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Li S, FeiyuTeng, Zhang J, Zhang P, Li M, Wang X, Li K. Tanshinone IIA potentiates the chemotherapeutic effect of doxorubicin against breast cancer cells and attenuates the cardiotoxicity of doxorubicin by regulating ERK1/2 pathway. J Biochem Mol Toxicol 2024; 38:e23851. [PMID: 39267350 DOI: 10.1002/jbt.23851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 08/07/2024] [Accepted: 09/03/2024] [Indexed: 09/17/2024]
Abstract
Doxorubicin (Dox) is frequently employed as a chemotherapy agent for breast cancer. As the chemotherapy moves forward, breast cancer cells tend to develop resistance to Dox, besides that, Dox are also easy to cause cardiotoxicity related to cumulative dose. Therefore, how to potentiate the chemosensitivity of breast cancer cells to Dox while attenuating its cardiotoxicity has become a research hotspot. Tanshinone IIA (Tan IIA) is known for its anticancer activity as well as for its cardioprotective effects. In view of the aforementioned facts, we assessed whether Tan IIA possesses synergism and attenuation effect on Dox for breast cancer chemotherapy. Our studies in vitro indicated that, Tan IIA could potentiate the effect of Dox on breast cancer cells proliferation inhibition and apoptosis promotion by inhibiting ERK1/2 pathway, but interestingly, Tan IIA attenuated the cytotoxicity of Dox to myocardial cells by activating ERK1/2 pathway. Additionally, our studies in vivo also suggested that Tan IIA potentiated the chemotherapeutic effect of Dox against breast cancer while attenuating Dox-induced myocardial injury. Given that Tan IIA had a synergism and attenuation effect on Dox, we believed that Tan IIA can be used as an ideal drug in combination with Dox for breast cancer therapy.
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Affiliation(s)
- Shizheng Li
- Department of Emergency Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - FeiyuTeng
- Department of Clinical Laboratory, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Jianing Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Puwei Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Manyuan Li
- Department of Clinical Laboratory, Jinzhou Women and Children's Hospital, Jinzhou, China
| | - Xuezhe Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Kun Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
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Bahadar N, Bahadar S, Sajid A, Wahid M, Ali G, Alghamdi A, Zada H, Khan T, Ullah S, Sun Q. Epigallocatechin gallate and curcumin inhibit Bcl-2: a pharmacophore and docking based approach against cancer. Breast Cancer Res 2024; 26:114. [PMID: 38978121 PMCID: PMC11229278 DOI: 10.1186/s13058-024-01868-9] [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: 11/09/2023] [Accepted: 07/01/2024] [Indexed: 07/10/2024] Open
Abstract
The protein Bcl-2, well-known for its anti-apoptotic properties, has been implicated in cancer pathogenesis. Identifying the primary gene responsible for promoting improved cell survival and development has provided compelling evidence for preventing cellular death in the progression of malignancies. Numerous research studies have provided evidence that the abundance of Bcl-2 is higher in malignant cells, suggesting that suppressing Bcl-2 expression could be a viable therapeutic approach for cancer treatment. In this study, we acquired a compound collection using a database that includes constituents from Traditional Chinese Medicine (TCM). Initially, we established a pharmacophore model and utilized it to search the TCM database for potential compounds. Compounds with a fitness score exceeding 0.75 were selected for further analysis. The Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis identified six compounds with favorable therapeutic characteristics. The compounds that successfully passed the initial screening process based on the pharmacodynamic model were subjected to further evaluation. Extra-precision (XP) docking was employed to identify the compounds with the most favorable XP docking scores. Further analysis using the Molecular Mechanics Generalized Born Surface Area (MM-GBSA) method to calculate the overall free binding energy. The binding energy between the prospective ligand molecule and the target protein Bcl-2 was assessed by a 100 ns molecular dynamics simulation for curcumin and Epigallocatechin gallate (EGCG). The findings of this investigation demonstrate the identification of a molecular structure that effectively inhibits the functionality of the Bcl-2 when bound to the ligand EGCG. Consequently, this finding presents a novel avenue for the development of pharmaceuticals capable of effectively addressing both inflammatory and tumorous conditions.
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Affiliation(s)
- Noor Bahadar
- Department of Otorhinolaryngology, Head and Neck Surgery, The China-Japan Union Hospital of Jilin University, Xiantai Street 126, 130033, Changchun, Jilin, China
- Key Laboratory of Molecular Epigenetics of the Ministry of Education (MOE), School of Life Sciences, Northeast Normal University, Renmin Street, Changchun, Jilin, 130024, China
| | - Sher Bahadar
- College of Veterinary Sciences and Animal Husbandry, Abdul Wali Khan University Mardan, Mardan, Khyber Pakhtunkhwa, Pakistan
| | - Abdul Sajid
- College of Veterinary Sciences and Animal Husbandry, Abdul Wali Khan University Mardan, Mardan, Khyber Pakhtunkhwa, Pakistan
| | - Muqeet Wahid
- Department of Pharmacy, Bahauddin Zakariya University, Multan, 60800, Pakistan
| | - Ghadir Ali
- Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, 54700, Pakistan
| | - Abdullah Alghamdi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia
| | - Hakeem Zada
- Mubarak Diagnostic Laboratory and Research Center, Peshawar, Pakistan
| | - Tamreez Khan
- College of Veterinary Sciences and Animal Husbandry, Abdul Wali Khan University Mardan, Mardan, Khyber Pakhtunkhwa, Pakistan
| | - Shafqat Ullah
- College of Veterinary Sciences and Animal Husbandry, Abdul Wali Khan University Mardan, Mardan, Khyber Pakhtunkhwa, Pakistan
| | - Qingjia Sun
- Department of Otorhinolaryngology, Head and Neck Surgery, The China-Japan Union Hospital of Jilin University, Xiantai Street 126, 130033, Changchun, Jilin, China.
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Kim S, Yoon H, Park SK. Butein Increases Resistance to Oxidative Stress and Lifespan with Positive Effects on the Risk of Age-Related Diseases in Caenorhabditis elegans. Antioxidants (Basel) 2024; 13:155. [PMID: 38397753 PMCID: PMC10886231 DOI: 10.3390/antiox13020155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 01/21/2024] [Accepted: 01/24/2024] [Indexed: 02/25/2024] Open
Abstract
Butein is a flavonoid found in many plants, including dahlia, butea, and coreopsis, and has both antioxidant and sirtuin-activating activities. In light of the postulated role of free radicals in aging, we examined the effects of butein on aging and on genetic or nutritional models of age-related diseases in Caenorhabditis elegans. Butein showed radical scavenging activity and increased resistance to oxidative stress in Caenorhabditis elegans. The mean lifespan of Caenorhabditis elegans was significantly increased by butein, from 22.7 days in the untreated control to 25.0 days in the butein-treated group. However, the lifespan-extending effect of butein was accompanied by reduced production of progeny as a trade-off. Moreover, the age-related decline in motility was delayed by butein supplementation. Genetic analysis showed that the lifespan-extending effect of butein required the autophagic protein BEC-1 and the transcription factor DAF-16 to regulate stress response and aging. At the genetic level, expression of the DAF-16 downstream target genes hsp-16.2 and sod-3 was induced in butein-treated worms. Butein additionally exhibited a preventive effect in models of age-related diseases. In an Alzheimer's disease model, butein treatment significantly delayed the paralysis caused by accumulation of amyloid-beta in muscle, which requires SKN-1, not DAF-16. In a high-glucose-diet model of diabetes mellitus, butein markedly improved survival, requiring both SKN-1 and DAF-16. In a Parkinson's disease model, dopaminergic neurodegeneration was completely inhibited by butein supplementation and the accumulation of α-synuclein was significantly reduced. These findings suggest the use of butein as a novel nutraceutical compound for aging and age-related diseases.
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Affiliation(s)
- Seona Kim
- Department of Medical Sciences, General Graduate School, Soonchunhyang University, 22 Soonchunhyang-ro, Asan 31538, Republic of Korea
| | - Hyemin Yoon
- Department of Medical Biotechnology, Soonchunhyang University, 22 Soonchunhyang-ro, Asan 31538, Republic of Korea
| | - Sang-Kyu Park
- Department of Medical Sciences, General Graduate School, Soonchunhyang University, 22 Soonchunhyang-ro, Asan 31538, Republic of Korea
- Department of Medical Biotechnology, Soonchunhyang University, 22 Soonchunhyang-ro, Asan 31538, Republic of Korea
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Aravindan N, Natarajan M, Somasundaram DB, Aravindan S. Chemoprevention of neuroblastoma: progress and promise beyond uncertainties. JOURNAL OF CANCER METASTASIS AND TREATMENT 2023; 9:9. [PMID: 38249515 PMCID: PMC10798790 DOI: 10.20517/2394-4722.2022.40] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/23/2024]
Abstract
Neuroblastoma is the most common extracranial solid tumor in children and comprises one-tenth of all childhood cancer deaths. The current clinical therapy for this deadly disease is multimodal, involving an induction phase with alternating regimens of high-dose chemotherapeutic drugs and load reduction surgery; a consolidation phase with more intensive chemotherapy, radiotherapy, and stem cell transplant; and a maintenance phase with immunotherapy and immune-activating cytokine treatment. Despite such intensive treatment, children with neuroblastoma have unacceptable life quality and survival, warranting preventive measures to regulate the cellular functions that orchestrate tumor progression, therapy resistance, metastasis, and tumor relapse/recurrence. Globally, active efforts are underway to identify novel chemopreventive agents, define their mechanism(s) of action, and assess their clinical benefit. Some chemoprevention strategies (e.g., retinoids, difluoromethylornithine) have already been adopted clinically as part of maintenance phase therapy. Several agents are in the pipeline, while many others are in preclinical characterization. Here we review the classes of chemopreventive agents investigated for neuroblastoma, including cellular events targeted, mode(s) of action, and the level of development. Our review: (i) highlights the pressing need for new and improved chemopreventive strategies for progressive neuroblastoma; (ii) lists the emerging classes of chemopreventive agents for neuroblastoma; and (iii) recognizes the relevance of targeting dynamically evolving hallmark functions of tumor evolution (e.g., survival, differentiation, lineage transformation). With recent gains in the understanding of tumor evolution processes and preclinical and clinical efforts, it is our strong opinion that effective chemopreventive strategies for aggressive neuroblastoma are a near reality.
