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Yuan J, Liu Z, Dong Y, Gao F, Xia X, Wang P, Luo Y, Zhang Z, Yan D, Zhang W. Pioneering 4,11-Dioxo-4,11-dihydro-1 H-anthra[2,3- d]imidazol-3-ium Compounds as Promising Survivin Inhibitors by Targeting ILF3/NF110 for Cancer Therapy. J Med Chem 2023; 66:16843-16868. [PMID: 38079530 DOI: 10.1021/acs.jmedchem.3c01551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2023]
Abstract
Survivin is a novel attractive target for cancer therapy; however, it is considered undruggable because it lacks enzymatic activities. Herein, we describe our efforts toward the discovery of a novel series of 4,11-dioxo-4,11-dihydro-1H-anthra[2,3-d]imidazol-3-ium derivatives as survivin inhibitors by targeting ILF3/NF110. Intensive structural modifications led us to identify a lead compound AQIM-I, which remarkably inhibited nonsmall cell lung cancer cells A549 with an IC50 value of 9 nM and solid tumor cell proliferation with more than 700-fold selectivity against human normal cells. Further biological studies revealed that compound AQIM-I significantly inhibited survivin expression and colony formation and induced ROS production, apoptosis, cell cycle arrest, DNA damage, and autophagy. Furthermore, the promoter-luciferase reporter assay showed that AQIM-I attenuated the survivin promoter activity enhanced by the overexpression of ILF3/NF110 in a concentration-dependent manner, and specific binding (KD = 163 nM) of AQIM-I to ILF3/NF110 was detected by surface plasmon resonance.
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Affiliation(s)
- Jing Yuan
- Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
| | - Zhanxiong Liu
- Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
| | - Yachun Dong
- Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
| | - Feng Gao
- Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
| | - Xuelin Xia
- Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
| | - Penghui Wang
- Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
| | - Yanli Luo
- Department of Pathology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, P. R. China
| | - Zhenfeng Zhang
- Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
| | - Deyue Yan
- Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
| | - Wanbin Zhang
- Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
- Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
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Akçay EY, Tepeoğlu M, Atılgan AO, Yağcı S, Kılıç D, Özdemir BH. The prognostic significance of tumor budding and the expression of focal adhesion kinase and survivin in lung adenocarcinoma. Ann Diagn Pathol 2023; 66:152167. [PMID: 37329750 DOI: 10.1016/j.anndiagpath.2023.152167] [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: 04/25/2023] [Revised: 05/15/2023] [Accepted: 05/18/2023] [Indexed: 06/19/2023]
Abstract
OBJECTIVES Adenocarcinoma is the tumor group with the highest incidence among lung cancers with poor prognosis. Tumor budding (TB) is the migration of single tumor cells or small clusters of cells from the neoplastic epithelium to the invasive front of the tumor. Focal adhesion kinase (FAK) and survivin are considered as poor prognostic factors in several tumors. Hence, we investigated TB, FAK, and survivin expression in lung adenocarcinoma. METHODS The study included 103 cases of lung adenocarcinoma in the resection materials. In tumoral tissues; TB was counted and scored in one high-power field (HPF), as low if <5 in 1 HPF and high if ≥5 in 1 HPF. FAK and survivin were studied immunohistochemically. RESULTS The mean number of TB in 1 HPF is 3.96 ± 2.8. Low-grade TB was observed in 45 (43.7 %) and high-grade TB was observed in 58 (56.3 %) patients. There was a positive correlation between TB and pT stage (p = 0.017), clinical stage (p = 0.002), lymphovascular invasion (p = 0.001), and perineural invasion (p = 0.045). The 4-year survival rate in patients was 90 % in those with low-grade TB and 60 % in those with high-grade TB (p = 0.001). FAK and survivin expressions were significantly increased in tumors with high-grade TB (p < 0.05). CONCLUSION A significant correlation was found between the grade of TB and pT stage, clinical stage, lymphovascular and perineural invasion in lung adenocarcinoma. TB can be considered as a histological parameter showing poor prognosis. It is thought that high expression of FAK and survivin also affect the prognosis in these patients by increasing TB.
