09/13/2023] [Accepted: 09/14/2023] [Indexed: 10/29/2023] Open
Abstract
Reactive oxygen species are frequently associated with various cancers including pancreatic ductal adenocarcinomas (PDACs). Superoxide dismutase 2 (SOD2) is an enzyme that plays an important role in reactive oxygen species (ROS) signaling. Investigating the molecular function and biological functions of SOD2 can help us develop new therapeutic options and uncover new biomarkers for PDAC diagnosis and prognosis. Here, we show that nimbolide (NB), a triterpene limonoid, effectively blocks the growth and metastasis of PDACs by suppressing the expression and activity of SOD2. To identify the role of SOD2 in NB-induced anticancer activity, we used RNA interference to silence and plasmid transfection to overexpress it. Silencing SOD2 significantly reduced the growth and metastatic characteristics like epithelial-to-mesenchymal transition, invasion, migration, and colony-forming capabilities of PDACs, and NB treatment further reduced these characteristics. Conversely, the overexpression of SOD2 enhanced these metastatic characteristics. ROS signaling has a strong feedback mechanism with the PI3K/Akt signaling pathway, which could be mediated through SOD2. Finally, NB treatment to SOD2-overexpressing PDAC xenografts resulted in significant inhibition of tumor growth and metastasis. Overall, this work suggests that NB, a natural and safe phytochemical that silences SOD2 to induce high levels of ROS generation, results in increased apoptosis and reduced growth and progression of PDACs. The role of SOD2 in regulating NB-induced ROS generation presents itself as a therapeutic option for PDACs.
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Affiliation(s)
- Tugba Mehmetoglu-Gurbuz
- Center of Emphasis in Cancer Research, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
| | - Rajkumar Lakshmanaswamy
- Center of Emphasis in Cancer Research, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
- Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
| | - Karla Perez
- Center of Emphasis in Cancer Research, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
| | - Mayra Sandoval
- Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
| | - Casandra A. Jimenez
- Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
| | - Jackelyn Rocha
- Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
| | - Rachel Madeline Goldfarb
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
| | - Courtney Perry
- Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
| | - Alejandra Bencomo
- Center of Emphasis in Cancer Research, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
| | - Nishkala Neela
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
| | - Jose A. Barragan
- Center of Emphasis in Cancer Research, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
| | - Raquel Sanchez
- Center of Emphasis in Cancer Research, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
| | - Risa Mia Swain
- Center of Emphasis in Cancer Research, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
| | - Ramadevi Subramani
- Center of Emphasis in Cancer Research, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
- Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
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Chandel S, Singh R, Gautam A, Ravichandiran V. Screening of Azadirachta indica phytoconstituents as GSK-3β inhibitor and its implication in neuroblastoma: molecular docking, molecular dynamics, MM-PBSA binding energy, and in-vitro study. J Biomol Struct Dyn 2022; 40:12827-12840. [PMID: 34569452 DOI: 10.1080/07391102.2021.1977705] [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] [Indexed: 02/07/2023]
Abstract
Glycogen synthase kinase-3 (GSK-3), a constitutively active serine/threonine kinase, primary regulator of various cellular activities varying from glycogen metabolism to cell proliferation and regulation. GSK-3β is associated with the pathogenesis of numerous human diseases, including cancer, metabolic disorder, and Alzheimer's disease. In this study, Azadirachta indica compounds were selected and further screened on the BOILED-Egg model. The compounds showing good GIT absorption were docked with the crystal structure of GSK-3β. The compounds with high docking score were submitted for the molecular dynamic simulation (MDS) and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA). Based upon the MDS and MM-PBSA study, gedunin showed the highest binding energy throughout the MDS process. Gedunin was isolated from the Azadirachta indica, and its efficacy on GSK-3β inhibition was studied in the human neuroblastoma (SH-SY5Y) cells. Gedunin induced apoptosis and anti-proliferative activity by arresting G2/M phase, as evident by cell-cycle analysis. From immunoblot study, gedunin significantly enhanced the expression of an inhibitory form of GSK-3β (p-GSK-3β Ser9) in concentration-dependent manner. Our findings demonstrate that gedunin may act as an effective GSK-3β inhibitor suggesting that this compound may be used for the management of neuroblastoma. Further preclinical and clinical investigation is desirable.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Shivani Chandel
- Department of Natural Products, National Institute of Pharmaceutical Education and Research, Kolkata, India
| | - Rajveer Singh
- Department of Natural Products, National Institute of Pharmaceutical Education and Research, Kolkata, India
| | - Anupam Gautam
- Institute for Bioinformatics and Medical Informatics, University of Tübingen, Tübingen, Germany.,International Max Planck Research School "From Molecules to Organisms", Max Planck Institute for Developmental Biology, Tübingen, Germany
| | - Velayutham Ravichandiran
- Department of Natural Products, National Institute of Pharmaceutical Education and Research, Kolkata, India
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Feng Z, Zhu S, Li W, Yao M, Song H, Wang RB. Current approaches and strategies to identify Hedgehog signaling pathway inhibitors for cancer therapy. Eur J Med Chem 2022; 244:114867. [DOI: 10.1016/j.ejmech.2022.114867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 10/19/2022] [Accepted: 10/19/2022] [Indexed: 11/30/2022]
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Zhou H, Li F, Li Y. Anti-Cancer Activity of Gedunin by Induction of Apoptosis in Human Gastric Cancer AGS Cells. Appl Biochem Biotechnol 2022; 194:5322-5332. [PMID: 35759172 DOI: 10.1007/s12010-022-04001-8] [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] [Accepted: 05/27/2022] [Indexed: 11/02/2022]
Abstract
Currently, gastric cancer is considered one of the major causes of high mortality and morbidity worldwide. Recent advances in therapeutics, clinical treatment, staging procedures, and imaging techniques are high, yet the prevalence of gastric cancer has not been reduced. Usage of the synthetic drug has many side effects that can lead to other ailments. Gedunin, a phytochemical derived from Azadirachta indica (neem tree), exhibits several pharmacological activities including antitumor, anti-inflammatory, antiulcer, antipyretics, antibacterial, antifungal, anti-diabetic, and antimalarial properties. In the current investigation, the effect of gedunin on the cell viability; reactive oxygen species (ROS) generation by DCFH-DA staining; mitochondrial membrane potential (MMP) by Rh-123 staining; apoptosis by AO/EtBr staining; cell migration and wound healing ability by wound scratch assay; and Bcl-2, Bax, caspase-3, and caspase-9 by ELISA techniques were analyzed in the AGS cells. The treatment with gedunin effectively inhibited the cell viability with IC50 = 20µM, increased the ROS generation, and triggered the apoptosis in AGS cells. The gedunin-treated AGS cells also demonstrated a decreased MMP status. The increment in the ROS generation leads to oxidative stress which in turn induce the apoptosis. The activity of Bax gene was upregulated and the activity of Bcl-2 gene was down-regulated in the AGS cells after the treatment with gedunin. In the AGS cells treated with gedunin, the caspase-3 and caspase-9 activities were increased. In overall, these findings suggested that gedunin can be used as a potent chemotherapeutic agent in the future to treat gastric cancer.
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Affiliation(s)
- Heying Zhou
- Department of General Surgery, Jiyang District People's Hospital, No. 17, Xinyuan Road, Jiyang District, 251400, Ji Nan City, China
| | - Fengxia Li
- College of Health, Binzhou Polytechnic, No. 919, Huanghe 12th Road, 256603, Binzhou City, China
| | - Yanli Li
- College of Health, Binzhou Polytechnic, No. 919, Huanghe 12th Road, 256603, Binzhou City, China.
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12
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Luo J, Sun Y, Li Q, Kong L. Research progress of meliaceous limonoids from 2011 to 2021. Nat Prod Rep 2022; 39:1325-1365. [PMID: 35608367 DOI: 10.1039/d2np00015f] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Covering: July 2010 to December 2021Limonoids, a kind of natural tetranortriterpenoids with diverse skeletons and valuable insecticidal and medicinal bioactivities, are the characteristic metabolites of most plants of the Meliaceae family. The chemistry and bioactivities of meliaceous limonoids are a continuing hot area of natural products research; to date, about 2700 meliaceous limonoids have been identified. In particular, more than 1600, including thirty kinds of novel rearranged skeletons, have been isolated and identified in the past decade due to their wide distribution and abundant content in Meliaceae plants and active biosynthetic pathways. In addition to the discovery of new structures, many positive medicinal bioactivities of meliaceous limonoids have been investigated, and extensive achievements regarding the chemical and biological synthesis have been made. This review summarizes the recent research progress in the discovery of new structures, medicinal and agricultural bioactivities, and chem/biosynthesis of limonoids from the plants of the Meliaceae family during the past decade, with an emphasis on the discovery of limonoids with novel skeletons, the medicinal bioactivities and mechanisms, and chemical synthesis. The structures, origins, and bioactivities of other new limonoids were provided as ESI. Studies published from July 2010 to December 2021 are reviewed, and 482 references are cited.