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Affiliation(s)
- Natarajan Aravindan
- Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Stephenson Cancer Center, Oklahoma City, OK 73104, USA
| | - Mohan Natarajan
- Department of Pathology and Laboratory Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio, TX 78229, USA
| | - Dinesh Babu Somasundaram
- Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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Kafoud A, Salahuddin Z, Ibrahim RS, Al-Janahi R, Mazurakova A, Kubatka P, Büsselberg D. Potential Treatment Options for Neuroblastoma with Polyphenols through Anti-Proliferative and Apoptotic Mechanisms. Biomolecules 2023; 13:563. [PMID: 36979499 PMCID: PMC10046851 DOI: 10.3390/biom13030563] [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: 01/24/2023] [Revised: 03/11/2023] [Accepted: 03/16/2023] [Indexed: 03/22/2023] Open
Abstract
Neuroblastoma (NB) is an extracranial tumor of the peripheral nervous system arising from neural crest cells. It is the most common malignancy in infants and the most common extracranial solid tumor in children. The current treatment for high-risk NB involves chemotherapy and surgical resection followed by high-dose chemotherapy with autologous stem-cell rescue and radiation treatment. However, those with high-risk NB are susceptible to relapse and the long-term side effects of standard chemotherapy. Polyphenols, including the sub-class of flavonoids, contain more than one aromatic ring with hydroxyl groups. The literature demonstrates their utility in inducing the apoptosis of neuroblastoma cells, mostly in vitro and some in vivo. This review explores the use of various polyphenols outlined in primary studies, underlines the pathways involved in apoptotic activity, and discusses the dosage and delivery of these polyphenols. Primary studies were obtained from multiple databases with search the terms "neuroblastoma", "flavonoid", and "apoptosis". The in vitro studies showed that polyphenols exert an apoptotic effect on several NB cell lines. These polyphenols include apigenin, genistein, didymin, rutin, quercetin, curcumin, resveratrol, butein, bisphenols, and various plant extracts. The mechanisms of the therapeutic effects include calpain-dependent pathways, receptor-mediated apoptosis, and, notably, and most frequently, mitochondrial apoptosis pathways, including the mitochondrial proteins Bax and Bcl-2. Overall, polyphenols demonstrate potency in decreasing NB proliferation and inducing apoptosis, indicating significant potential for further in vivo research.
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Affiliation(s)
- Aisha Kafoud
- Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha P.O. Box 24144, Qatar
| | - Zoya Salahuddin
- Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha P.O. Box 24144, Qatar
| | - Raghad Sabaawi Ibrahim
- Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha P.O. Box 24144, Qatar
| | - Reem Al-Janahi
- Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha P.O. Box 24144, Qatar
| | - Alena Mazurakova
- Department of Anatomy, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Dietrich Büsselberg
- Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha P.O. Box 24144, Qatar
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Brassinin Enhances Apoptosis in Hepatic Carcinoma by Inducing Reactive Oxygen Species Production and Suppressing the JAK2/STAT3 Pathway. APPLIED SCIENCES-BASEL 2022. [DOI: 10.3390/app12094733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Plants from the family Brassicaceae produce brassinin (BSN), which is an essential indole phytoalexin. BSN can kill certain types of cancer cells. Using hepatocarcinoma (HCC) cells, we examined the molecular mechanisms of BSN. We found that HCC cell growth was suppressed and apoptosis was induced by BSN via the downregulation of the JAK/STAT3 pathway. The cytoplasmic latent transcription factor STAT3, belonging to the STAT family, acted as both a signal transducer and an activator and was linked to tumor progression and decreased survival. BSN incubation caused HCC cells to produce reactive oxygen species (ROS). By activating caspase-9/-3 and PARP cleavage, Bcl-2 was reduced, and apoptosis was increased. BSN inhibited constitutive STAT3, JAK2, and Src phosphorylation. The JAK/STAT signaling cascade was confirmed by siRNA silencing STAT3 in HCC cells. BSN also suppressed apoptosis by Z-Val-Ala-Asp-Fluoromethylketone (Z-VAD-FMK), an apoptotic inhibitor. N-acetylcysteine (NAC) inhibited the production of ROS and diminished BSN-induced apoptosis. Our findings suggested that BSN has potential as a treatment for cancer.
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Ashraf W, Ahmad T, Almalki NAR, Krifa M, Zaayter L, Pizzi A, Muller CD, Hamiche A, Mély Y, Bronner C, Mousli M. Tannin extract from maritime pine bark exhibits anticancer properties by targeting the epigenetic UHRF1/DNMT1 tandem leading to the re-expression of TP73. Food Funct 2022; 13:316-326. [PMID: 34897340 DOI: 10.1039/d1fo01484f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Maritime pine bark is a rich source of polyphenolic compounds and is commonly employed as a herbal supplement worldwide. This study was designed to check the potential of maritime pine tannin extract (MPTE) in anticancer therapy and to determine the underlying mechanism of action. Our results showed that MPTE, containing procyanidin oligomers and lanostane type terpenoids, has an inhibitory effect on cancer cell proliferation through cell cycle arrest in the G2/M phase. Treatment with MPTE also induced apoptosis in a concentration-dependent manner in human cancer cell lines (HeLa and U2OS), as evidenced by the enhanced activation of caspase 3 and the cleavage of PARP along with the downregulation of the antiapoptotic protein Bcl-2. Interestingly, human non-cancerous fibroblasts are much less sensitive to MPTE, suggesting that it preferentially targets cancer cells. MPTE played a pro-oxidant role in cancer cells and promoted the expression of the p73 tumor suppressor gene in p53-deficient cells. It also downregulated the protooncogenic proteins UHRF1 and DNMT1, mediators of the DNA methylation machinery, and reduced the global methylation levels in HeLa cells. Overall, our results show that maritime pine tannin extract can play a favorable role in cancer treatment, and can be further explored by the pharmaceutical industry.
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Affiliation(s)
- Waseem Ashraf
- Laboratory of Bioimaging and Pathologies, UMR 7021 CNRS, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France. .,Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Tanveer Ahmad
- Laboratory of Bioimaging and Pathologies, UMR 7021 CNRS, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
| | - Naif A R Almalki
- Department of Functional Genomics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964 CNRS UMR 7104, Université de Strasbourg, Equipe labellisée Ligue contre le Cancer, Illkirch, France
| | - Mounira Krifa
- Laboratory of Bioimaging and Pathologies, UMR 7021 CNRS, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France. .,Unit of Bioactive and Natural Substances and Biotechnology UR17ES49, Faculty of Dental Medicine, University of Monastir, Monastir, Tunisia
| | - Liliyana Zaayter
- Laboratory of Bioimaging and Pathologies, UMR 7021 CNRS, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
| | | | - Christian D Muller
- Institut Pluridisciplinaire Hubert Curien, UMR 7178 CNRS Université de Strasbourg, Illkirch, France
| | - Ali Hamiche
- Department of Functional Genomics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964 CNRS UMR 7104, Université de Strasbourg, Equipe labellisée Ligue contre le Cancer, Illkirch, France
| | - Yves Mély
- Laboratory of Bioimaging and Pathologies, UMR 7021 CNRS, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
| | - Christian Bronner
- Department of Functional Genomics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964 CNRS UMR 7104, Université de Strasbourg, Equipe labellisée Ligue contre le Cancer, Illkirch, France
| | - Marc Mousli
- Laboratory of Bioimaging and Pathologies, UMR 7021 CNRS, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
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Tuli HS, Joshi R, Aggarwal D, Kaur G, Kaur J, Kumar M, Parashar NC, Khan MA, Sak K. Molecular mechanisms underlying chemopreventive potential of butein: Current trends and future perspectives. Chem Biol Interact 2021; 350:109699. [PMID: 34648814 DOI: 10.1016/j.cbi.2021.109699] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 09/29/2021] [Accepted: 10/09/2021] [Indexed: 01/07/2023]
Abstract
Despite extensive efforts, cancer is still often considered as an incurable disease and initiation of novel drug development programs is crucial to improve the prognosis and clinical outcome of patients. One of the major approaches in designing the novel cancer drugs has historically comprised studies of natural agents with diverse anticancer properties. As only a marginal part of natural compounds has been investigated, this approach still represents an attractive source of new potential antitumor molecules. In this review article, different anticancer effects of plant-derived chalcone, butein, are discussed, including its growth inhibitory action, proapoptotic, antiangiogenic and antimetastatic activities in a variety of cancer cells. The molecular mechanisms underlying these effects are presented in detail, revealing interactions of butein with multiple cellular targets (Bcl-2/Bax, caspases, STAT3, cyclins, NF-κB, COX-2, MMP-9, VEGF/R etc.) and regulation of a wide range of intracellular signal transduction pathways. These data altogether allow a good basis for initiating further in vivo studies as well as clinical trials. Along with the efforts to overcome low bioavailability issues generally characteristic to plant metabolites, butein can be considered as a potential lead compound for safe and more efficient cancer drugs in the future.