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Affiliation(s)
- Eda Yılmaz Akçay
- Department of Pathology, Baskent University, Faculty of Medicine, Bahcelievler, Ankara, Turkey
| | - Merih Tepeoğlu
- Department of Pathology, Baskent University, Faculty of Medicine, Bahcelievler, Ankara, Turkey.
| | - Alev Ok Atılgan
- Department of Pathology, Baskent University, Faculty of Medicine, Bahcelievler, Ankara, Turkey
| | - Sergen Yağcı
- Department of Pathology, Baskent University, Faculty of Medicine, Bahcelievler, Ankara, Turkey
| | - Dalokay Kılıç
- Department of Thoracic Surgery, Baskent University, Faculty of Medicine, Bahcelievler, Ankara, Turkey
| | - B Handan Özdemir
- Department of Pathology, Baskent University, Faculty of Medicine, Bahcelievler, Ankara, Turkey
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Londero AP, Orsaria M, Viola L, Marzinotto S, Bertozzi S, Galvano E, Andreetta C, Mariuzzi L. Survivin, Sonic hedgehog, Krüppel-like factors, and p53 pathway in serous ovarian cancer: an immunohistochemical study. Hum Pathol 2022; 127:92-101. [PMID: 35777700 DOI: 10.1016/j.humpath.2022.06.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 06/22/2022] [Accepted: 06/22/2022] [Indexed: 11/04/2022]
Abstract
OBJECTIVE Survivin was previously associated with tumor stage and grade in ovarian cancer and interfered with the tumor's drug sensitivity. In addition, Survivin expression was found to be regulated by the Sonic hedgehog (Shh) pathway, Krüppel-like factor (KLF) family proteins, and p53 pathway. The main aim of this study was to assess the prognostic values of immunohistochemical expression of Survivin, Klf5, Klf11, Shh, p53, p21, and Mdm2 in a cohort of high grade ovarian serous cancers. Other aims were comparison between high- and low-grade ovarian serous cancer and between platinum-resistant and the other cases. The last aim was to assess the correlations among the immunohistochemical expression of the studied proteins. METHODS Retrospective cohort study to assess immunohistochemical expression of Survivin, Klf5, Klf11, Shh, p53, p21, and Mdm2 in a tissue microarray of primary tumor samples among 73 women affected by high-grade ovarian serous cancer and 9 by low-grade ovarian serous cancer. RESULTS Klf5 and Shh cytoplasmic staining were associated to short overall survival (HR 6.38, CI.95 2.25 - 18.01, p<0.05 and 2.25, CI.95 1.19-4.23, p<0.05 respectively). In addition, cytoplasmic Klf5 staining, high Klf11 and p53 nuclear staining were associated with platinum resistance (p<0.05). Cytoplasmic Shh score was significantly correlated to the immunohistochemical expression of Klf5, Klf11, Mdm2, and Survivin. CONCLUSIONS Our data highlight the possible role of Klf5 and Shh as prognostic markers, meanwhile confirming the role of the KLF family proteins and p53 in ovarian cancer drug resistance. Moreover, Shh appeared to play an important role in the intracellular network of ovarian neoplasia.
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Affiliation(s)
- Ambrogio P Londero
- Academic Unit of Obstetrics and Gynaecology; Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Infant Health, University of Genoa, Genova, Italy; Ennergi Research (non-profit organization), 33050 Lestizza (UD).