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Affiliation(s)
- Jun Luo
- Jiangsu Key Laboratory of Bioactive Natural Product Research, State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
| | - Yunpeng Sun
- Jiangsu Key Laboratory of Bioactive Natural Product Research, State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
| | - Qiurong Li
- Jiangsu Key Laboratory of Bioactive Natural Product Research, State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
| | - Lingyi Kong
- Jiangsu Key Laboratory of Bioactive Natural Product Research, State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
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13
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Sankaran H, Negi S, McShane LM, Zhao Y, Krushkal J. Pharmacogenomics of in vitro response of the NCI-60 cancer cell line panel to Indian natural products. BMC Cancer 2022; 22:512. [PMID: 35525914 PMCID: PMC9077913 DOI: 10.1186/s12885-022-09580-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 04/20/2022] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Indian natural products have been anecdotally used for cancer treatment but with limited efficacy. To better understand their mechanism, we examined the publicly available data for the activity of Indian natural products in the NCI-60 cell line panel. METHODS We examined associations of molecular genomic features in the well-characterized NCI-60 cancer cell line panel with in vitro response to treatment with 75 compounds derived from Indian plant-based natural products. We analyzed expression measures for annotated transcripts, lncRNAs, and miRNAs, and protein-changing single nucleotide variants in cancer-related genes. We also examined the similarities between cancer cell line response to Indian natural products and response to reference anti-tumor compounds recorded in a U.S. National Cancer Institute (NCI) Developmental Therapeutics Program database. RESULTS Hierarchical clustering based on cell line response measures identified clustering of Phyllanthus and cucurbitacin products with known anti-tumor agents with anti-mitotic mechanisms of action. Curcumin and curcuminoids mostly clustered together. We found associations of response to Indian natural products with expression of multiple genes, notably including SLC7A11 involved in solute transport and ATAD3A and ATAD3B encoding mitochondrial ATPase proteins, as well as significant associations with functional single nucleotide variants, including BRAF V600E. CONCLUSION These findings suggest potential mechanisms of action and novel associations of in vitro response with gene expression and some cancer-related mutations that increase our understanding of these Indian natural products.
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Affiliation(s)
- Hari Sankaran
- Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rockville, MD, 20850, USA.
| | - Simarjeet Negi
- Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rockville, MD, 20850, USA
| | - Lisa M McShane
- Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rockville, MD, 20850, USA
| | - Yingdong Zhao
- Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rockville, MD, 20850, USA
| | - Julia Krushkal
- Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rockville, MD, 20850, USA.
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14
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Wang GK, Sun YP, Jin WF, Yu Y, Zhu JY, Liu JS. Limonoids from Swietenia macrophylla and their antitumor activities in A375 human malignant melanoma cells. Bioorg Chem 2022; 123:105780. [PMID: 35395448 DOI: 10.1016/j.bioorg.2022.105780] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 03/26/2022] [Accepted: 03/29/2022] [Indexed: 11/02/2022]
Abstract
Swietelinins A - C (1-3) and swieteliacates F - R (4-16), sixteen new limonoids and 18 known limonoids (17-34) were isolated from Swietenia macrophylla. The absolute configurations of these compounds were defined by using a combination of electronic circular dichroism data analysis and single-crystal X-ray diffraction data. Swieteliacate J (10) is the first limonoid possessing an unusual 8β, 9β-epoxy ring system. All of the compounds were tested for cytotoxicity against four human tumor cell lines (SMMC-7721, SW620, A549, and A375). Compounds 10, 11, and 19 exhibited selectively moderate cytotoxicity against four tumor cell lines, especially 19 exhibited significant cytotoxic effects against A375 with IC50 an value of 9.8 μM and was more active than the positive control, dacarbazine with an IC50 value of 22.4 μM. Compound 19 effectively induced apoptosis of A375, which was associated with G2/M-phase cell cycle arrest. Flow cytometric analysis showed that the treatment by 19 significantly induced A375 cell apoptosis in a dose-dependent manner.
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Affiliation(s)
- Guo-Kai Wang
- School of Pharmacy, Anhui University of Chinese Medicine, Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei 230012, PR China.
| | - Yun-Peng Sun
- School of Pharmacy, Anhui University of Chinese Medicine, Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei 230012, PR China
| | - Wen-Fang Jin
- School of Pharmacy, Anhui University of Chinese Medicine, Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei 230012, PR China
| | - Yang Yu
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, PR China
| | - Jian-Yong Zhu
- Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, PR China.
| | - Jin-Song Liu
- School of Pharmacy, Anhui University of Chinese Medicine, Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei 230012, PR China.
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15
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Triantafillidis JK, Triantafyllidi E, Sideris M, Pittaras T, Papalois AE. Herbals and Plants in the Treatment of Pancreatic Cancer: A Systematic Review of Experimental and Clinical Studies. Nutrients 2022; 14:619. [PMID: 35276978 PMCID: PMC8839014 DOI: 10.3390/nu14030619] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/27/2022] [Accepted: 01/27/2022] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Pancreatic cancer represents the most lethal malignancy among all digestive cancers. Despite the therapeutic advances achieved during recent years, the prognosis of this neoplasm remains disappointing. An enormous amount of experimental (mainly) and clinical research has recently emerged referring to the effectiveness of various plants administered either alone or in combination with chemotherapeutic agents. Apart from Asian countries, the use of these plants and herbals in the treatment of digestive cancer is also increasing in a number of Western countries as well. The aim of this study is to review the available literature regarding the efficacy of plants and herbals in pancreatic cancer. METHODS The authors have reviewed all the experimental and clinical studies published in Medline and Embase, up to June 2021. RESULTS More than 100 plants and herbals were thoroughly investigated. Favorable effects concerning the inhibition of cancer cell lines in the experimental studies and a favorable clinical outcome after combining various plants with established chemotherapeutic agents were observed. These herbals and plants exerted their activity against pancreatic cancer via a number of mechanisms. The number and severity of side-effects are generally of a mild degree. CONCLUSION A quite high number of clinical and experimental studies confirmed the beneficial effect of many plants and herbals in pancreatic cancer. More large, double-blind clinical studies assessing these natural products, either alone or in combination with chemotherapeutic agents should be conducted.
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Affiliation(s)
- John K. Triantafillidis
- GI Department, Metropolitan General Hospital, 15562 Holargos, Greece;
- Hellenic Society of Gastrointestinal Oncology, 354, Iera Odos Street, Haidari, 12461 Athens, Greece;
| | - Eleni Triantafyllidi
- Hellenic Society of Gastrointestinal Oncology, 354, Iera Odos Street, Haidari, 12461 Athens, Greece;
| | - Michail Sideris
- Women’s Health Research Unit, Queen Mary University of London, London E1 2AB, UK;
| | - Theodoros Pittaras
- Hematology Laboratory-Blood Bank, Aretaieion Hospital, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece;
| | - Apostolos E. Papalois
- Hellenic Society of Gastrointestinal Oncology, 354, Iera Odos Street, Haidari, 12461 Athens, Greece;
- Special Unit for Biomedical Research and Education, School of Medicine, Aristotle University of Thessaloniki, 60 El. Venizelou Street, Aghia Paraskevi, 15341 Athens, Greece
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16
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Gupta S, Kumar A, Tejavath KK. A pharmacognostic approach for mitigating pancreatic cancer: emphasis on herbal extracts and phytoconstituents. FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES 2021. [DOI: 10.1186/s43094-021-00246-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Abstract
Background
Pancreatic cancer is studied as one of the most lethal cancers with currently no control of its lethality, mainly due to its late diagnosis and lack of foolproof treatment processes. Despite continuous efforts being made in looking for therapies to deal with cancer, it keeps on being a labyrinth for the researchers. Efforts like discovering new treatment options, repurposing existing drugs, are continuously made to deal with this cancer.
Main body
With the urge to get answers and the fact that nature has all roots of therapeutics, efforts are made in the direction of finding those answers for providing ministrations for pancreatic cancer from plant products. Plant products are used as treatment options either directly in the form of extracts or an alternative to them is individual phytochemicals that are either isolated from the plants or are commercially synthesized for various purposes. In this review, we put forward such pharmacognostic initiatives made in combating pancreatic cancer, focusing mainly on plant extracts and various phytochemicals; along with the mechanisms which they triggered to fulfill the need for cytotoxicity to pancreatic cancer cells (in vitro and in vivo).
Conclusion
This study will thus provide insights into new combination therapy that can be used and also give a clue on which plant product and phytoconstituent can be used in dealing with pancreatic cancer.
Graphical abstract
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17
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Sulforaphane inhibits self-renewal of lung cancer stem cells through the modulation of sonic Hedgehog signaling pathway and polyhomeotic homolog 3. AMB Express 2021; 11:121. [PMID: 34424425 PMCID: PMC8382806 DOI: 10.1186/s13568-021-01281-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 08/13/2021] [Indexed: 12/24/2022] Open
Abstract
Sulforaphane (SFN), an active compound in cruciferous vegetables, has been characterized by its antiproliferative capacity. We investigated the role and molecular mechanism through which SFN regulates proliferation and self-renewal of lung cancer stem cells. CD133+ cells were isolated with MACs from lung cancer A549 and H460 cells. In this study, we found that SFN inhibited the proliferation of lung cancer cells and self-renewal of lung cancer stem cells simultaneously. Meanwhile, the mRNA and protein expressions of Shh, Smo, Gli1 and PHC3 were highly activated in CD133+ lung cancer cells. Compared with siRNA-control group, Knock-down of Shh inhibited proliferation of CD133+ lung cancer cells, and decreased the protein expression of PHC3 in CD133+ lung cancer cells. Knock-down of PHC3 also affected the proliferation and decreased the Shh expression level in CD133+ lung cancer cells. In addition, SFN inhibited the activities of Shh, Smo, Gli1 and PHC3 in CD133+ lung cancer cells. Furthermore, the inhibitory effect of SFN on the proliferation of siRNA-Shh and siRNA-PHC3 cells was weaker than that on the proliferation of siRNA-control cells. Sonic Hedgehog signaling pathway might undergo a cross-talk with PHC3 in self-renewal of lung cancer stem cells. SFN might be an effective new drug which could inhibit self-renewal of lung cancer stem cells through the modulation of Sonic Hedgehog signaling pathways and PHC3. This study could provide a novel way to improve therapeutic efficacy for lung cancer stem cells.