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Affiliation(s)
- Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana, 133207, India.
| | - Ruchira Joshi
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM's NMIMS, Mumbai, 56, Maharashtra, India
| | - Diwakar Aggarwal
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana, 133207, India
| | - Ginpreet Kaur
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM's NMIMS, Mumbai, 56, Maharashtra, India
| | - Jagjit Kaur
- Graduate School of Biomedical Engineering, ARC Centre of Excellence in Nanoscale Biophotonics (CNBP), Faculty of Engineering, The University of New South Wales, Sydney, 2052, Australia
| | - Manoj Kumar
- Department of Chemistry, Maharishi Markandeshwar University, Sadopur, 134007, Haryana, India
| | | | - Md Asaduzzaman Khan
- The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, 646000, China
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Hsu YK, Chen HY, Wu CC, Huang YC, Hsieh CP, Su PF, Huang YF. Butein induces cellular senescence through reactive oxygen species-mediated p53 activation in osteosarcoma U-2 OS cells. ENVIRONMENTAL TOXICOLOGY 2021; 36:773-781. [PMID: 33325610 DOI: 10.1002/tox.23079] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 12/06/2020] [Indexed: 06/12/2023]
Abstract
Butein is a flavonoid isolated from various medicinal plants. It is known to have different biological activities including anti-inflammation, anti-adipogenesis, and anti-angiogenesis. In the study, we demonstrated the anti-proliferative effect of butein in human osteosarcoma U-2 OS cells. Our data showed that butein significantly suppressed the viability and colony formation ability of U-2 OS cells. Further experiments revealed butein exposure resulted in a cell cycle arrest at S and G2/M phase in U-2 OS cells. Importantly, we found that butein activated the tumor suppressor p53, and trigged a p53-dependent senescence in U-2 OS cells. Knockdown of p53 suppressed the senescence and rescued the viability in butein-treated U-2 OS cells. Furthermore, we observed that butein exposure significantly enhanced reactive oxygen species (ROS) levels in U-2 OS cells. Co-administration of the ROS inhibitor NAC largely abolished the up-regulated p53 protein level, and rescued the suppressed viability and colony formation ability in butein-exposed U-2 OS cells. Taken together, our data proposed the increased ROS by butein exposure activated p53, and the activated p53 was involved in the anti-proliferative effect of butein via inducing senescence in U-2 OS cells. This report suggests that butein is a promising candidate for cancer therapy against osteosarcoma.
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Affiliation(s)
- Yung-Ken Hsu
- Department of Orthopedic Surgery, Changhua Christian Hospital, Changhua, Taiwan
| | - Hsuan-Ying Chen
- Orthopedics and Sports Medicine Laboratory, Changhua Christian Hospital, Changhua, Taiwan
| | - Chia-Chieh Wu
- Department of Orthopedic Surgery, Changhua Christian Hospital, Changhua, Taiwan
- School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ying-Chih Huang
- Department of Research, Changhua Christian Hospital, Changhua, Taiwan
| | - Cheng-Pu Hsieh
- Department of Orthopedic Surgery, Changhua Christian Hospital, Changhua, Taiwan
- Orthopedics and Sports Medicine Laboratory, Changhua Christian Hospital, Changhua, Taiwan
| | - Po-Feng Su
- Department of Orthopedic Surgery, Changhua Christian Hospital, Changhua, Taiwan
| | - Yi-Fu Huang
- Orthopedics and Sports Medicine Laboratory, Changhua Christian Hospital, Changhua, Taiwan
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Butein Promotes Lineage Commitment of Bone Marrow-Derived Stem Cells into Osteoblasts via Modulating ERK1/2 Signaling Pathways. Molecules 2020; 25:molecules25081885. [PMID: 32325749 PMCID: PMC7221720 DOI: 10.3390/molecules25081885] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 04/13/2020] [Accepted: 04/17/2020] [Indexed: 01/16/2023] Open
Abstract
Butein is a phytochemical that belongs to the chalcone family of flavonoids and has antitumor, anti-inflammatory, and anti-osteoclastic bone resorption activities. This study aims to investigate the effects of butein on the differentiation potential of mouse primary bone marrow-derived mesenchymal stem cells (mBMSCs) into osteoblast and adipocyte lineages. Primary cultures of mBMSCs are treated with different doses of butein during its differentiation. Osteoblast differentiation is assessed by alkaline phosphatase (ALP) activity quantification and Alizarin red staining for matrix mineralization, while adipogenesis is assessed by quantification of lipid accumulation using Oil Red O staining. Osteoblastic and adipocytic gene expression markers are determined by quantitative real-time PCR (qPCR). Western blot analysis is used to study the activation of extracellular signal-regulated kinase (ERK1/2). Interestingly, butein promotes the lineage commitment of mBMSCs into osteoblasts, while suppressing their differentiation into adipocytes in a dose-dependent manner. A similar effect of butein is confirmed in human (h) primary BMSCs. Occurring at the molecular level, butein significantly upregulates the mRNA expression of osteoblast-related genes, while downregulating the expression of adipocyte-related genes. The mechanism of butein-induced osteogenesis is found to be mediated by activating the ERK1/2 signaling pathway. To conclude, we identify butein as a novel nutraceutical compound with an osteo-anabolic activity to promote the lineage commitment of BMSCs into osteoblast versus adipocyte. Thus, butein can be a plausible therapeutic drug for enhancing bone formation in osteoporotic patients.
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Lieberknecht V, Engel D, Rodrigues ALS, Gabilan NH. Neuroprotective effects of mirtazapine and imipramine and their effect in pro- and anti-apoptotic gene expression in human neuroblastoma cells. Pharmacol Rep 2020; 72:563-570. [DOI: 10.1007/s43440-019-00009-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 07/19/2019] [Accepted: 08/25/2019] [Indexed: 12/13/2022]
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12
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Ohmoto M, Shibuya Y, Taniguchi S, Nakade T, Nomura M, Ikeda-Matsuo Y, Daikoku T. Protective effects of butein on corticosterone-induced cytotoxicity in Neuro2A cells. IBRO Rep 2020; 8:82-90. [PMID: 32181410 PMCID: PMC7066037 DOI: 10.1016/j.ibror.2020.02.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 02/26/2020] [Indexed: 12/28/2022] Open
Abstract
Butein protected Neuro2A cells from CORT-induced apoptosis via mitochondrial dysfunction, caspase-3 activation, and DNA damage. CORT suppressed retinoic acid-induced neurite outgrowth in Neuro2A cells. Butein inhibited CORT-suppressed neurite outgrowth in Neuro2A cells. High doses of butein induced cytotoxicity in Neuro2A cells. A functional understanding of the relationship between glucocorticoids and neuronal apoptosis induced by the production of reactive oxygen species (ROS) may lead to a novel strategy for the treatment or prevention of depression. Previous reports suggest that butein, a type of flavonoids, may be a potent candidate against depression-related neuronal cell apoptosis caused by oxidative stress; however, the protective effects of butein on damaged corticosterone (CORT)-treated neuronal cells has not been elucidated. In the present study, we examined the protective effect of butein on CORT-induced cytotoxicity and neurite growth during cell differentiation of mouse neuroblastoma Neuro2A (N2A) cells. Moreover, the effect on cultured cells by high concentrations of butein was confirmed. Our results demonstrate that CORT treatment significantly decreases cell viability and induces cell death. CORT was suggested to induce apoptosis via mitochondrial dysfunction and caspase-3 activation; this apoptosis may be attributed to DNA damage by ROS generation, found in this study to be significantly inhibited by pretreatment with butein. We found that CORT produced significant growth suppression of retinoic acid-induced neurite outgrowth in N2A cells; however, butein significantly increased neurite length and induced dose-dependent apoptotic cytotoxicity in N2A cells. This study suggests that low concentration of butein can prevent CORT-induced cytotoxicity in N2A cells, and provides preliminary results supporting some of the beneficial roles of butein in neuroprotection.
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Affiliation(s)
- Masanori Ohmoto
- Department of Pharmacy Practice and Sciences, Faculty of Pharmaceutical Sciences, Hokuriku University, Japan
| | - Yukina Shibuya
- Department of Pharmacy Practice and Sciences, Faculty of Pharmaceutical Sciences, Hokuriku University, Japan
| | - Shihori Taniguchi
- Department of Pharmacy Practice and Sciences, Faculty of Pharmaceutical Sciences, Hokuriku University, Japan
| | - Tomoki Nakade
- Department of Pharmacy Practice and Sciences, Faculty of Pharmaceutical Sciences, Hokuriku University, Japan
| | - Masaaki Nomura
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Hokuriku University, Japan
| | - Yuri Ikeda-Matsuo
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Hokuriku University, Japan
| | - Tohru Daikoku
- Department of Pharmaceutical Life Sciences, Faculty of Pharmaceutical Sciences, Hokuriku University, Japan
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Sun B, Zhao X, Ming J, Liu X, Liu D, Jiang C. Stepwise detection and evaluation reveal miR-10b and miR-222 as a remarkable prognostic pair for glioblastoma. Oncogene 2019; 38:6142-6157. [PMID: 31289362 PMCID: PMC6756080 DOI: 10.1038/s41388-019-0867-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 03/31/2019] [Accepted: 05/01/2019] [Indexed: 11/08/2022]
Abstract
Despite the existence of many clinical and molecular factors reported that contribute to survival in glioblastoma, prevailing studies fell into partial or local feature selection for survival analysis. We proposed a feature selection strategy including not only joint covariate detection but also its evaluations, and performed it on miRNA expression profiles with glioblastoma. MiR-10b and miR-222 were selected as the most significant two-dimensional feature. Crucially, we integrated in vitro experiments on GBM cells and in vivo studies on a mouse model of human glioma to elucidate the synergistic effects between miR-10b and miR-222. Inhibition of miR-10b and miR-222 strongly suppress GBM cells growth, invasion, and induce apoptosis by co-targeting PTEN and leading to activation of p53 ultimately. We also demonstrated that miR-10b and miR-222 co-target BIM to induce apoptosis independent of p53 status. The results define mir-10b and mir-222 important roles in gliomagenesis and provided a reliable survival analysis strategy.
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Affiliation(s)
- Bo Sun
- Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, 150086, Harbin, China
| | - Xudong Zhao
- College of Information and Computer Engineering, Northeast Forestry University, 150040, Harbin, China.
| | - Jianguang Ming
- Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, 150086, Harbin, China
| | - Xing Liu
- Beijing Neurosurgical Institute, 100050, Beijing, China
| | - Daming Liu
- Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, 150086, Harbin, China
| | - Chuanlu Jiang
- Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, 150086, Harbin, China.