| | - Maria Orsaria
- Institute of Pathologic Anatomy, DAME, University Hospital of Udine, 33100 Udine (UD)
| | - Luigi Viola
- Department of Radiology & Radiotherapy, University of Campania "Luigi Vanvitelli", 80100 Naples, Italy
| | - Stefania Marzinotto
- Institute of Pathologic Anatomy, DAME, University Hospital of Udine, 33100 Udine (UD)
| | - Serena Bertozzi
- Ennergi Research (non-profit organization), 33050 Lestizza (UD); Breast Unit, DAME, University Hospital of Udine, 33100 Udine (UD)
| | - Elena Galvano
- Lombardi Comprehensive Cancer Center (LCCC), Georgetown University, Washington, DC 20057, USA
| | | | - Laura Mariuzzi
- Institute of Pathologic Anatomy, DAME, University Hospital of Udine, 33100 Udine (UD)
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Ubaid S, Pandey S, Akhtar MS, Rumman M, Singh B, Mahdi AA. SIRT1 Mediates Neuroprotective and Neurorescue Effects of Camel α-Lactalbumin and Oleic Acid Complex on Rotenone-Induced Parkinson's Disease. ACS Chem Neurosci 2022; 13:1263-1272. [PMID: 35385250 DOI: 10.1021/acschemneuro.1c00876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Parkinson's disease (PD) is the second most common devastating neurodegenerative disorder. Presently used therapies for PD have severe side effects and are limited to only temporary improvement. Therefore, a new therapeutic approach to treat PD urgently needs to be developed. α-Lactalbumin, the most abundant milk protein in camel milk, has been attributed to various medicinal properties. This study intended to investigate the neuroprotective efficacy of the camel α-lactalbumin and oleic acid (CLOA) complex. One mechanism postulated to underlie neuroprotection by the CLOA complex is the induction of silent information regulatory protein (SIRT1). SIRT1 is known to be involved in several pathological and physiological processes, and it has been suggested that SIRT1 plays a protective role in PD. Oxidative stress, inflammation, mitochondrial dysfunction, and apoptosis are involved in PD pathogenesis. Our results revealed that SIRT1 inhibits oxidative stress by maintaining HIF-1α in a deacetylated state. SIRT1 upregulates the expression of FOXO3a and HSF-1, thus inhibiting apoptosis and maintaining the homeostasis of cellular proteins. Increased SIRT1 expression reduces the levels of TNF-α, IL-6, and IL-8, which in turn inhibits neuroinflammation. In addition to SIRT1, the CLOA complex also enhances the expression of survivin and leptin and promotes the survival of neuroblastoma cells. Altogether, our results suggest that the CLOA complex might be a novel therapeutic molecule that could ameliorate neuronal cell damage in PD.
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Affiliation(s)
- Saba Ubaid
- Department of Biochemistry, King George’s Medical University (KGMU), Lucknow 226003, Uttar Pradesh, India
| | - Shivani Pandey
- Department of Biochemistry, King George’s Medical University (KGMU), Lucknow 226003, Uttar Pradesh, India
| | - Mohd. Sohail Akhtar
- Division of Molecular & Structural Biology, Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India
| | - Mohammad Rumman
- Department of Biochemistry, King George’s Medical University (KGMU), Lucknow 226003, Uttar Pradesh, India
| | - Babita Singh
- Department of Biochemistry, King George’s Medical University (KGMU), Lucknow 226003, Uttar Pradesh, India
| | - Abbas Ali Mahdi
- Department of Biochemistry, King George’s Medical University (KGMU), Lucknow 226003, Uttar Pradesh, India
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Subramaiam H, Chu WL, Radhakrishnan AK, Chakravarthi S, Selvaduray KR, Kok YY. Evaluating Anticancer and Immunomodulatory Effects of Spirulina (Arthrospira) platensis and Gamma-Tocotrienol Supplementation in a Syngeneic Mouse Model of Breast Cancer. Nutrients 2021; 13:2320. [PMID: 34371830 PMCID: PMC8308567 DOI: 10.3390/nu13072320] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/18/2021] [Accepted: 06/23/2021] [Indexed: 12/13/2022] Open
Abstract
Nutrition can modulate host immune responses as well as promote anticancer effects. In this study, two nutritional supplements, namely gamma-tocotrienol (γT3) and Spirulina, were evaluated for their immune-enhancing and anticancer effects in a syngeneic mouse model of breast cancer (BC). Five-week-old female BALB/c mice were fed Spirulina, γT3, or a combination of Spirulina and γT3 (Spirulina + γT3) for 56 days. The mice were inoculated with 4T1 cells into their mammary fat pad on day 28 to induce BC. The animals were culled on day 56 for various analyses. A significant reduction (p < 0.05) in tumor volume was only observed on day 37 and 49 in animals fed with the combination of γT3 + Spirulina. There was a marked increase (p < 0.05) of CD4/CD127+ T-cells and decrease (p < 0.05) of T-regulatory cells in peripheral blood from mice fed with either γT3 or Spirulina. The breast tissue of the combined group showed abundant areas of necrosis, but did not prevent metastasis to the liver. Although there was a significant increase (p < 0.05) of MIG-6 and Cadherin 13 expression in tumors from γT3-fed animals, there were no significant (p > 0.05) differences in the expression of MIG-6, Cadherin 13, BIRC5, and Serpine1 upon combined feeding. This showed that combined γT3 + Spirulina treatment did not show any synergistic anticancer effects in this study model.