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18
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Janthamala S, Jusakul A, Kongpetch S, Kimawaha P, Klanrit P, Loilome W, Namwat N, Techasen A. Arctigenin inhibits cholangiocarcinoma progression by regulating cell migration and cell viability via the N-cadherin and apoptosis pathway. Naunyn Schmiedebergs Arch Pharmacol 2021; 394:2049-2059. [PMID: 34283274 DOI: 10.1007/s00210-021-02123-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 07/02/2021] [Indexed: 12/28/2022]
Abstract
Northeast Thailand has the highest incidence of cholangiocarcinoma (CCA) in the world. The lack of promising diagnostic markers and appropriate therapeutic drugs is the main problem for metastatic stage CCA patients who have a poor prognosis. N-cadherin, a cell adhesion molecule, is usually upregulated in cancers and has been proposed as an important mediator in epithelial-mesenchymal transition (EMT), one of the metastasis processes. Additionally, it has been shown that arctigenin, a seed isolated compound from Arctium lappa, can inhibit cancer cell progression via suppression of N-cadherin pathway. In this study, we investigated the protein expression of N-cadherin and its correlation with clinicopathological data of CCA patients, as well as the impact of arctigenin on KKU-213A and KKU-100 CCA cell lines and its underlying mechanisms. Immunohistochemistry results demonstrated that high expression of N-cadherin was significantly associated with severe CCA stage (p = 0.027), and shorter survival time (p = 0.002) of CCA patients. The mean overall survival times between low and high expression of N-cadherin were 31.6 and 14.8 months, respectively. Wound healing assays showed that arctigenin significantly inhibited CCA cell migration by downregulating N-cadherin whereas upregulating E-cadherin expression. Immunocytochemical staining revealed that arctigenin suppressed the expression of N-cadherin in both CCA cell lines. Furthermore, flow cytometry and western blot analysis revealed that arctigenin significantly reduced CCA cell viability and induced apoptosis via the Bax/Bcl-2/caspase-3 pathway. This research supports the use of N-cadherin as a prognostic marker for CCA and arctigenin as a potential alternative therapy for improving CCA treatment outcomes.
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Affiliation(s)
- Sutthiwan Janthamala
- Biomedical Sciences Program, Graduate School, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Apinya Jusakul
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Sarinya Kongpetch
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Phongsaran Kimawaha
- Biomedical Sciences Program, Graduate School, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Poramate Klanrit
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Watcharin Loilome
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Nisana Namwat
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Anchalee Techasen
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand.
- Department of Clinical Microbiology, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand.
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19
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Exploring the Crosstalk between Inflammation and Epithelial-Mesenchymal Transition in Cancer. Mediators Inflamm 2021; 2021:9918379. [PMID: 34220337 PMCID: PMC8219436 DOI: 10.1155/2021/9918379] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 05/31/2021] [Indexed: 02/07/2023] Open
Abstract
Tumor cells undergo invasion and metastasis through epithelial-to-mesenchymal cell transition (EMT) by activation of alterations in extracellular matrix (ECM) protein-encoding genes, enzymes responsible for the breakdown of ECM, and activation of genes that drive the transformation of the epithelial cell to the mesenchymal type. Inflammatory cytokines such as TGFβ, TNFα, IL-1, IL-6, and IL-8 activate transcription factors such as Smads, NF-κB, STAT3, Snail, Twist, and Zeb that drive EMT. EMT drives primary tumors to metastasize in different parts of the body. T and B cells, dendritic cells (DCs), and tumor-associated macrophages (TAMs) which are present in the tumor microenvironment induce EMT. The current review elucidates the interaction between EMT tumor cells and immune cells under the microenvironment. Such complex interactions provide a better understanding of tumor angiogenesis and metastasis and in defining the aggressiveness of the primary tumors. Anti-inflammatory molecules in this context may open new therapeutic options for the better treatment of tumor progression. Targeting EMT and the related mechanisms by utilizing natural compounds may be an important and safe therapeutic alternative in the treatment of tumor growth.
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Sahai R, Bhattacharjee A, Shukla VN, Yadav P, Hasanain M, Sarkar J, Narender T, Mitra K. Gedunin isolated from the mangrove plant Xylocarpus granatum exerts its anti-proliferative activity in ovarian cancer cells through G2/M-phase arrest and oxidative stress-mediated intrinsic apoptosis. Apoptosis 2021; 25:481-499. [PMID: 32399945 DOI: 10.1007/s10495-020-01605-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Gedunin is a natural tetranorterpenoid secondary metabolite found in plants of the Meliaceae family, which has been reported for its antiparasitic, antifungal and anticancer activities. Here, we describe the molecular mechanisms underlying the in vitro anti proliferative activity of gedunin (isolated from the mangrove plant Xylocarpus granatum) in human ovarian cancer cells. We observed that gedunin triggered severe ROS generation leading to DNA damage and cell cycle arrest in G2/M phase thus inhibiting cell proliferation. ROS upregulation also led to mitochondrial stress and membrane depolarization, which eventually resulted in mitochondria-mediated apoptosis following cytochrome C release, caspase 9, 3 activation, and PARP cleavage. Transmission electron microscopy of gedunin treated cells revealed sub-cellular features typical of apoptosis. Moreover, an upregulation in stress kinases like phospho-ERK 1/2, phospho-p38 and phospho-JNK was also observed in gedunin treated cells. Free radical scavenger N-Acetyl-L-Cysteine (NAC) reversed all these effects resulting in increased cell survival, abrogation of cell cycle arrest, rescue of mitochondrial membrane potential and suppression of apoptotic markers. Interestingly, gedunin is also an inhibitor of the evolutionarily conserved molecular chaperone Heat Shock Protein 90 (hsp90) responsible for maintaining cellular homeostasis. Targeting this chaperone could be an attractive strategy for developing cancer therapeutics since many oncogenic proteins are also client proteins of hsp90. Collectively, our findings provide insights into the molecular mechanism of action of gedunin, which may aid drug development efforts against ovarian cancer.
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Affiliation(s)
- Rohit Sahai
- Electron Microscopy Unit, Sophisticated Analytical Instrument Facility and Research, CSIR - Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow, Uttar Pradesh, 226 031, India
| | - Arindam Bhattacharjee
- Electron Microscopy Unit, Sophisticated Analytical Instrument Facility and Research, CSIR - Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow, Uttar Pradesh, 226 031, India
| | - Vishwa Nath Shukla
- Medicinal and Process Chemistry Division, CSIR - Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow, Uttar Pradesh, 226 031, India
| | - Pragya Yadav
- Medicinal and Process Chemistry Division, CSIR - Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow, Uttar Pradesh, 226 031, India.,Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201 002, India
| | - Mohammad Hasanain
- Division of Biochemistry, CSIR - Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow, Uttar Pradesh, 226 031, India.,Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201 002, India
| | - Jayanta Sarkar
- Division of Biochemistry, CSIR - Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow, Uttar Pradesh, 226 031, India.,Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201 002, India
| | - T Narender
- Medicinal and Process Chemistry Division, CSIR - Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow, Uttar Pradesh, 226 031, India.,Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201 002, India
| | - Kalyan Mitra
- Electron Microscopy Unit, Sophisticated Analytical Instrument Facility and Research, CSIR - Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow, Uttar Pradesh, 226 031, India. .,Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201 002, India.
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21
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Sandhir R, Khurana M, Singhal NK. Potential benefits of phytochemicals from Azadirachta indica against neurological disorders. Neurochem Int 2021; 146:105023. [PMID: 33753160 DOI: 10.1016/j.neuint.2021.105023] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 03/12/2021] [Accepted: 03/14/2021] [Indexed: 12/16/2022]
Abstract
Azadirachta indica or Neem has been extensively used in the Indian traditional medical system because of its broad range of medicinal properties. Neem contains many chemically diverse and structurally complex phytochemicals such as limonoids, flavonoids, phenols, catechins, gallic acid, polyphenols, nimbins. These phytochemicals possess vast array of therapeutic activities that include anti-feedant, anti-viral, anti-malarial, anti-bacterial, anti-cancer properties. In recent years, many phytochemicals from Neem have been shown to be beneficial against various neurological disorders like Alzheimer's and Parkinson's disease, mood disorders, ischemic-reperfusion injury. The neuroprotective effects of the phytochemicals from Neem are primarily mediated by their anti-oxidant, anti-inflammatory and anti-apoptotic activities along with their ability to modulate signaling pathways. However, extensive studies are still required to fully understand the molecular mechanisms involved in neuropotective effects of phytochemicals from Neem. This review is an attempt to cover the neuroprotective properties of various phytochemicals from Neem along with their mechanism of action so that the potential of the compounds could be realized to reduce the burden of neurodegenerative diseases.
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Affiliation(s)
- Rajat Sandhir
- Department of Biochemistry, Basic Medical Science Block-II, Panjab University, Chandigarh, 160014, India.
| | - Mehak Khurana
- Department of Biochemistry, Basic Medical Science Block-II, Panjab University, Chandigarh, 160014, India
| | - Nitin Kumar Singhal
- National Agri-Food Biotechnology Institute (NABI) Sector-81 (Knowledge City), PO Manauli, S.A.S. Nagar, Mohali, 140306, Punjab, India
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22
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Thakur G, Kumar R, Kim SB, Lee SY, Lee SL, Rho GJ. Therapeutic Status and Available Strategies in Pancreatic Ductal Adenocarcinoma. Biomedicines 2021; 9:biomedicines9020178. [PMID: 33670230 PMCID: PMC7916947 DOI: 10.3390/biomedicines9020178] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/03/2021] [Accepted: 02/08/2021] [Indexed: 02/06/2023] Open
Abstract
One of the most severe and devastating cancer is pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the major pancreatic exocrine cancer with a poor prognosis and growing prevalence. It is the most deadly disease, with an overall five-year survival rate of 6% to 10%. According to various reports, it has been demonstrated that pancreatic cancer stem cells (PCSCs) are the main factor responsible for the tumor development, proliferation, resistance to anti-cancer drugs, and recurrence of tumors after surgery. PCSCs have encouraged new therapeutic methods to be explored that can specifically target cancer cells. Furthermore, stem cells, especially mesenchymal stem cells (MSCs), are known as influential anti-cancer agents as they function through anti-inflammatory, paracrine, cytokines, and chemokine's action. The properties of MSCs, such as migration to the site of infection and host immune cell activation by its secretome, seem to control the microenvironment of the pancreatic tumor. MSCs secretome exhibits similar therapeutic advantages as a conventional cell-based therapy. Moreover, the potential for drug delivery could be enhanced by engineered MSCs to increase drug bioactivity and absorption at the tumor site. In this review, we have discussed available therapeutic strategies, treatment hurdles, and the role of different factors such as PCSCs, cysteine, GPCR, PKM2, signaling pathways, immunotherapy, and NK-based therapy in pancreatic cancer.