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TTK promotes mesenchymal signaling via multiple mechanisms in triple negative breast cancer. Oncogenesis 2018; 7:69. [PMID: 30206215 PMCID: PMC6133923 DOI: 10.1038/s41389-018-0077-z] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Revised: 05/16/2018] [Accepted: 06/15/2018] [Indexed: 02/06/2023] Open
Abstract
Abnormal expression of TTK kinase has been associated with the initiation, progression, and therapeutic resistance of breast and other cancers, but its roles remain to be clarified. In this study, we examined the role of TTK in triple negative breast cancer (TNBC), and found that higher TTK expression correlated with mesenchymal and proliferative phenotypes in TNBC cells. Pharmacologic inhibition and genomic silencing of TTK not only reversed the epithelial-to-mesenchymal transition (EMT) in TNBC cells, but also increased the expression of KLF5, an effector of TGF-β signaling and inhibitor of EMT. In addition, TTK inhibition decreased the expression of EMT-associated micro-RNA miR-21 but increased the expression of miR-200 family members and suppressed TGF-β signaling. To test if upregulation of KLF5 plays a role in TTK-induced EMT, TTK and KLF5 were silenced simultaneously, which reversed the decreased EMT caused by loss of TTK. Consistently, the decrease in miR-21 expression and increase in miR-200 expression caused by TTK silencing were rescued by loss of KLF5. Altogether, this study highlights a novel role and signaling pathway for TTK in regulating EMT of TN breast cancer cells through TGF-β and KLF5 signaling, highlighting targetable signaling pathways for TTK inhibitors in aggressive breast cancer.
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Jayasooriya RGPT, Molagoda IMN, Park C, Jeong JW, Choi YH, Moon DO, Kim MO, Kim GY. Molecular chemotherapeutic potential of butein: A concise review. Food Chem Toxicol 2017; 112:1-10. [PMID: 29258953 DOI: 10.1016/j.fct.2017.12.028] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Revised: 12/14/2017] [Accepted: 12/15/2017] [Indexed: 12/13/2022]
Abstract
Butein is a biologically active flavonoid isolated from the bark of Rhus verniciflua Stokes, which is known to have therapeutic potential against various cancers. Notably, butein inhibits cancer cell growth by inducing G2/M phase arrest and apoptosis. Butein-induced G2/M phase arrest is associated with increased phosphorylation of ataxia telangiectasia mutated (ATM) and Chk1/2, and consequently, with reduced cdc25C levels. In addition, butein-induced apoptosis is mediated through the activation of caspase-3, which is associated with changes in the expression of Bcl-2 and Bax proteins. Intriguingly, butein sensitizes cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis via ERK-mediated Sp1 activation, which promotes the transcription of specific death receptor 5. Butein also inhibits the migration and invasion of human cancer cells by suppressing nuclear factor-κB- and extracellular signal-regulated kinases 1/2-mediated expression of matrix metalloproteinase-9 and vascular endothelial growth factor. Additionally, butein downregulates the expression of human telomerase reverse transcriptase and causes a concomitant decrease in telomerase activity. These findings provide the basis for the pharmaceutical development of butein. The aim of this review is to provide an update on the mechanisms underlying the anticancer activity of butein, with a special focus on its effects on different cellular signaling cascades.
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Affiliation(s)
- Rajapaksha Gedara Prasad Tharanga Jayasooriya
- Department of Marine Life Sciences, Jeju National University, Jeju 63243, Republic of Korea; Department of Biological Sciences, Faculty of Applied Science, University of Rajarata, Mihintale 50300, Sri Lanka
| | | | - Cheol Park
- Department of Molecular Biology, College of Natural Sciences and Human Ecology, Dongeui University, Busan 67340, Republic of Korea
| | - Jin-Woo Jeong
- Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan 47227, Republic of Korea
| | - Yung Hyun Choi
- Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan 47227, Republic of Korea
| | - Dong-Oh Moon
- Department of Biology Education, Daegu University, Jillyang, Gyeongsan, Gyeonsangbuk-do 38453, Republic of Korea
| | - Mun-Ock Kim
- Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Chungcheongbuk-do 28116, Republic of Korea
| | - Gi-Young Kim
- Department of Marine Life Sciences, Jeju National University, Jeju 63243, Republic of Korea.
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Alzhrani RM, Alhadidi Q, Bachu RD, Shah Z, Dey S, Boddu SH. Tanshinone IIA Inhibits VEGF Secretion and HIF-1α Expression in Cultured Human Retinal Pigment Epithelial Cells under Hypoxia. Curr Eye Res 2017; 42:1667-1673. [PMID: 28937825 DOI: 10.1080/02713683.2017.1355467] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
PURPOSE The current work intends to study the activity of tanshinone IIA on secretion of vascular endothelial growth factor (VEGF) and expression of hypoxia inducible factor 1α (HIF-1α) in human retinal pigment epithelial cells (ARPE-19 cells) under hypoxic condition. METHODS The cytotoxicity of tanshinone IIA was tested in ARPE-19 cells by MTT assay. ARPE-19 cells were incubated with different concentrations of cobalt chloride (100, 150, and 200 µM) for 12 h, and levels of expressed HIF-1α and secreted VEGF were quantified through Western blot and ELISA, respectively. Further, ARPE-19 cells were pretreated for 1 h with different concentrations of tanshinone IIA (5, 10, 15, and 18 µM). After 1 h, the cells were subjected to hypoxic condition using 150 µM cobalt chloride for 12 h in the presence and absence of tanshinone IIA. The cells were then harvested, and the secreted VEGF and expressed HIF-1α was studied. RESULTS Tanshinone IIA at concentrations of 5, 10, 15, and 18 μM did not show cytotoxicity in ARPE-19 cells. Chemical hypoxia induced by cobalt chloride caused a significant increase in VEGF level in a dose-dependent manner, and HIF-1α expression peaked at 150 µM. Based on the data, cobalt chloride concentration was maintained at 150 μM for further studies. Tanshinone IIA decreased the level of HIF-1α and VEGF secretion in a dose-dependent manner under hypoxic condition. CONCLUSION Tanshinone IIA could be explored as a new potential candidate for treating wet AMD.
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Affiliation(s)
- Rami M Alzhrani
- a Department of Pharmacy Practice , The University of Toledo, Health Science Campus , Toledo , OH , USA
| | - Qasim Alhadidi
- b Department of Medicinal and Biological Chemistry , The University of Toledo, Health Science Campus , Toledo , OH , USA
| | - Rinda Devi Bachu
- a Department of Pharmacy Practice , The University of Toledo, Health Science Campus , Toledo , OH , USA
| | - Zahoor Shah
- b Department of Medicinal and Biological Chemistry , The University of Toledo, Health Science Campus , Toledo , OH , USA
| | - Surajit Dey
- c College of Pharmacy , Roseman University of Health Sciences , Henderson , NV , USA
| | - Sai Hs Boddu
- a Department of Pharmacy Practice , The University of Toledo, Health Science Campus , Toledo , OH , USA
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van Beijnum JR, Giovannetti E, Poel D, Nowak-Sliwinska P, Griffioen AW. miRNAs: micro-managers of anticancer combination therapies. Angiogenesis 2017; 20:269-285. [PMID: 28474282 PMCID: PMC5519663 DOI: 10.1007/s10456-017-9545-x] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 03/11/2017] [Indexed: 12/15/2022]
Abstract
Angiogenesis is one of the hallmarks of cancer progression and as such has been considered a target of therapeutic interest. However, single targeted agents have not fully lived up to the initial promise of anti-angiogenic therapy. Therefore, it has been suggested that combining therapies and agents will be the way forward in the oncology field. In recent years, microRNAs (miRNAs) have received considerable attention as drivers of tumor development and progression, either acting as tumor suppressors or as oncogenes (so-called oncomiRs), as well as in the process of tumor angiogenesis (angiomiRs). Not only from a functional, but also from a therapeutic view, miRNAs are attractive tools. Thus far, several mimics and antagonists of miRNAs have entered clinical development. Here, we review the provenance and promise of miRNAs as targets as well as therapeutics to contribute to anti-angiogenesis-based (combination) treatment of cancer.
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Affiliation(s)
- Judy R van Beijnum
- Angiogenesis Laboratory, Department of Medical Oncology, VUMC - Cancer Center Amsterdam, VU University Medical Center (VUmc), Amsterdam, The Netherlands
| | - Elisa Giovannetti
- Laboratory Medical Oncology, Department of Medical Oncology, VUMC - Cancer Center Amsterdam, VU University Medical Center (VUmc), Amsterdam, The Netherlands
| | - Dennis Poel
- Angiogenesis Laboratory, Department of Medical Oncology, VUMC - Cancer Center Amsterdam, VU University Medical Center (VUmc), Amsterdam, The Netherlands
| | | | - Arjan W Griffioen
- Angiogenesis Laboratory, Department of Medical Oncology, VUMC - Cancer Center Amsterdam, VU University Medical Center (VUmc), Amsterdam, The Netherlands.
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Padmavathi G, Roy NK, Bordoloi D, Arfuso F, Mishra S, Sethi G, Bishayee A, Kunnumakkara AB. Butein in health and disease: A comprehensive review. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2017; 25:118-127. [PMID: 28190465 DOI: 10.1016/j.phymed.2016.12.002] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Revised: 12/03/2016] [Accepted: 12/11/2016] [Indexed: 06/06/2023]
Abstract
BACKGROUND The risk of suffering from many chronic diseases seems to have made no improvement despite the advancement in medications available in the modern world. Moreover, the use of synthetic chemicals as medications has proved to worsen the scenario due to the various adverse side effects associated with them. PURPOSE Extensive research on natural medicines provides ample evidence on the safety and efficacy of phytochemicals and nutraceuticals against diverse chronic ailments. Therefore, it is advisable to use natural products in the management of such diseases. This article aims to present a comprehensive and critical review of known pharmacological and biological effects of butein, an important chalcone polyphenol first isolated from Rhus verniciflua Stokes, implicated in the prevention and treatment of various chronic disease conditions. METHODS An extensive literature search was conducted using PubMed, ScienceDirect, Scopus and Web of ScienceTM core collections using key words followed by evaluation of the bibliographies of relevant articles. RESULTS Butein has been preclinically proven to be effective against several chronic diseases because it possesses a wide range of biological properties, including antioxidant, anti-inflammatory, anticancer, antidiabetic, hypotensive and neuroprotective effects. Furthermore, it has been shown to affect multiple molecular targets, including the master transcription factor nuclear factor-κB and its downstream molecules. Moreover, since it acts on multiple pathways, the chances of non-responsiveness and resistance development is reduced, supporting the use of butein as a preferred treatment option. CONCLUSION Based on numerous preclinical studies, butein shows significant therapeutic potential against various diseases. Nevertheless, well-designed clinical studies are urgently needed to validate the preclinical findings.