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Affiliation(s)
- Gitika Thakur
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Raj Kumar
- Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Solan 173 234, Himachal Pradesh, India;
| | - Saet-Byul Kim
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Sang-Yeob Lee
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Sung-Lim Lee
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Gyu-Jin Rho
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
- Correspondence:
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Jeon HJ, Kim K, Kim C, Kim MJ, Kim TO, Lee SE. Molecular Mechanisms of Anti-Melanogenic Gedunin Derived from Neem Tree ( Azadirachta indica) Using B16F10 Mouse Melanoma Cells and Early-Stage Zebrafish. PLANTS 2021; 10:plants10020330. [PMID: 33572083 PMCID: PMC7914499 DOI: 10.3390/plants10020330] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/03/2021] [Accepted: 02/07/2021] [Indexed: 12/21/2022]
Abstract
Melanogenesis represents a series of processes that produce melanin, a protective skin pigment (against ultraviolet rays), and determines human skin color. Chemicals reducing melanin production have always been in demand in the cosmetic market because of skincare interests, such as whitening. The main mechanism for inhibiting melanin production is the inhibition of tyrosinase (TYR), a key enzyme for melanogenesis. Here, we evaluated gedunin (Ged), a representative limonoid, for its anti-melanogenesis action. Melanin production in vitro was stimulated by alpha-melanocyte stimulating hormone (α-MSH) in B16F10 mouse melanoma cells. Ged reduced α-MSH-stimulated melanin production, inhibiting TYR activity and protein amount. We confirmed this result in vivo in a zebrafish model for melanogenesis. There was no sign of toxicity and malformation of zebrafish embryos during development in all treated concentrations. Ged reduced the number of produced zebrafish embryo pigment dots and melanin contents of embryos. The highly active concentration of Ged (100 µM) was much lower than the positive control, kojic acid (8 mM). Hence, Ged could be a fascinating candidate for anti-melanogenesis reagents.
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Affiliation(s)
- Hwang-Ju Jeon
- Department of Applied Biosciences, Kyungpook National University, Daegu 41566, Korea; (H.-J.J.); (K.K.); (M.-J.K.)
| | - Kyeongnam Kim
- Department of Applied Biosciences, Kyungpook National University, Daegu 41566, Korea; (H.-J.J.); (K.K.); (M.-J.K.)
| | - Chaeeun Kim
- Department of Integrative Biology Kyungpook National University, Daegu 41566, Korea;
| | - Myoung-Jin Kim
- Department of Applied Biosciences, Kyungpook National University, Daegu 41566, Korea; (H.-J.J.); (K.K.); (M.-J.K.)
| | - Tae-Oh Kim
- College of Civil and Environmental Engineering, Kumoh National Institute of Technology, Gumi 39253, Korea;
- Department of Energy Engineering Convergence, Kumoh National Institute of Technology, Gumi 39177, Korea
- Department of Environmental Engineering, Kumoh National Institute of Technology, Gumi 39177, Korea
| | - Sung-Eun Lee
- Department of Applied Biosciences, Kyungpook National University, Daegu 41566, Korea; (H.-J.J.); (K.K.); (M.-J.K.)
- Department of Integrative Biology Kyungpook National University, Daegu 41566, Korea;
- Correspondence: ; Tel.: +82-53-950-7768; Fax: +82-53-953-7233
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Azadirachta indica MicroRNAs: Genome-Wide Identification, Target Transcript Prediction, and Expression Analyses. Appl Biochem Biotechnol 2021; 193:1924-1944. [PMID: 33523368 DOI: 10.1007/s12010-021-03500-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 01/07/2021] [Indexed: 10/22/2022]
Abstract
MicroRNAs are short, endogenous, non-coding RNAs, liable for essential regulatory function. Numerous miRNAs have been identified and studied in plants with known genomic or small RNA resources. Despite the availability of genomic and transcriptomic resources, the miRNAs have not been reported in the medicinal tree Azadirachta indica (Neem) till date. Here for the first time, we report extensive identification of miRNAs and their possible targets in A. indica which might help to unravel their therapeutic potential. A comprehensive search of miRNAs in the A. indica genome by C-mii tool was performed. Overall, 123 miRNAs classified into 63 families and their stem-loop hairpin structures were predicted. The size of the A. indica (ain)-miRNAs ranged between 19 and 23 nt in length, and their corresponding ain-miRNA precursor sequence MFEI value averaged as -1.147 kcal/mol. The targets of ain-miRNAs were predicted in A. indica as well as Arabidopsis thaliana plant. The gene ontology (GO) annotation revealed the involvement of ain-miRNA targets in developmental processes, transport, stress, and metabolic processes including secondary metabolism. Stem-loop qRT-PCR was carried out for 25 randomly selected ain-miRNAs and differential expression patterns were observed in different A. indica tissues. Expression of miRNAs and its targets shows negative correlation in a dependent manner.
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Azadirachta indica A. Juss. In Vivo Toxicity-An Updated Review. Molecules 2021; 26:molecules26020252. [PMID: 33419112 PMCID: PMC7825405 DOI: 10.3390/molecules26020252] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 12/30/2020] [Accepted: 01/03/2021] [Indexed: 01/12/2023] Open
Abstract
The Neem tree, Azadirachta indica A. Juss., is known for its large spectrum of compounds with biological and pharmacological interest. These include, among others, activities that are anticancer, antibacterial, antiviral, and anti-inflammatory. Some neem compounds are also used as insecticides, herbicides, and/or antifeedants. The safety of these compounds is not always taken into consideration and few in vivo toxicity studies have been performed. The current study is a literature review of the latest in vivo toxicity of A. indica. It is divided in two major sections-aquatic animals toxicity and mammalian toxicity-each related to neem's application as a pesticide or a potential new therapeutic drug, respectively.
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Ren Y, Kinghorn AD. Development of Potential Antitumor Agents from the Scaffolds of Plant-Derived Terpenoid Lactones. J Med Chem 2020; 63:15410-15448. [PMID: 33289552 PMCID: PMC7812702 DOI: 10.1021/acs.jmedchem.0c01449] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Naturally occurring terpenoid lactones and their synthetic derivatives have attracted increasing interest for their promising antitumor activity and potential utilization in the discovery and design of new antitumor agents. In the present perspective article, selected plant-derived five-membered γ-lactones and six-membered δ-lactones that occur with terpenoid scaffolds are reviewed, with their structures, cancer cell line cytotoxicity and in vivo antitumor activity, structure-activity relationships, mechanism of action, and the potential for developing cancer chemotherapeutic agents discussed in each case. The compounds presented include artemisinin (ART, 1), parthenolide (PTL, 2), thapsigargin (TPG, 3), andrographolide (AGL, 4), ginkgolide B (GKL B, 5), jolkinolide B (JKL B, 6), nagilactone E (NGL E, 7), triptolide (TPL, 8), bruceantin (BRC, 9), dichapetalin A (DCT A, 10), and limonin (LMN, 11), and their naturally occurring analogues and synthetic derivatives. It is hoped that this contribution will be supportive of the future development of additional efficacious anticancer agents derived from natural products.
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Affiliation(s)
- Yulin Ren
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States
| | - A. Douglas Kinghorn
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States
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Subramani R, Medel J, Flores K, Perry C, Galvez A, Sandoval M, Rivera S, Pedroza DA, Penner E, Chitti M, Lakshmanaswamy R. Hepatocyte nuclear factor 1 alpha influences pancreatic cancer growth and metastasis. Sci Rep 2020; 10:20225. [PMID: 33214606 PMCID: PMC7678871 DOI: 10.1038/s41598-020-77287-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 10/26/2020] [Indexed: 12/14/2022] Open
Abstract
Hepatocyte nuclear factor 1 homeobox alpha (HNF1α) is a transcription factor involved in endodermal organogenesis and pancreatic precursor cell differentiation and development. Earlier studies have reported a role for HNF1α in pancreatic ductal adenocarcinoma (PDAC) but it is controversial. The mechanism by which it impacts PDAC is yet to be explored in depth. In this study, using the online databases we observed that HNF1α is upregulated in PDAC, which was also confirmed by our immunohistochemical analysis of PDAC tissue microarray. Silencing HNF1α reduced the proliferative, migratory, invasive and colony forming capabilities of pancreatic cancer cells. Key markers involved in these processes (pPI3K, pAKT, pERK, Bcl2, Zeb, Snail, Slug) were significantly changed in response to alterations in HNF1α expression. On the other hand, overexpression of HNF1α did not induce any significant change in the aggressiveness of pancreatic cancer cells. Our results demonstrate that reduced expression of HNF1α leads to inhibition of pancreatic cancer growth and progression, which indicates that it could be a potential oncogene and target for PDAC.
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Affiliation(s)
- Ramadevi Subramani
- Center of Emphasis in Cancer Research, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, Paul L. Foster School of Medicine, El Paso, TX, 79905, USA. .,Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA.
| | - Joshua Medel
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA.,Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Kristina Flores
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA
| | - Courtney Perry
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA
| | - Adriana Galvez
- Center of Emphasis in Cancer Research, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, Paul L. Foster School of Medicine, El Paso, TX, 79905, USA
| | - Mayra Sandoval
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA
| | - Servando Rivera
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA
| | - Diego A Pedroza
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA
| | - Elizabeth Penner
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA.,Department of Pathology and Laboratory Medicine, McGovern Medical School, UT Health Science Center at Houston, Houston, TX, 77030, USA
| | - Mahika Chitti
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA
| | - Rajkumar Lakshmanaswamy
- Center of Emphasis in Cancer Research, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, Paul L. Foster School of Medicine, El Paso, TX, 79905, USA. .,Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA.
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Zhang QB, Ye RF, Ye LY, Zhang QY, Dai NG. Isocorydine decrease gemcitabine-resistance by inhibiting epithelial-mesenchymal transition via STAT3 in pancreatic cancer cells. Am J Transl Res 2020; 12:3702-3714. [PMID: 32774728 PMCID: PMC7407734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 06/04/2020] [Indexed: 06/11/2023]
Abstract
Gemcitabine is widely used as an anticancer chemotherapy drug for a variety of solid tumors, and it has become the standard treatment option for locally advanced and metastatic pancreatic cancer. However, pancreatic cancer cells develop resistance to gemcitabine after a few weeks of treatment, resulting in poor therapeutic effects. Isocorydine (ICD) is a typical natural aporphine alkaloid, and ICD and its derivatives inhibit the proliferation of many types of cancer cells in vitro. In this study, ICD was found to synergistically inhibit cell viability with gemcitabine in pancreatic cancer cells. A microarray analysis showed that ICD can inhibit the upregulation of STAT3 and EMT in pancreatic cancer cells induced by gemcitabine. STAT3 is closely related to tumor EMT, migration and invasion. After knocking down the expression of STAT3 in pancreatic cancer cells, the combination index (CI) of ICD and gemcitabine decreased. ICD can reverse the increase in the expression of EMT-related transcription factors and proteins caused by gemcitabine, thereby inhibiting the enhanced cell migration and invasion ability caused by gemcitabine. Finally, the synergistic treatment effect of the combination treatment of ICD and gemcitabine in pancreatic cancer cells was confirmed in established xenograft models.
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Affiliation(s)
- Quan-Bo Zhang
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical UniversityWenzhou, China
| | - Rui-Fan Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical UniversityWenzhou, China
| | - Long-Yun Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical UniversityWenzhou, China
| | - Qi-Yu Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical UniversityWenzhou, China
| | - Ning-Gao Dai
- Department of Traumatology, The First Affiliated Hospital of Wenzhou Medical UniversityWenzhou, China
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Hsp90 inhibitor gedunin causes apoptosis in A549 lung cancer cells by disrupting Hsp90:Beclin-1:Bcl-2 interaction and downregulating autophagy. Life Sci 2020; 256:118000. [PMID: 32585246 DOI: 10.1016/j.lfs.2020.118000] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 06/17/2020] [Accepted: 06/19/2020] [Indexed: 12/18/2022]
Abstract
AIMS Hsp90 is regarded as an important therapeutic target in cancer treatment. Client proteins of Hsp90 like Beclin-1, PI3K, and AKT, are associated with tumor development, poor prognosis, and resistance to cancer therapies. This study aims to analyze the role of Gedunin, an Hsp-90 inhibitor, in mediation of crosstalk between apoptosis and autophagy by targeting Beclin-1:Bcl-2 interaction, and ER stress. MAIN METHODS A549 cells were treated with different concentrations of gedunin, and inhibitory rate was evaluated by MTT assay. Effect of gedunin on generation of reactive oxygen species, mitochondrial membrane potential, and chromatin condensation was studied by staining methods like DCFH-DA, MitoTracker, and DAPI. Expression of EGFR, PIK3CA, AKT, marker genes for apoptosis and autophagy were studied using semi-quantitative RT-PCR. Interaction study of Hsp90:Beclin-1:Bcl-2 was done by immunoprecipitation analysis. Protein expression of autophagy and apoptosis markers along with Grp78, Hsp70, and Hsp90 was analyzed by immunoblotting. KEY FINDINGS Gedunin exerts cytotoxic effects, causes increase in ROS generation, downregulates mitochondrial membrane potential and induces loss in DNA integrity. mRNA expression analysis revealed that gedunin sensitized A549 cells towards apoptosis by downregulating EGFR, PIK3CA, AKT, and autophagy. Gedunin also inhibited interaction between Hsp90:Beclin-1:Bcl-2, leading to downregulation of autophagy (Beclin-1, Atg5-12 complex, and LC3) and antiapoptotic protein Bcl-2, which may result in ER stress-induced apoptosis. Moreover, Hsp90 inhibition by gedunin did not cause upregulation of Hsp70 expression. SIGNIFICANCE Gedunin induces apoptosis in lung cancer cells by disrupting Hsp90:Beclin-1:Bcl-2 interaction and autophagy downregulation, thus making gedunin a good drug lead for targeting lung cancer.
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Mazumdar S, Marar T, Patki J, Devarajan S, Zambare V, Swami D. In silico and in vitro analysis reveal multi-target anti-hyperglycaemic properties of gedunin, a limonoid from neem (Azadirachta indica). CLINICAL PHYTOSCIENCE 2020. [DOI: 10.1186/s40816-020-00175-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Abstract
Background
Insulin secretion and insulin related pathways have been the prime targets in the treatment of diabetes for a long time. However, recently a lot of attention is being directed towards addressing hyperglycaemia as the main perpetrator of the symptoms in this metabolic disorder. This new treatment approach also involves greater inclination to plant derived therapeutic agents for their safety and probable minimal side effects. The objective of the present study was to scientifically elucidate the potential of gedunin (a limonoid from Neem tree) as an anti-hyperglycaemic agent.
Methods
The effect of gedunin on pancreatic and salivary amylase activity and glucose transport across yeast cell membrane was tested at three different concentrations (5 μM, 10 μM and 20 μM) using known inhibitor acarbose as the standard. Multiple Ligand Simultaneous Docking was used to study the interaction of gedunin with salivary and pancreatic amylase and determine binding affinity and specificity of this interaction.
Results
The in vitro results documented a steady, linear pancreatic alpha amylase (ovine) inhibition in a concentration dependent manner with gedunin showing lower IC50 value of 20.25 μM against acarbose (IC50 = 31.12 μM) a known enzyme inhibitor used as standard in the present study. The inhibition of salivary amylase by gedunin was also distinct. Yeast cell glucose uptake studies revealed remarkable inhibition of glucose absorption at 10 μM and 20 μM concentration of gedunin (5.45% and 13.87% respectively with respect to control). Corroborating the in vitro findings even in the docking studies gedunin exhibited higher docking score (− 8.12 Kcal/mol) and higher enzyme inhibition potency (Ki = 1.12 μM) with human pancreatic amylase-substrate complex as compared to acarbose (docking score-5.24 Kcal/mol, Ki = 110.8 μM). The studies further suggested a non-competitive, mixed kind of inhibition by gedunin. As evident from this current in vitro study, gedunin had shown significant inhibition of alpha amylases and glucose uptake at much lower concentration (5, 10 and 20 μM) than previous studies where the concentrations used were (20.7–124.3 μM).
Conclusion
This study lays strong evidence to the rationale of gedunin being an important lead compound to developing a promising hyperglycaemic agent, simultaneously targeting glucose absorption in the intestine and enzymatic digestion of polysaccharides.
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31
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Braga TM, Rocha L, Chung TY, Oliveira RF, Pinho C, Oliveira AI, Morgado J, Cruz A. Biological Activities of Gedunin-A Limonoid from the Meliaceae Family. Molecules 2020; 25:E493. [PMID: 31979346 PMCID: PMC7037920 DOI: 10.3390/molecules25030493] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 01/16/2020] [Accepted: 01/20/2020] [Indexed: 12/12/2022] Open
Abstract
Gedunin is an important limonoid present in several genera of the Meliaceae family, mainly in seeds. Several biological activities have been attributed to gedunin, including antibacterial, insecticidal, antimalarial, antiallergic, anti-inflammatory, anticancer, and neuroprotective effects. The discovery of gedunin as a heat shock protein (Hsp) inhibitor represented a very important landmark for its application as a biological therapeutic agent. The current study is a critical literature review based on the several biological activities so far described for gedunin, its therapeutic effect on some human diseases, and future directions of research for this natural compound.
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Affiliation(s)
- Teresa M. Braga
- Centro de Investigação em Saúde e Ambiente, Escola Superior de Saúde, Instituto Politécnico do Porto, 4200-072 Porto, Portugal; (L.R.); (T.Y.C.); (R.F.O.); (C.P.); (A.I.O.)
| | - Lídia Rocha
- Centro de Investigação em Saúde e Ambiente, Escola Superior de Saúde, Instituto Politécnico do Porto, 4200-072 Porto, Portugal; (L.R.); (T.Y.C.); (R.F.O.); (C.P.); (A.I.O.)
| | - Tsz Yan Chung
- Centro de Investigação em Saúde e Ambiente, Escola Superior de Saúde, Instituto Politécnico do Porto, 4200-072 Porto, Portugal; (L.R.); (T.Y.C.); (R.F.O.); (C.P.); (A.I.O.)
| | - Rita F. Oliveira
- Centro de Investigação em Saúde e Ambiente, Escola Superior de Saúde, Instituto Politécnico do Porto, 4200-072 Porto, Portugal; (L.R.); (T.Y.C.); (R.F.O.); (C.P.); (A.I.O.)
| | - Cláudia Pinho
- Centro de Investigação em Saúde e Ambiente, Escola Superior de Saúde, Instituto Politécnico do Porto, 4200-072 Porto, Portugal; (L.R.); (T.Y.C.); (R.F.O.); (C.P.); (A.I.O.)
| | - Ana I. Oliveira
- Centro de Investigação em Saúde e Ambiente, Escola Superior de Saúde, Instituto Politécnico do Porto, 4200-072 Porto, Portugal; (L.R.); (T.Y.C.); (R.F.O.); (C.P.); (A.I.O.)
| | - Joaquim Morgado
- Bio4Life4You, 4460-170 Porto, Portugal;
- World Neem Organization, Mumbai 400101, India
| | - Agostinho Cruz
- Centro de Investigação em Saúde e Ambiente, Escola Superior de Saúde, Instituto Politécnico do Porto, 4200-072 Porto, Portugal; (L.R.); (T.Y.C.); (R.F.O.); (C.P.); (A.I.O.)