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Affiliation(s)
- Ganesan Padmavathi
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology, Guwahati, Assam 781 039, India
| | - Nand Kishor Roy
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology, Guwahati, Assam 781 039, India
| | - Devivasha Bordoloi
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology, Guwahati, Assam 781 039, India
| | - Frank Arfuso
- Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, West Australia 6009, Australia
| | - Srishti Mishra
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; School of Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences Research Precinct, Curtin University, Western Australia 6009, Australia.
| | - Anupam Bishayee
- Department of Pharmaceutical Sciences, College of Pharmacy, Larkin Health Sciences Institute, Miami, FL 33169, USA.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology, Guwahati, Assam 781 039, India.
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Chang HL, Chang YM, Lai SC, Chen KM, Wang KC, Chiu TT, Chang FH, Hsu LS. Naringenin inhibits migration of lung cancer cells via the inhibition of matrix metalloproteinases-2 and -9. Exp Ther Med 2016; 13:739-744. [PMID: 28352360 DOI: 10.3892/etm.2016.3994] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2016] [Accepted: 09/15/2016] [Indexed: 12/11/2022] Open
Abstract
Lung cancer is among the most common causes of cancer-related mortality. It has a high mortality rate and resistance to chemotherapy due to its high metastatic potential. Naringenin, a bioactive compound identified in several fruits, displays anti-inflammatory and antitumor effects. Furthermore, naringenin mitigates the migration of several human cancer cell types. However, the effects of naringenin on lung cancer remain unclear. The current study investigated the mechanisms of naringenin on the migration of lung cancer A549 cells. The results indicate that significant alteration in A549 cell proliferation was observed in response to naringenin (0-300 µM) treatment for 24 and 48 h. Furthermore, a dose-dependent migration inhibition of A549 in the presence of naringenin was observed by healing and transwell migration assays. In addition, a zymography assay revealed that naringenin exhibited a concentration-dependent inhibition of matrix metalloproteinase (MMP)-2 and -9 activities. Furthermore, naringenin also inhibited the activities of AKT in a dose-dependent manner. These observations indicated that naringenin inhibited the migration of lung cancer A549 cells through several mechanisms, including the inhibition of AKT activities and reduction of MMP-2 and -9 activities.
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Affiliation(s)
- Huai-Lu Chang
- Department of Thoracic Surgery of Zouying Branch, Kaohsiung Armed Force General Hospital, Kaohsiung 81342, Taiwan, R.O.C
| | - Yuh-Ming Chang
- Department of Neurology, Division of Internal Medicine, Hsinchu Mackay Memorial Hospital, Hsinchu 30071, Taiwan, R.O.C.; Institutes of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C
| | - Shih-Chan Lai
- Department of Parasitology, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C
| | - Ke-Min Chen
- Department of Parasitology, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C
| | - Kuan-Chu Wang
- School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C
| | - Tsu-Ting Chiu
- School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C
| | - Fu-Hsin Chang
- Department of Biomedical Research, Asia-Pacific Biotech Developing, Kaohsiung 80681, Taiwan, R.O.C.; Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, R.O.C
| | - Li-Sung Hsu
- Institutes of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C.; Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 40201, Taiwan, R.O.C
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20
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Zhao C, Lv C, Li H, Du S, Liu X, Li Z, Xin W, Zhang W. Geniposide Protects Primary Cortical Neurons against Oligomeric Aβ1-42-Induced Neurotoxicity through a Mitochondrial Pathway. PLoS One 2016; 11:e0152551. [PMID: 27046221 PMCID: PMC4821580 DOI: 10.1371/journal.pone.0152551] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2015] [Accepted: 03/16/2016] [Indexed: 12/16/2022] Open
Abstract
Mitochondrial dysfunction plays a key role in the progression of Alzheimer’s disease (AD). The accumulation of amyloid-beta peptide (Aβ) in the brains of AD patients is thought to be closely related to neuronal mitochondrial dysfunction and oxidative stress. Therefore, protecting mitochondria from Aβ-induced neurotoxicity is an effective strategy for AD therapeutics. In a previous study, we found that geniposide, a pharmacologically active compound purified from gardenia fruit, has protective effects on oxidative stress and mitochondrial dysfunction in AD transgenic mouse models. However, whether geniposide has a protective effect on Aβ-induced neuronal dysfunction remains unknown. In the present study, we demonstrate that geniposide protects cultured primary cortical neurons from Aβ-mediated mitochondrial dysfunction by recovering ATP generation, mitochondrial membrane potential (MMP), and cytochrome c oxidase (CcO) and caspase 3/9 activity; by reducing ROS production and cytochrome c leakage; as well as by inhibiting apoptosis. These findings suggest that geniposide may attenuate Aβ-induced neuronal injury by inhibiting mitochondrial dysfunction and oxidative stress.
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Affiliation(s)
- Chunhui Zhao
- Beijing Area Major Laboratory of Protection and Utilization of Traditional Chinese Medicine, Beijing Normal University, Beijing, China
- College of Resources Science Technology, Beijing Normal University, Beijing, China
- Engineering Research Center of Natural Medicine, Ministry of Education, Beijing Normal University, Beijing, China
| | - Cui Lv
- Beijing Area Major Laboratory of Protection and Utilization of Traditional Chinese Medicine, Beijing Normal University, Beijing, China
- Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Shandong Academy of science, Jinan, China
- College of Resources Science Technology, Beijing Normal University, Beijing, China
| | - Hang Li
- Beijing Area Major Laboratory of Protection and Utilization of Traditional Chinese Medicine, Beijing Normal University, Beijing, China
- College of Resources Science Technology, Beijing Normal University, Beijing, China
- Engineering Research Center of Natural Medicine, Ministry of Education, Beijing Normal University, Beijing, China
| | - Shijing Du
- Beijing Area Major Laboratory of Protection and Utilization of Traditional Chinese Medicine, Beijing Normal University, Beijing, China
- College of Resources Science Technology, Beijing Normal University, Beijing, China
- Engineering Research Center of Natural Medicine, Ministry of Education, Beijing Normal University, Beijing, China
| | - Xiaoli Liu
- Engineering Research Center of Natural Medicine, Ministry of Education, Beijing Normal University, Beijing, China
- Engineering Research Center of Sanqi Biotechnology and Pharmaceutical, Yun Nan Province, Kunming, China
| | - Zhi Li
- Engineering Research Center of Natural Medicine, Ministry of Education, Beijing Normal University, Beijing, China
| | - Wenfeng Xin
- Engineering Research Center of Natural Medicine, Ministry of Education, Beijing Normal University, Beijing, China
- Engineering Research Center of Sanqi Biotechnology and Pharmaceutical, Yun Nan Province, Kunming, China
| | - Wensheng Zhang
- Beijing Area Major Laboratory of Protection and Utilization of Traditional Chinese Medicine, Beijing Normal University, Beijing, China
- College of Resources Science Technology, Beijing Normal University, Beijing, China
- Engineering Research Center of Natural Medicine, Ministry of Education, Beijing Normal University, Beijing, China
- Engineering Research Center of Sanqi Biotechnology and Pharmaceutical, Yun Nan Province, Kunming, China
- * E-mail:
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Shi M, Zhou W, Zhang J, Huang S, Wang H, Kai G. Methyl jasmonate induction of tanshinone biosynthesis in Salvia miltiorrhiza hairy roots is mediated by JASMONATE ZIM-DOMAIN repressor proteins. Sci Rep 2016; 6:20919. [PMID: 26875847 PMCID: PMC4753458 DOI: 10.1038/srep20919] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Accepted: 01/13/2016] [Indexed: 02/04/2023] Open
Abstract
Jasmonic acid (JA) is an important plant hormone involved in regulation of many aspects of plant growth and development including secondary metabolism and JASMONATE ZIM-DOMAIN (JAZ) proteins are key components in JA signal processes. In this study, two new JAZ genes named SmJAZ3 and SmJAZ9 were cloned from S. miltiorrhiza hairy roots and characterized. Expression profiles under methyl jasmonate (MJ) treatment revealed that SmJAZ3 and SmJAZ9 were both MJ-responsive. Subcellular localization assay showed that SmJAZ3 was located in nucleus while SmJAZ9 was preferentially in nucleus. Expression of SmJAZ3 and SmJAZ9 in S. miltiorrhiza hairy roots differently affected the production of tanshinone. Over-expression of SmJAZ3 or SmJAZ9 in hairy roots produced lower level of tanshinone compared with the control, tanshinone production was as low as 0.077 mg/g DW in line SmJAZ3-3 and 0.266 mg/g DW in line SmJAZ9-22. Whereas, down-regulation of SmJAZs enhanced tanshione production, the content of tanshinone increased to 2.48 fold in anti-SmJAZ3-3 line, and 1.35-fold in anti-SmJAZ9-23 line. Our work indicated that SmJAZ3 and SmJAZ9 are involved in regulation of tanshinone biosynthesis and act as repressive transcriptional regulators in the JA signaling pathway, which paves the way to further dissect molecular mechanism in details in the future.
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Affiliation(s)
- Min Shi
- Zhejiang Provincial Key Laboratory for Genetic Improvement and Quality Control of Medicinal Plants, Hangzhou Normal University, Hangzhou 310018, People's Republic of China.,Institute of Plant Biotechnology, Development Center of Plant Germplasm Resources, College of Life and Environment Sciences, Shanghai Normal University, Shanghai 200234, People's Republic of China
| | - Wei Zhou
- Institute of Plant Biotechnology, Development Center of Plant Germplasm Resources, College of Life and Environment Sciences, Shanghai Normal University, Shanghai 200234, People's Republic of China
| | - Jianlin Zhang
- Institute of Plant Biotechnology, Development Center of Plant Germplasm Resources, College of Life and Environment Sciences, Shanghai Normal University, Shanghai 200234, People's Republic of China
| | - Shengxiong Huang
- Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People's Republic of China
| | - Huizhong Wang
- Zhejiang Provincial Key Laboratory for Genetic Improvement and Quality Control of Medicinal Plants, Hangzhou Normal University, Hangzhou 310018, People's Republic of China
| | - Guoyin Kai
- Institute of Plant Biotechnology, Development Center of Plant Germplasm Resources, College of Life and Environment Sciences, Shanghai Normal University, Shanghai 200234, People's Republic of China
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Abstract
Natural compounds isolated from various plant sources have been used for therapeutic purpose for centuries. These compounds have been routinely used for the management of various chronic ailments and have gained considerable attention because of their significant efficacy and comparatively low side effects. Butein, a chacolnoid compound that has been isolated from various medicinal plants has exhibited a wide range of beneficial pharmacological effects, such as anti-inflammatory, anticancer, antioxidant, and anti-angiogenic in diverse disease models. This article briefly summarizes the past published literature related to the therapeutic and protective effects of butein, as demonstrated in various models of human chronic diseases. Further analysis of its important cellular targets, toxicity, and pharmacokinetic profile may further significantly expand its therapeutic application.
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Pacifico S, Piccolella S, Papale F, Nocera P, Lettieri A, Catauro M. A polyphenol complex from Thymus vulgaris L. plants cultivated in the Campania Region (Italy): New perspectives against neuroblastoma. J Funct Foods 2016. [DOI: 10.1016/j.jff.2015.11.008] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
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Padmavathi G, Rathnakaram SR, Monisha J, Bordoloi D, Roy NK, Kunnumakkara AB. Potential of butein, a tetrahydroxychalcone to obliterate cancer. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2015; 22:1163-1171. [PMID: 26598915 DOI: 10.1016/j.phymed.2015.08.015] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2015] [Revised: 08/15/2015] [Accepted: 08/23/2015] [Indexed: 06/05/2023]
Abstract
BACKGROUND Despite the major advances made in the field of cancer biology, it still remains one of the most fatal diseases in the world. It is now well established that natural products are safe and efficacious and have high potential in the prevention and treatment of different diseases including cancer. Butein is one such compound which is now found to have anti-cancer properties against various malignancies. PURPOSE To thoroughly review the literature available on the anti-cancer properties of butein against different cancers and its molecular targets. METHODS A thorough literature search has been done in PubMed for butein, its biological activities especially cancer and its molecular targets. RESULTS Our search retrieved several reports on the various biological activities of butein in which around 43 articles reported that butein shows potential anti-proliferative effect against a wide range of neoplasms and the molecular target varies with cancer types. Most often it targets NF-κB and its downstream pathways. In addition, butein induces the expression of genes which mediate the cell death and apoptosis in cancer cells. It also inhibits tumor angiogenesis, invasion and metastasis in prostate, liver and bladder cancers through the inhibition of MMPs, VEGF etc. Moreover, it inhibits the overexpression of several proteins and enzymes such as STAT3, ERK, CXCR4, COX-2, Akt, EGFR, Ras etc. involved in tumorigenesis. CONCLUSION Collectively, all these findings suggest the enormous potential and efficacy of butein as a multitargeted chemotherapeutic, chemopreventive and chemosensitizing agent against a wide range of cancers with minimal or no adverse side effects.
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Affiliation(s)
- Ganesan Padmavathi
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Sivakumar Raju Rathnakaram
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Javadi Monisha
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Devivasha Bordoloi
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Nand Kishor Roy
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India .
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Bertucci A, Prasetyanto EA, Septiadi D, Manicardi A, Brognara E, Gambari R, Corradini R, De Cola L. Combined Delivery of Temozolomide and Anti-miR221 PNA Using Mesoporous Silica Nanoparticles Induces Apoptosis in Resistant Glioma Cells. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2015; 11:5687-95. [PMID: 26395266 DOI: 10.1002/smll.201500540] [Citation(s) in RCA: 104] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Revised: 07/22/2015] [Indexed: 05/14/2023]
Abstract
Mesoporous silica nanoparticles (MSNPs), 100 nm in size, incorporating a Cy5 fluorophore within the silica framework, are synthesized and loaded with the anti-cancer drug temozolomide (TMZ), used in the treatment of gliomas. The surface of the particles is then decorated, using electrostatic interactions, with a polyarginine-peptide nucleic acid (R8-PNA) conjugate targeting the miR221 microRNA. The multi-functional nanosystem thus obtained is rapidly internalized into glioma C6 or T98G cells. The anti-miR activity of the PNA is retained, as confirmed by reverse transcription polymerase chain reaction (RT-PCR) measurements and induction of apoptosis is observed in temozolomide-resistant cell lines. The TMZ-loaded MSNPs show an enhanced pro-apoptotic effect, and the combined effect of TMZ and R8-PNA in the MSNPs shows the most effective induction of apoptosis (70.9% of apoptotic cells) thus far achieved in the temozolomide-resistant T98G cell line.
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Affiliation(s)
- Alessandro Bertucci
- Institut de science et d'ingénierie supramoléculaire (ISIS) & icFRC, Université de Strasbourg & CNRS, 8 Rue Gaspard Monge, Strasbourg, 67000, France
- Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze 17/A, Parma, 43124, Italy
| | - Eko Adi Prasetyanto
- Institut de science et d'ingénierie supramoléculaire (ISIS) & icFRC, Université de Strasbourg & CNRS, 8 Rue Gaspard Monge, Strasbourg, 67000, France
| | - Dedy Septiadi
- Institut de science et d'ingénierie supramoléculaire (ISIS) & icFRC, Université de Strasbourg & CNRS, 8 Rue Gaspard Monge, Strasbourg, 67000, France
| | - Alex Manicardi
- Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze 17/A, Parma, 43124, Italy
| | - Eleonora Brognara
- Dipartimento di Scienze della Vita e Biotecnologie, Università di Ferrara, Via Luigi Borsari 46, Ferrara, 44121, Italy
| | - Roberto Gambari
- Dipartimento di Scienze della Vita e Biotecnologie, Università di Ferrara, Via Luigi Borsari 46, Ferrara, 44121, Italy
| | - Roberto Corradini
- Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze 17/A, Parma, 43124, Italy
| | - Luisa De Cola
- Institut de science et d'ingénierie supramoléculaire (ISIS) & icFRC, Université de Strasbourg & CNRS, 8 Rue Gaspard Monge, Strasbourg, 67000, France
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Mitotic arrest deficient-like 1 is correlated with poor prognosis in small-cell lung cancer after surgical resection. Tumour Biol 2015; 37:4393-8. [PMID: 26499943 DOI: 10.1007/s13277-015-4302-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 10/20/2015] [Indexed: 02/07/2023] Open
Abstract
Mitotic arrest deficient-like 1 (MAD1L1) whose dysfunction is associated with chromosomal instability plays a pathogenic role in a few human cancers. However, the status of MAD1L1 expression in small-cell lung cancer (SCLC) remains unknown. Immunohistochemistry was used to determine the expression of MAD1L1 protein in 32 lymph node metastasis (LN-M) tissues and 88 primary SCLCs compared with 32 adjacent noncancerous tissues. The associations of MAD1L1 protein expression with the clinicopathologic features and clinical outcomes in patients with SCLC were analyzed. The ratio of MAD1L1 positive expression was higher in primary SCLC tissues (39.8 %) and LN-M tissues (46.9 %) compared with adjacent noncancerous tissues (9.4 %). MAD1L1 positive expression was associated with tumor-node-metastasis (TNM) stage (P = 0.003), International Association for the Study of Lung Cancer (IASLC) stage (P = 0.004), tumor size (P = 0.015), lymph node metastasis (P = 0.014), and recurrence (P < 0.001). Multivariate analysis suggested that MAD1L1 positive expression was an independent factor for overall survival (hazard ratio (HR) 2.002; 95 % confidence interval (CI) 1.065-3.763; P = 0.031) and recurrence-free survival (HR 2.263; 95 % CI 1.197-4.276; P = 0.012). To sum up, MAD1L1 positive expression may be associated with tumour progression and metastasis in SCLCs and may thus serve as a new biomarker for prognosis in these patients.
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Bai X, Ma Y, Zhang G. Butein suppresses cervical cancer growth through the PI3K/AKT/mTOR pathway. Oncol Rep 2015; 33:3085-92. [PMID: 25962638 DOI: 10.3892/or.2015.3922] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Accepted: 04/02/2015] [Indexed: 11/05/2022] Open
Abstract
Cervical cancer is the second most common women carcinoma worldwide and the fourth leading cause of cancer-associated mortality in women. Butein, a bioactive flavonoid isolated from numerous native plants, has been shown to induce apoptosis and inhibits migration and invasion in numerous human cancer cells. However, to the best of our knowledge, the effect of butein on human cervical cancer cells has not been reported. The present study aimed to determine the effect of butein on cell growth, apoptosis, migration and invasion and identify the associated molecular mechanism involved using HeLa human cervical cancer cells in vitro, and on tumor growth in a nude mouse model. It was found that butein notably inhibited cell viability, colony formation, migration and invasion, induced cell cycle at the G2/M stage and cell apoptosis, as well as enhanced caspase-3, -8 and -9 activity in HeLa cells in a dose-dependent manner. When administered intraperitoneally, butein inhibited the tumor growth of human cervical cancer xenograft tumors in the nude mouse model. Additionally, treatment with butein significantly increased reactive oxygen species (ROS) generation and reduced the phosphorylation of PI3K, AKT and mTOR expression, which contributes to the inhibition of the tumor growth of cervical cancer and reduction of oxidative stress. These findings suggested that butein serves as a potential therapeutic agent for the treatment of cervical cancer.