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Costa TEMM, Raghavendra NM, Penido C. Natural heat shock protein 90 inhibitors in cancer and inflammation. Eur J Med Chem 2020; 189:112063. [PMID: 31972392 DOI: 10.1016/j.ejmech.2020.112063] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 01/09/2020] [Accepted: 01/10/2020] [Indexed: 12/11/2022]
Abstract
Heat shock protein (HSP)90 is the most abundant HSPs, which are chaperone molecules whose major roles are cell protection and maintenance by means of aiding the folding, the stabilization and the remodeling of a wide range of proteins. A few hundreds of proteins depend on HSP90 chaperone activity, including kinases and transcriptional factors that play essential roles in cancer and inflammation, so that HSP90-targeted therapies have been considered as a potential strategy for the treatment of cancer and inflammatory-associated diseases. HSP90 inhibition by natural, semi-synthetic and synthetic compounds have yield promising results in pre-clinical studies and clinical trials for different types of cancers and inflammation. Natural products are a huge source of biologically active compounds widely used in drug development due to the great diversity of their metabolites which are capable to modulate several protein functions. HSP90 inhibitors have been isolated from bacteria, fungi and vegetal species. These natural compounds have a noteworthy ability to modulate HSP90 activity as well as serve as scaffolds for the development of novel synthetic or semi-synthetic inhibitors. Over a hundred clinical trials have evaluated the effect of HSP90 inhibitors as adjuvant treatment against different types of tumors and, currently, new studies are being developed to gain sight on novel promising and more effective approaches for cancer treatment. In this review, we present the naturally occurring HSP90 inhibitors and analogues, discussing their anti-cancer and anti-inflammatory effects.
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Affiliation(s)
- Thadeu E M M Costa
- Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation, Rio de Janeiro, 21040-361, Brazil; Laboratory of Applied Pharmacology, Institute of Drug Technology, Farmanguinhos, 21041-250, Rio de Janeiro, Brazil.
| | - Nulgumnalli Manjunathaiah Raghavendra
- Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation, Rio de Janeiro, 21040-361, Brazil; Department of Pharmaceutical Chemistry, Acharya and BM Reddy College of Pharmacy, Bengaluru, 560090, India.
| | - Carmen Penido
- Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation, Rio de Janeiro, 21040-361, Brazil; Laboratory of Applied Pharmacology, Institute of Drug Technology, Farmanguinhos, 21041-250, Rio de Janeiro, Brazil.
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Lee CH. Reversal of Epithelial-Mesenchymal Transition by Natural Anti-Inflammatory and Pro-Resolving Lipids. Cancers (Basel) 2019; 11:E1841. [PMID: 31766574 PMCID: PMC6966475 DOI: 10.3390/cancers11121841] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 11/16/2019] [Accepted: 11/19/2019] [Indexed: 02/08/2023] Open
Abstract
Epithelial mesenchymal transition (EMT) is a key process in the progression of malignant cancer. Therefore, blocking the EMT can be a critical fast track for the development of anticancer drugs. In this paper, we update recent research output of EMT and we explore suppression of EMT by natural anti-inflammatory compounds and pro-resolving lipids.
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Affiliation(s)
- Chang Hoon Lee
- College of Pharmacy, Dongguk University, Seoul 100-715, Korea
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Bickel D, Gohlke H. C-terminal modulators of heat shock protein of 90 kDa (HSP90): State of development and modes of action. Bioorg Med Chem 2019; 27:115080. [DOI: 10.1016/j.bmc.2019.115080] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 07/29/2019] [Accepted: 08/25/2019] [Indexed: 12/22/2022]
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Avila-Carrasco L, Majano P, Sánchez-Toméro JA, Selgas R, López-Cabrera M, Aguilera A, González Mateo G. Natural Plants Compounds as Modulators of Epithelial-to-Mesenchymal Transition. Front Pharmacol 2019; 10:715. [PMID: 31417401 PMCID: PMC6682706 DOI: 10.3389/fphar.2019.00715] [Citation(s) in RCA: 132] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Accepted: 06/05/2019] [Indexed: 12/13/2022] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) is a self-regulated physiological process required for tissue repair that, in non-controled conditions may lead to fibrosis, angiogenesis, loss of normal organ function or cancer. Although several molecular pathways involved in EMT regulation have been described, this process does not have any specific treatment. This article introduces a systematic review of effective natural plant compounds and their extract that modulates the pathological EMT or its deleterious effects, through acting on different cellular signal transduction pathways both in vivo and in vitro. Thereby, cryptotanshinone, resveratrol, oxymatrine, ligustrazine, osthole, codonolactone, betanin, tannic acid, gentiopicroside, curcumin, genistein, paeoniflorin, gambogic acid and Cinnamomum cassia extracts inhibit EMT acting on transforming growth factor-β (TGF-β)/Smads signaling pathways. Gedunin, carnosol, celastrol, black rice anthocyanins, Duchesnea indica, cordycepin and Celastrus orbiculatus extract downregulate vimectin, fibronectin and N-cadherin. Sulforaphane, luteolin, celastrol, curcumin, arctigenin inhibit β-catenin signaling pathways. Salvianolic acid-A and plumbagin block oxidative stress, while honokiol, gallic acid, piperlongumine, brusatol and paeoniflorin inhibit EMT transcription factors such as SNAIL, TWIST and ZEB. Plectranthoic acid, resveratrol, genistein, baicalin, polyphyllin I, cairicoside E, luteolin, berberine, nimbolide, curcumin, withaferin-A, jatrophone, ginsenoside-Rb1, honokiol, parthenolide, phoyunnanin-E, epicatechin-3-gallate, gigantol, eupatolide, baicalin and baicalein and nitidine chloride inhibit EMT acting on other signaling pathways (SIRT1, p38 MAPK, NFAT1, SMAD, IL-6, STAT3, AQP5, notch 1, PI3K/Akt, Wnt/β-catenin, NF-κB, FAK/AKT, Hh). Despite the huge amount of preclinical data regarding EMT modulation by the natural compounds of plant, clinical translation is poor. Additionally, this review highlights some relevant examples of clinical trials using natural plant compounds to modulate EMT and its deleterious effects. Overall, this opens up new therapeutic alternatives in cancer, inflammatory and fibrosing diseases through the control of EMT process.
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Affiliation(s)
- Lorena Avila-Carrasco
- Therapeutic and Pharmacology Department, Health and Human Science Research, Academic Unit of Human Medicine and Health Sciences, Autonomous University of Zacatecas, Zacatecas, Mexico
| | - Pedro Majano
- Molecular Biology Unit, Research Institute of University Hospital La Princesa (IP), Madrid, Spain
| | - José Antonio Sánchez-Toméro
- Department and Nephrology, Research Institute of University Hospital La Princesa (IP), Madrid, Spain.,Renal research network REDINREN, Madrid, Spain
| | - Rafael Selgas
- Research Institute of La Paz (IdiPAZ), University Hospital La Paz, Madrid, Spain.,Renal research network REDINREN, Madrid, Spain
| | - Manuel López-Cabrera
- Renal research network REDINREN, Madrid, Spain.,Molecular Biology Research Centre Severo Ochoa, Spanish Council for Scientific Research (CSIC), Madrid, Spain
| | - Abelardo Aguilera
- Molecular Biology Unit, Research Institute of University Hospital La Princesa (IP), Madrid, Spain.,Renal research network REDINREN, Madrid, Spain
| | - Guadalupe González Mateo
- Research Institute of La Paz (IdiPAZ), University Hospital La Paz, Madrid, Spain.,Renal research network REDINREN, Madrid, Spain.,Molecular Biology Research Centre Severo Ochoa, Spanish Council for Scientific Research (CSIC), Madrid, Spain
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Diamantopoulou E, Baxendale S, de la Vega de León A, Asad A, Holdsworth CJ, Abbas L, Gillet VJ, Wiggin GR, Whitfield TT. Identification of compounds that rescue otic and myelination defects in the zebrafish adgrg6 ( gpr126) mutant. eLife 2019; 8:44889. [PMID: 31180326 PMCID: PMC6598766 DOI: 10.7554/elife.44889] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 06/08/2019] [Indexed: 12/18/2022] Open
Abstract
Adgrg6 (Gpr126) is an adhesion class G protein-coupled receptor with a conserved role in myelination of the peripheral nervous system. In the zebrafish, mutation of adgrg6 also results in defects in the inner ear: otic tissue fails to down-regulate versican gene expression and morphogenesis is disrupted. We have designed a whole-animal screen that tests for rescue of both up- and down-regulated gene expression in mutant embryos, together with analysis of weak and strong alleles. From a screen of 3120 structurally diverse compounds, we have identified 68 that reduce versican b expression in the adgrg6 mutant ear, 41 of which also restore myelin basic protein gene expression in Schwann cells of mutant embryos. Nineteen compounds unable to rescue a strong adgrg6 allele provide candidates for molecules that may interact directly with the Adgrg6 receptor. Our pipeline provides a powerful approach for identifying compounds that modulate GPCR activity, with potential impact for future drug design.
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Affiliation(s)
- Elvira Diamantopoulou
- Bateson Centre and Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom
| | - Sarah Baxendale
- Bateson Centre and Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom
| | | | - Anzar Asad
- Bateson Centre and Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom
| | - Celia J Holdsworth
- Bateson Centre and Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom
| | - Leila Abbas
- Bateson Centre and Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom
| | - Valerie J Gillet
- Information School, University of Sheffield, Sheffield, United Kingdom
| | | | - Tanya T Whitfield
- Bateson Centre and Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom
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Dutta Gupta S, Bommaka MK, Banerjee A. Inhibiting protein-protein interactions of Hsp90 as a novel approach for targeting cancer. Eur J Med Chem 2019; 178:48-63. [PMID: 31176095 DOI: 10.1016/j.ejmech.2019.05.073] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 05/17/2019] [Accepted: 05/27/2019] [Indexed: 12/26/2022]
Abstract
The ninety kilo Dalton molecular weight heat shock protein (Hsp90) is an attractive target for the discovery of novel anticancer agents. Several strategies have been employed for the development of inhibitors against this polypeptide. The most successful strategy is targeting the N-terminal ATP binding region of the chaperone. However, till date not a single molecule reached Phase-IV of clinical trials from this class of Hsp90 inhibitors. The other approach is to target the Cterminal region of the protein. The success with this approach has been limited due to lack of well-defined ligand binding pocket in this terminal. The other promising strategy is to prevent the interaction of client proteins/co-chaperones with Hsp90 protein, i.e., protein-protein interaction inhibitors of Hsp90. The review focuses on advantage of this approach along with the recent advances in the discovery of inhibitors by following this strategy. Additionally, the biology of the client protein/co-chaperone binding site of Hsp90 is also discussed.
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Affiliation(s)
- Sayan Dutta Gupta
- Department of Pharmaceutical Chemistry, Gokaraju Rangaraju College of Pharmacy, Osmania University, Hyderabad, India.
| | - Manish Kumar Bommaka
- Department of Pharmaceutical Chemistry, Gokaraju Rangaraju College of Pharmacy, Osmania University, Hyderabad, India; School of Chemistry, University of Hyderabad, Hyderabad, India
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Hu YT, Li BF, Zhang PJ, Wu D, Li YY, Li ZW, Shen L, Dong B, Gao J, Zhu X. Dbx2 exhibits a tumor-promoting function in hepatocellular carcinoma cell lines via regulating Shh-Gli1 signaling. World J Gastroenterol 2019; 25:923-940. [PMID: 30833799 PMCID: PMC6397724 DOI: 10.3748/wjg.v25.i8.923] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 12/25/2018] [Accepted: 12/27/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. HCC patients suffer from a high mortality-to-incidence ratio and low cure rate since we still have no specific and effective treatment. Although tremendous advances have been made in the investigation of HCC, the specific mechanisms of the progression of this disease are still only partially established. Hence, more research is needed to elucidate the underlying potential mechanisms to develop effective strategies for HCC. AIM To determine the role of developing brain homeobox 2 (Dbx2) gene in promoting the development of HCC. METHODS Dbx2 expression in clinical specimens and HCC cell lines was detected by Western blot (WB) and immunohistochemistry. Gain and loss of Dbx2 function assays were performed in vitro and in vivo. Cell viability assays were used to investigate cell growth, flow cytometry was employed to assess cell cycle and apoptosis, and trans-well assays were conducted to evaluate cell migration, invasion, and metastasis. The expression of key molecules in the sonic hedgehog (Shh) signaling was determined by WB. RESULTS Compared to matched adjacent non-tumorous tissues, Dbx2 was overexpressed in 5 HCC cell lines and 76 surgically resected HCC tissues. Dbx2 overexpression was correlated with large tumor size. Both gain and loss of function assays indicated that Dbx2 promoted HCC cell proliferation by facilitating the transition from G1 to S phase, attenuating apoptosis and promoted HCC proliferation, migration, and invasion in vitro and in vivo. Mechanistically, Dbx2 modulated Shh signaling by enhancing FTCH1 and GLi1 expression in HCC cells that overexpressed Dbx2, which was reversed in HCC cells with Dbx2 knockdown. CONCLUSION Our results indicate that Dbx2 is significantly upregulated in HCC tissues and plays significant roles in proliferation and metastasis of HCC cells by activating the Shh pathway.
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Affiliation(s)
- Yan-Ting Hu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Bei-Fang Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Peng-Jun Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Di Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Yan-Yan Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | | | - Lin Shen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Bin Dong
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Jing Gao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Xu Zhu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital and Institute, Beijing 100142, China
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Moga MA, Bălan A, Anastasiu CV, Dimienescu OG, Neculoiu CD, Gavriș C. An Overview on the Anticancer Activity of Azadirachta indica (Neem) in Gynecological Cancers. Int J Mol Sci 2018; 19:ijms19123898. [PMID: 30563141 PMCID: PMC6321405 DOI: 10.3390/ijms19123898] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Revised: 12/02/2018] [Accepted: 12/03/2018] [Indexed: 12/17/2022] Open
Abstract
In recent years, a wide range of studies have pointed out the importance of nutraceuticals as reservoirs of therapeutic compounds for several diseases, including cancer. This study is centered on the role of some nutraceuticals as anticancer agents and on their efficiency in the oncological gynecological field. Gynecological cancers include cervical, ovarian, and breast neoplasia and these are the major causes of morbidity and mortality in the female population. Cervical neoplasia affects sexually active women aged between 30 and 40 years and is considered the second leading cause of death for women worldwide. Epidemiological studies have shown a strong association of this cancer with human papilloma virus (HPV) infection, independent of any others risk factors. Ovarian cancer represents about 4% of all women’s cancers and breast neoplasia registers 52.8 new cases per 100,000 women annually. Since ancient times, herbal therapies have shown a wide range of beneficial effects and a high potential for safeguarding human health. Azadirachta indica (Neem) is a medicinal plant of Indian origin, a tree with more of 140 isolated compounds and at least 35 biologically active principles that have shown an important influence as tumor suppressors by interfering with the carcinogenesis process. Used for centuries in Asia as a natural remedy for cancer, neem compounds present in bark, leaves, flowers, and seed oil have been shown to possess properties such as chemopreventive capacity, apoptotic activities, immunomodulatory effects, and induction of p53-independent apoptosis. The current study is a systematic literature review based on the anticarcinogenic potential of neem compounds in gynecological cancers.
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Affiliation(s)
- Marius Alexandru Moga
- Department of Medical and Surgical Specialties, Faculty of Medicine, Transilvania University of Brasov, 500019 Brasov, Romania.
| | - Andreea Bălan
- Department of Medical and Surgical Specialties, Faculty of Medicine, Transilvania University of Brasov, 500019 Brasov, Romania.
| | - Costin Vlad Anastasiu
- Department of Medical and Surgical Specialties, Faculty of Medicine, Transilvania University of Brasov, 500019 Brasov, Romania.
| | - Oana Gabriela Dimienescu
- Department of Medical and Surgical Specialties, Faculty of Medicine, Transilvania University of Brasov, 500019 Brasov, Romania.
| | - Carmen Daniela Neculoiu
- Department of Fundamental, Prophylactic and Clinical Sciences, Faculty of Medicine, University Transilvania Braşov, 500019 Brasov, Romania.
| | - Claudia Gavriș
- Department of Medical and Surgical Specialties, Faculty of Medicine, Transilvania University of Brasov, 500019 Brasov, Romania.
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Jian W, Bai Y, Li X, Kang J, Lei Y, Xue Y. Phosphatidylethanolamine‐binding protein 4 promotes the epithelial‐to‐mesenchymal transition in non–small cell lung cancer cells by activating the sonic hedgehog signaling pathway. J Cell Biochem 2018; 120:5386-5395. [PMID: 30367510 DOI: 10.1002/jcb.27817] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 09/12/2018] [Indexed: 12/24/2022]
Affiliation(s)
- Wen Jian
- Department of Respiratory Medicine The First Affiliated Hospital of the Fourth Military Medical University Xi'an China
| | - Yinlan Bai
- Department of Basic Microbiology The Fourth Military Medical University Xi'an China
| | - Xin Li
- Department of Oncology Dongguan Kanghua Hospital Dongguan China
| | - Jian Kang
- Department of Basic Microbiology The Fourth Military Medical University Xi'an China
| | - Yingfeng Lei
- Department of Basic Microbiology The Fourth Military Medical University Xi'an China
| | - Ying Xue
- Department of Oncology Dongguan Kanghua Hospital Dongguan China
- Department of Radiation Oncology The First Affiliated Hospital of the Fourth Military Medical University Xi'an China
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41
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Yang B, Miao S, Li Y. SCUBE2 inhibits the proliferation, migration and invasion of human non-small cell lung cancer cells through regulation of the sonic hedgehog signaling pathway. Gene 2018; 672:143-149. [DOI: 10.1016/j.gene.2018.06.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 05/13/2018] [Accepted: 06/04/2018] [Indexed: 12/14/2022]
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Sabol M, Trnski D, Musani V, Ozretić P, Levanat S. Role of GLI Transcription Factors in Pathogenesis and Their Potential as New Therapeutic Targets. Int J Mol Sci 2018; 19:2562. [PMID: 30158435 PMCID: PMC6163343 DOI: 10.3390/ijms19092562] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 08/17/2018] [Accepted: 08/25/2018] [Indexed: 02/05/2023] Open
Abstract
GLI transcription factors have important roles in intracellular signaling cascade, acting as the main mediators of the HH-GLI signaling pathway. This is one of the major developmental pathways, regulated both canonically and non-canonically. Deregulation of the pathway during development leads to a number of developmental malformations, depending on the deregulated pathway component. The HH-GLI pathway is mostly inactive in the adult organism but retains its function in stem cells. Aberrant activation in adult cells leads to carcinogenesis through overactivation of several tightly regulated cellular processes such as proliferation, angiogenesis, EMT. Targeting GLI transcription factors has recently become a major focus of potential therapeutic protocols.