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Affiliation(s)
- Xue Bai
- No. 202 Hospital of PLA, Heping, Shenyang, Liaoning 110112, P.R. China
| | - Yaxin Ma
- Shenyang Military General Hospital, Shenyang, Liaoning 110115, P.R. China
| | - Guobin Zhang
- No. 202 Hospital of PLA, Heping, Shenyang, Liaoning 110112, P.R. China
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Lee SD, Choe JW, Lee BJ, Kang MH, Joo MK, Kim JH, Yeon JE, Park JJ, Kim JS, Bak YT. Butein effects in colitis and interleukin-6/signal transducer and activator of transcription 3 expression. World J Gastroenterol 2015; 21:465-474. [PMID: 25593461 PMCID: PMC4292277 DOI: 10.3748/wjg.v21.i2.465] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Revised: 06/08/2014] [Accepted: 07/11/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the effects of butein on inflammatory cytokines, matrix metalloproteinase-9 (MMP-9), and colitis in interleukin (IL)-10-/- mice.
METHODS: To synchronize colitis, 8- to 10-wk-old IL-10-/- mice were fed pellet-chow containing piroxicam for 2 wk. Subsequently, phosphate-buffered saline or butein (1 mg/kg per day, ip) was injected for 4 wk. Histologic scores, inflammatory cytokines, MMP-9 and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) expressions were analyzed in IL-10-/- mice and in Colo 205 cells.
RESULTS: Butein reduced the colonic inflammatory score by > 50%. Expression levels of IL-6, IL-1β, interferon (IFN)-γ and MMP-9 were decreased in the colons of mice exposed to butein, whereas other inflammatory cytokines (IL-17A, IL-21 and IL-22) were unchanged. Immunohistochemical staining for pSTAT3 and MMP-9 was significantly decreased in the butein-treated groups compared with the controls. Butein inhibited IL-6-induced activation of STAT3 in Colo 205 cells.
CONCLUSION: Butein ameliorated colitis in IL-10-/- mice by regulating IL-6/STAT3 and MMP-9 activation.
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Larráyoz IM, Martínez-Herrero S, García-Sanmartín J, Ochoa-Callejero L, Martínez A. Adrenomedullin and tumour microenvironment. J Transl Med 2014; 12:339. [PMID: 25475159 PMCID: PMC4272513 DOI: 10.1186/s12967-014-0339-2] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Accepted: 11/21/2014] [Indexed: 01/03/2023] Open
Abstract
Adrenomedullin (AM) is a regulatory peptide whose involvement in tumour progression is becoming more relevant with recent studies. AM is produced and secreted by the tumour cells but also by numerous stromal cells including macrophages, mast cells, endothelial cells, and vascular smooth muscle cells. Most cancer patients present high levels of circulating AM and in some cases these higher levels correlate with a worst prognosis. In some cases it has been shown that the high AM levels return to normal following surgical removal of the tumour, thus indicating the tumour as the source of this excessive production of AM. Expression of this peptide is a good investment for the tumour cell since AM acts as an autocrine/paracrine growth factor, prevents apoptosis-mediated cell death, increases tumour cell motility and metastasis, induces angiogenesis, and blocks immunosurveillance by inhibiting the immune system. In addition, AM expression gets rapidly activated by hypoxia through a HIF-1α mediated mechanism, thus characterizing AM as a major survival factor for tumour cells. Accordingly, a number of studies have shown that inhibition of this peptide or its receptors results in a significant reduction in tumour progression. In conclusion, AM is a great target for drug development and new drugs interfering with this system are being developed.
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Affiliation(s)
- Ignacio M Larráyoz
- Oncology Area, Center for Biomedical Research of La Rioja CIBIR, C/Piqueras 98, Logroño, 26006, Spain.
| | - Sonia Martínez-Herrero
- Oncology Area, Center for Biomedical Research of La Rioja CIBIR, C/Piqueras 98, Logroño, 26006, Spain.
| | - Josune García-Sanmartín
- Oncology Area, Center for Biomedical Research of La Rioja CIBIR, C/Piqueras 98, Logroño, 26006, Spain.
| | - Laura Ochoa-Callejero
- Oncology Area, Center for Biomedical Research of La Rioja CIBIR, C/Piqueras 98, Logroño, 26006, Spain.
| | - Alfredo Martínez
- Oncology Area, Center for Biomedical Research of La Rioja CIBIR, C/Piqueras 98, Logroño, 26006, Spain.
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Huang TC, Renuse S, Pinto S, Kumar P, Yang Y, Chaerkady R, Godsey B, Mendell JT, Halushka MK, Civin CI, Marchionni L, Pandey A. Identification of miR-145 targets through an integrated omics analysis. MOLECULAR BIOSYSTEMS 2014; 11:197-207. [PMID: 25354783 DOI: 10.1039/c4mb00585f] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and protein synthesis. To characterize functions of miRNAs and to assess their potential applications, we carried out an integrated multi-omics analysis to study miR-145, a miRNA that has been shown to suppress tumor growth. We employed gene expression profiling, miRNA profiling and quantitative proteomic analysis of a pancreatic cancer cell line. In our transcriptomic analysis, overexpression of miR-145 was found to suppress the expression of genes that are implicated in development of cancer such as ITGA11 and MAGEA4 in addition to previously described targets such as FSCN1, YES1 and PODXL. Based on miRNA profiling, overexpression of miR-145 also upregulated other miRNAs including miR-124, miR-133b and miR-125a-3p, all of which are implicated in suppression of tumors and are generally co-regulated with miR-145 in other cancers. Using the SILAC system, we identified miR-145-induced downregulation of several oncoproteins/cancer biomarkers including SET, RPA1, MCM2, ABCC1, SPTBN1 and SPTLC1. Luciferase assay validation carried out on a subset of downregulated candidate targets confirmed them to be novel direct targets of miR-145. Overall, this multi-omics approach provided insights into miR-145-mediated tumor suppression and could be used as a general strategy to study the targets of individual miRNAs.
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Affiliation(s)
- Tai-Chung Huang
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Han EB, Chang BY, Jung YS, Kim SY. Lantana camara Induces Apoptosis by Bcl-2 Family and Caspases Activation. Pathol Oncol Res 2014; 21:325-31. [DOI: 10.1007/s12253-014-9824-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Accepted: 07/24/2014] [Indexed: 11/29/2022]
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Min Z, Wang L, Jin J, Wang X, Zhu B, Chen H, Cheng Y. Pyrroloquinoline Quinone Induces Cancer Cell Apoptosis via Mitochondrial-Dependent Pathway and Down-Regulating Cellular Bcl-2 Protein Expression. J Cancer 2014; 5:609-24. [PMID: 25161699 PMCID: PMC4143536 DOI: 10.7150/jca.9002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Accepted: 06/16/2014] [Indexed: 02/04/2023] Open
Abstract
Pyrroloquinoline quinone (PQQ) has been reported as a promising agent that might contribute to tumor cell apoptosis and death, yet little is known on its mechanisms. In current study, the effect of PQQ on cell proliferation and mitochondrial-dependent apoptosis were examined in 3 solid tumor cell lines (A549, Neuro-2A and HCC-LM3). PQQ treatment at low to medium dosage exhibited potent anti-tumor activity on A549 and Neuro-2A cells, while had comparably minimal impact on the viabilities of 2 human normal cell lines (HRPTEpiC and HUVEC). The apoptosis of the 3 tumor cell lines induced by PQQ were increased in a concentration-dependent manner, which might be attributed to the accumulation of intracellular reactive oxygen species (ROS), decline in ATP levels and dissipation of mitochondrial membrane potential (MMP), in conjunction with down-regulation of Bcl-2 protein expression, up-regulation of activated caspase-3, and disturbed phosphorylated MAPK protein levels. PQQ induced tumor cells apoptosis was significantly alleviated by pan-caspase inhibitor Z-VAD-FMK. The present work highlights the potential capability of PQQ as an anti-tumor agent with low toxicity towards normal cells through activating mitochondrial-dependent apoptosis pathways, and warrants its development for cancer therapy.
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Affiliation(s)
- Zhihui Min
- 1. Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China; ; 2. Biomedical Research Center, Zhongshan Hospital Qingpu Branch, Shanghai, 201700 China; ; 3. Shanghai key laboratory of organ transplantation, Shanghai, 200032, China
| | - Lingyan Wang
- 1. Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jianjun Jin
- 1. Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China; ; 2. Biomedical Research Center, Zhongshan Hospital Qingpu Branch, Shanghai, 201700 China
| | - Xiangdong Wang
- 1. Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China; ; 2. Biomedical Research Center, Zhongshan Hospital Qingpu Branch, Shanghai, 201700 China; ; 3. Shanghai key laboratory of organ transplantation, Shanghai, 200032, China
| | - Bijun Zhu
- 1. Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Hao Chen
- 4. Department of Cardiothoracic Surgery, Tongji Hospital, Tongji University, Shanghai 200065, China
| | - Yunfeng Cheng
- 1. Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China; ; 3. Shanghai key laboratory of organ transplantation, Shanghai, 200032, China; ; 5. Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; ; 6. Department of Hematology, Zhongshan Hospital Qingpu Branch, Shanghai, 201700 China
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Identification of temozolomide resistance factors in glioblastoma via integrative miRNA/mRNA regulatory network analysis. Sci Rep 2014; 4:5260. [PMID: 24919120 PMCID: PMC4052714 DOI: 10.1038/srep05260] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Accepted: 05/23/2014] [Indexed: 12/21/2022] Open
Abstract
Drug resistance is a major issue in the treatment of glioblastoma. Almost all glioblastomas are intrinsically resistant to chemotherapeutic temozolomide (TMZ) or develop resistance during treatment. The interaction networks of microRNAs (miRNAs) and mRNAs likely regulate most biological processes and can be employed to better understand complex processes including drug resistance in cancer. In this study, we examined if integrative miRNA/mRNA network analysis using the web-service tool mirConnX could be used to identify drug resistance factors in glioblastoma. We used TMZ-resistant glioblastoma cells and their integrated miRNA/mRNA networks to identify TMZ-sensitizing factors. TMZ resistance was previously induced in glioblastoma cell lines U87, Hs683, and LNZ308. miRNA/mRNA expression profiling of these cells and integration of the profiles using mirConnX resulted in the identification of plant homeodomain (PHD)-like finger 6 (PHF6) as a potential TMZ-sensitizing factor in resistant glioblastoma cells. Analysis of PHF6 expression showed significant upregulation in glioblastoma as compared to normal tissue. Interference with PHF6 expression in three TMZ-resistant subclones significantly enhanced TMZ-induced cell kill in two of these cell lines. Altogether, these results demonstrate that mirConnX is a feasible and useful tool to investigate miRNA/mRNA interactions in TMZ-resistant cells and has potential to identify drug resistance factors in glioblastoma.