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Affiliation(s)
- Maja Sabol
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia.
| | - Diana Trnski
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia.
| | - Vesna Musani
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia.
| | - Petar Ozretić
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia.
| | - Sonja Levanat
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia.
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Zhang B, Dai XH, Yu XP, Zou W, Teng W, Sun XW, Yu WW, Liu H, Wang H, Sun MJ, Li M. Baihui (DU20)-penetrating- Qubin (GB7) acupuncture inhibits apoptosis in the perihemorrhagic penumbra. Neural Regen Res 2018; 13:1602-1608. [PMID: 30127121 PMCID: PMC6126129 DOI: 10.4103/1673-5374.237123] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Baihui (DU20)-penetrating-Qubin (GB7) acupuncture can inhibit inflammatory reactions and activate signaling pathways related to proliferation after intracerebral hemorrhage. However, there is no research showing the relationship between this treatment and cell apoptosis. Rat models of intracerebral hemorrhage were established by injecting 60 μL of autologous blood into the right side of the caudate-putamen. Six hours later, the needle traveled subcutaneously from the Baihui acupoint to Qubin acupoint. The needle was alternately rotated (180 ± 10 turns/min) manually along clockwise and counter-clockwise directions. Stimulation lasted for 7 days, and was performed three times each for 6 minutes with 6-minute intervals between stimulations. Rats intraperitoneally receiving Sonic hedgehog pathway activator, purmorphamine (1 mg/kg per day), served as positive controls. Motor and sensory function were assessed using the Ludmila Belayev test. Extent of pathological changes were measured in the perihemorrhagic penumbra using hematoxylin-eosin staining. Apoptosis was examined by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling assay. Expression of smoothened (Smo) and glioma-associated homolog 1 (Gli1) was determined by western blot assay. Our results showed that Baihui-penetrating-Qubin acupuncture promoted recovery of motor and sensory function, reduced the apoptotic cell percentage in the perihemorrhagic penumbra, and up-regulated Smo and Gli1 expression. We conclude that Baihui-penetrating-Qubin acupuncture can mitigate hemorrhage and promote functional recovery of the brain in a rat model of intracerebral hemorrhage, possibly by activating the Sonic hedgehog pathway.
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Affiliation(s)
- Beng Zhang
- Heilongjiang University of Chinese Medicine; First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China
| | - Xiao-Hong Dai
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China
| | - Xue-Ping Yu
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China
| | - Wei Zou
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine; Clinical Key Laboratory of Integrated Traditional Chinese and Western Medicine, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China
| | - Wei Teng
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China
| | - Xiao-Wei Sun
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China
| | - Wei-Wei Yu
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China
| | - Hao Liu
- Department of Acupuncture and Moxibustion, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, China
| | - Hui Wang
- Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China
| | - Meng-Juan Sun
- Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China
| | - Meng Li
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China
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Bao C, Kramata P, Lee HJ, Suh N. Regulation of Hedgehog Signaling in Cancer by Natural and Dietary Compounds. Mol Nutr Food Res 2017; 62. [PMID: 29164817 DOI: 10.1002/mnfr.201700621] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Revised: 11/14/2017] [Indexed: 12/12/2022]
Abstract
The aberrant Hedgehog (Hh) signaling induced by mutations or overexpression of the signaling mediators has been implicated in cancer, associated with processes including inflammation, tumor cell growth, invasion, and metastasis, as well as cancer stemness. Small molecules targeting the regulatory components of the Hh signaling pathway, especially Smoothened (Smo), have been developed for the treatment of cancer. However, acquired resistance to a Smo inhibitor vismodegib observed in clinical trials suggests that other Hh signaling components need to be explored as potential anticancer targets. Natural and dietary compounds provide a resource for the development of potent agents affecting intracellular signaling cascades, and numerous studies have been conducted to evaluate the efficacy of natural products in targeting the Hh signaling pathway. In this review, we summarize the role of Hh signaling in tumorigenesis, discuss results from recent studies investigating the effect of natural products and dietary components on Hh signaling in cancer, and provide insight on novel small molecules as potential Hh signaling inhibitors.
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Affiliation(s)
- Cheng Bao
- Department of Food Science and Technology, Chung-Ang University, Anseong, South Korea
| | - Pavel Kramata
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Hong Jin Lee
- Department of Food Science and Technology, Chung-Ang University, Anseong, South Korea
| | - Nanjoo Suh
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.,Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
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Li C, Lu Y, Du S, Li S, Zhang Y, Liu F, Chen Y, Weng D, Chen J. Dioscin Exerts Protective Effects Against Crystalline Silica-induced Pulmonary Fibrosis in Mice. Theranostics 2017; 7:4255-4275. [PMID: 29158824 PMCID: PMC5695011 DOI: 10.7150/thno.20270] [Citation(s) in RCA: 118] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2017] [Accepted: 08/29/2017] [Indexed: 12/15/2022] Open
Abstract
Inhalation of crystalline silica particles leads to pulmonary fibrosis, eventually resulting in respiratory failure and death. There are few effective drugs that can delay the progression of this disease; thus, patients with silicosis are usually only offered supportive care. Dioscin, a steroidal saponin, exhibits many biological activities and health benefits including its protective effects against hepatic fibrosis. However, the effect of dioscin on silicosis is unknown. Methods: We employed experimental mouse mode of silicosis. Different doses of dioscin were gavaged to the animals 1 day after crystalline silica instillation to see the effect of dioscin on crystalline silica induced pulmonary fibrosis. Also, we used RAW264.7 and NIH-3T3 cell lines to explore dioscin effects on macrophages and fibroblasts. Dioscin was also oral treatment but 10 days after crystalline silica instillation to see its effect on established pulmonary fibrosis. Results: Dioscin treatment reduced pro-inflammation and pro-fibrotic cytokine secretion by modulating innate and adaptive immune responses. It also reduced the recruitment of fibrocytes, protected epithelial cells from crystalline silica injury, inhibited transforming growth factor beta/Smad3 signaling and fibroblast activation. Together, these effects delayed the progression of crystalline silica-induced pulmonary fibrosis. The mechanism by which dioscin treatment alleviated CS-induced inflammation appeared to be via the reduction of macrophage, B lymphocyte, and T lymphocte infiltration into lung. Dioscin inhibits macrophages and fibroblasts from secreting pro-inflammatory cytokines and may also function as a modulator of T helper cells responses, concurrent with attenuated phosphorylation of the apoptosis signal-regulating kinase 1-p38/c-Jun N-terminal kinase pathway. Also, dioscin could block the phosphorylation of Smad3 in fibroblast. Oral treatment of dioscin could also effectively postpone the progression of established silicosis. Conclusion: Oral treatment dioscin delays crystalline silica-induced pulmonary fibrosis and exerts pulmonary protective effects in mice. Dioscin may be a novel and potent candidate for protection against crystalline silica-induced pulmonary fibrosis.
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Gao J, Long B, Wang Z. Role of Notch signaling pathway in pancreatic cancer. Am J Cancer Res 2017; 7:173-186. [PMID: 28337369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 10/12/2016] [Indexed: 09/28/2022] Open
Abstract
Pancreatic cancer (PC) is one of the highly aggressive malignancies in the United States. It has been shown that multiple signaling pathways are involved in the pathogenesis of PC, such as JNK, PI3K/AKT, Rho GTPase, Hedgehog (Hh) and Skp2. In recent years, accumulated evidence has demonstrated that Notch signaling pathway plays critical roles in the development and progression of PC. Therefore, in this review we discuss the recent literature regarding the function and regulation of Notch in the pathogenesis of PC. Moreover, we describe that Notch signaling pathway could be down-regulated by its inhibitors or natural compounds, which could be a novel approach for the treatment of PC patients.
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Affiliation(s)
- Jiankun Gao
- Sichuan College of Tranditional Chinese Medicine Mianyang, Sichuan, China
| | - Bo Long
- Department of Infectious Diseases, Mianyang 404 Hospital Mianyang, Sichuan, China
| | - Zhiwei Wang
- The Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow UniversitySuzhou 215123, China; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical SchoolMA 02215, USA
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Song L, Chen X, Gao S, Zhang C, Qu C, Wang P, Liu L. Ski modulate the characteristics of pancreatic cancer stem cells via regulating sonic hedgehog signaling pathway. Tumour Biol 2016; 37:16115–16125. [PMID: 27734340 DOI: 10.1007/s13277-016-5461-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 09/23/2016] [Indexed: 01/03/2023] Open
Abstract
Evidence from in vitro and in vivo studies shows that Ski may act as both a tumor proliferation-promoting factor and a metastatic suppressor in human pancreatic cancer and also may be a therapeutic target of integrative therapies. At present, pancreatic cancer stem cells (CSCs) are responsible for tumor recurrence accompanied by resistance to conventional therapies. Sonic hedgehog (Shh) signaling pathway is found to be aberrantly activated in CSCs. The objectives of this study were to investigate the role of Ski in modulating pancreatic CSCs and to examine the molecular mechanisms involved in pancreatic cancer treatment both in vivo and in vitro. In in vitro study, the results showed that enhanced Ski expression could increase the expression of pluripotency maintaining markers, such as CD24, CD44, Sox-2, and Oct-4, and also components of Shh signaling pathway, such as Shh, Ptch-1, Smo, Gli-1, and Gli-2, whereas depletion of Ski to the contrary. Then, we investigated the underlying mechanism and found that inhibiting Gli-2 expression by short interfering RNA (siRNA) can decrease the effects of Ski on the maintenance of pancreatic CSCs, indicating that Ski mediates the pluripotency of pancreatic CSCs mainly through Shh pathway. The conclusion is that Ski may be an important factor in maintaining the stemness of pancreatic CSCs through modulating Shh pathway.
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Affiliation(s)
- Libin Song
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiangyuan Chen
- Department of Anaesthesiology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Anaesthesiology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Song Gao
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Chenyue Zhang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Chao Qu
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Peng Wang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Luming Liu
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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