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Cho SG, Woo SM, Ko SG. Butein suppresses breast cancer growth by reducing a production of intracellular reactive oxygen species. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2014; 33:51. [PMID: 24919544 PMCID: PMC4064524 DOI: 10.1186/1756-9966-33-51] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Accepted: 06/02/2014] [Indexed: 02/08/2023]
Abstract
Background Butein has various functions in human diseases including cancer. While anti-cancer effects of butein have been revealed, it is urgent to understand a unique role of butein against cancer. In this study, we demonstrate that butein inhibition of reactive oxygen species (ROS) production results in suppression of breast cancer growth. Methods Different breast cancer cell lines were treated with butein and then subjected to cell viability and apoptosis assays. Butein-sensitive or -resistant breast cancer cells were injected into mammary fat pads of immunocompromised mice and then butein was injected. Breast cancer cells were categorized on the basis of butein sensitivity. Results Butein reduced viabilities of different breast cancer cells, while not affecting those of HER2-positive (HER2+) HCC-1419, SKBR-3 and HCC-2218 breast cancer cells. Butein reduction of ROS levels was correlated with apoptotic cell death. Furthermore, butein reduction of ROS level led to inhibitions of AKT phosphorylation. N-acetyl-L-cysteine (NAC), a free radical scavenger, also reduced ROS production and AKT phosphorylation, resulting in apoptotic cell death. In contrast, inhibitory effects of both butein and NAC on ROS production and AKT phosphorylation were not detected in butein-resistant HER2+ HCC-1419, SKBR-3 and HCC-2218 cells. In the in vivo tumor growth assays, butein inhibited tumor growth of butein-sensitive HER2+ BT-474 cells, while not affecting that of butein-resistant HER2+ HCC-1419 cells. Moreover, butein inhibition of ROS production and AKT phosphorylation was confirmed by in vivo tumor growth assays. Conclusions Our study first reveals that butein causes breast cancer cell death by the reduction of ROS production. Therefore, our finding provides better knowledge for butein effect on breast cancer and also suggests its treatment option.
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Affiliation(s)
| | | | - Seong-Gyu Ko
- Department of Preventive Medicine, College of Korean Medicine, Kyung Hee University, 1 Hoegi, Seoul 130701, Korea.
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Nam HJ, van Deursen JM. Cyclin B2 and p53 control proper timing of centrosome separation. Nat Cell Biol 2014; 16:538-49. [PMID: 24776885 PMCID: PMC4379487 DOI: 10.1038/ncb2952] [Citation(s) in RCA: 129] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Accepted: 03/17/2014] [Indexed: 12/14/2022]
Abstract
Cyclins B1 and B2 are frequently elevated in human cancers and are associated with tumour aggressiveness and poor clinical outcome; however, whether and how B-type cyclins drive tumorigenesis is unknown. Here we show that cyclin B1 and B2 transgenic mice are highly prone to tumours, including tumour types where B-type cyclins serve as prognosticators. Cyclins B1 and B2 both induce aneuploidy when overexpressed but through distinct mechanisms, with cyclin B1 inhibiting separase activation, leading to anaphase bridges, and cyclin B2 triggering aurora-A-mediated Plk1 hyperactivation, resulting in accelerated centrosome separation and lagging chromosomes. Complementary experiments revealed that cyclin B2 and p53 act antagonistically to control aurora-A-mediated centrosome splitting and accurate chromosome segregation in normal cells. These data demonstrate a causative link between B-type cyclin overexpression and tumour pathophysiology, and uncover previously unknown functions of cyclin B2 and p53 in centrosome separation that may be perturbed in many human cancers.
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Affiliation(s)
- Hyun-Ja Nam
- Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
| | - Jan M. van Deursen
- Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
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Brognara E, Fabbri E, Bazzoli E, Montagner G, Ghimenton C, Eccher A, Cantù C, Manicardi A, Bianchi N, Finotti A, Breveglieri G, Borgatti M, Corradini R, Bezzerri V, Cabrini G, Gambari R. Uptake by human glioma cell lines and biological effects of a peptide-nucleic acids targeting miR-221. J Neurooncol 2014; 118:19-28. [PMID: 24595467 DOI: 10.1007/s11060-014-1405-6] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2013] [Accepted: 02/17/2014] [Indexed: 10/25/2022]
Abstract
MicroRNAs are a family of small noncoding RNAs regulating gene expression by sequence-selective mRNA targeting, leading to a translational repression or mRNA degradation. The oncomiR miR-221 is highly expressed in human gliomas, as confirmed in this study in samples of low and high grade gliomas, as well in the cell lines U251, U373 and T98G. In order to alter the biological functions of miR-221, a peptide nucleic acid targeting miR-221 (R8-PNA-a221) was produced, bearing a oligoarginine peptide (R8) to facilitate uptake by glioma cells. The effects of R8-PNA-a221 were analyzed in U251, U373 and T98G glioma cells and found to strongly inhibit miR-221. In addition, the effects of R8-PNA-a221 on p27(Kip1) (a target of miR-221) were analyzed in U251 and T98G cells by RT-qPCR and by Western blotting. No change of p27(Kip1) mRNA content occurs in U251 cells in the presence of PNA-a221 (lacking the R8 peptide), whereas significant increase of p27(Kip1) mRNA was observed with the R8-PNA-a221. These data were confirmed by Western blot assay. A clear increment of p27(Kip1) protein expression in the samples treated with R8-PNA-a221 was detected. In addition, R8-PNA-a221 was found able to increase TIMP3 expression (another target of miR-221) in T98G cells. These results suggest that PNAs against oncomiRNA miR-221 might be proposed for experimental treatment of human gliomas.
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Affiliation(s)
- Eleonora Brognara
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
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Pallante P, Battista S, Pierantoni GM, Fusco A. Deregulation of microRNA expression in thyroid neoplasias. Nat Rev Endocrinol 2014; 10:88-101. [PMID: 24247220 DOI: 10.1038/nrendo.2013.223] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
MicroRNAs (miRNAs) have emerged as a class of powerful gene expression regulators. Acting at the post-transcriptional level, miRNAs modulate the expression of at least one-third of the mRNAs that are encoded by the human genome. The expression of a single gene can be regulated by several miRNAs, and every miRNA has more than one target gene. Thus, the miRNA regulatory circuit, which affects essential cellular functions, is of enormous complexity. Moreover, a fundamental role for miRNAs has been determined in the onset and progression of human cancers. Here, we summarize the main alterations in miRNA expression that have been identified in thyroid neoplasias and examine the mechanisms through which miRNA deregulation might promote thyroid cell transformation. We also discuss how the emerging knowledge on miRNA deregulation could be harnessed for the diagnosis and treatment of thyroid neoplasias.
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Affiliation(s)
- Pierlorenzo Pallante
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), Università degli Studi di Napoli "Federico II", via Pansini 5, 80131 Naples, Italy
| | - Sabrina Battista
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), Università degli Studi di Napoli "Federico II", via Pansini 5, 80131 Naples, Italy
| | - Giovanna Maria Pierantoni
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), Università degli Studi di Napoli "Federico II", via Pansini 5, 80131 Naples, Italy
| | - Alfredo Fusco
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), Università degli Studi di Napoli "Federico II", via Pansini 5, 80131 Naples, Italy
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Kapoor S. Butein and its emerging anti-proliferative and pro-apoptotic effects in systemic malignancies. Curr Eye Res 2013; 38:810. [PMID: 23621171 DOI: 10.3109/02713683.2013.785571] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Yang LH, Ho YJ, Lin JF, Yeh CW, Kao SH, Hsu LS. Butein inhibits the proliferation of breast cancer cells through generation of reactive oxygen species and modulation of ERK and p38 activities. Mol Med Rep 2012; 6:1126-32. [PMID: 22895548 DOI: 10.3892/mmr.2012.1023] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2012] [Accepted: 06/14/2012] [Indexed: 11/05/2022] Open
Abstract
Butein (3,4,2',4'-tetrahydroxychalcone) is a polyphenol derived from various natural plants and is capable of inducing several types of death in cancer cells. However, the molecular mechanisms underlying butein-induced breast cancer cell apoptosis remain unknown. The present study aimed to prove that butein inhibits the proliferation of MDA-MB‑231 human breast cancer cells in a dose- and time-dependent manner. Butein markedly induced the generation of reactive oxygen species (ROS), decreased the phosphorylation of extracellular signal-regulated kinase (ERK), increased p38 activity, diminished Bcl-2 expression, induced caspase 3 cleavage and was associated with poly(ADP-ribose) polymerase (PARP) cleavage. Our findings also indicate that ROS may play an important role in butein-induced apoptosis, as pre-treatment with the antioxidant, N-acetyl cysteine (NAC), prevented butein-induced apoptosis. In conclusion, our results demonstrate that butein inhibits the proliferation of breast cancer cells through the generation of ROS and the modulation of ERK and p38 activities. We also demonstrate that these effects may be abrogaged by pre-treatment with NAC. Our results suggest that butein may function as a potential therapeutic agent for the treatment of breast cancer.
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Affiliation(s)
- Li-Heng Yang
- Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan, ROC
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