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Affiliation(s)
- Hemavathy Subramaiam
- School of Medicine, International Medical University, Kuala Lumpur 57000, Malaysia
| | - Wan-Loy Chu
- School of Postgraduate Studies, International Medical University, Kuala Lumpur 57000, Malaysia
| | - Ammu Kutty Radhakrishnan
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Malaysia
| | - Srikumar Chakravarthi
- Faculty of Medicine, Bioscience and Nursing, MAHSA University, Bandar Saujana Putra 42610, Malaysia
| | - Kanga Rani Selvaduray
- Product Development and Advisory Services Division, Malaysian Palm Oil Board, Bandar Baru Bangi 43000, Malaysia
| | - Yih-Yih Kok
- School of Health Sciences, International Medical University, Kuala Lumpur 57000, Malaysia
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Dai X, Wu G, Zhang Y, Zhang X, Yin R, Qi X, Li J, Jiang T. Design, Synthesis, and In Vitro/In Vivo Anti-Cancer Activities of Novel (20 S)-10,11-Methylenedioxy-Camptothecin Heterocyclic Derivatives. Int J Mol Sci 2020; 21:E8495. [PMID: 33187360 PMCID: PMC7697887 DOI: 10.3390/ijms21228495] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 11/04/2020] [Accepted: 11/09/2020] [Indexed: 01/11/2023] Open
Abstract
A novel camptothecin analogue, (20S)-10,11-methylenedioxy-camptothecin (FL118), has been proven to show significant antitumor efficacy for a wide variety of solid tumors. However, the further development of FL118 is severely hindered due to its extremely poor water solubility and adverse side effects. Here, two series of novel 20-substituted (20S)-10,11-methylenedioxy-camptothecin coupled with 5-substituted uracils and other heterocyclic rings through glycine were synthesized. All the derivatives showed superior cytotoxic activities in vitro with IC50 values in the nanomolar range. Among them, 12e displayed higher cytotoxic activities in several cancer cell lines with better water solubility than FL118. Our results further showed that, like FL118, 12e inhibited cell proliferation resulting from cell cycle arrest and apoptosis by blocking the anti-apoptotic gene transcription of survivin, Mcl-1, Bcl-2, and XIAP in both A549 cells and NCI-H446 cells. Furthermore, 12e did not show any inhibitory activity on Topo I, which is involved in hematopoietic toxicity. In vivo, 12e showed similar antitumor efficacy to FL118 but lower toxicity. Our findings indicate that 12e is a promising therapeutic agent for cancer treatment, and the core structure of FL118 represents a promising platform to generate novel FL118-based antitumor drugs.
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Affiliation(s)
- Xiufen Dai
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; (X.D.); (G.W.); (Y.Z.); (X.Z.); (R.Y.); (T.J.)
| | - Guanzhao Wu
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; (X.D.); (G.W.); (Y.Z.); (X.Z.); (R.Y.); (T.J.)
| | - Yixuan Zhang
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; (X.D.); (G.W.); (Y.Z.); (X.Z.); (R.Y.); (T.J.)
| | - Xiaomin Zhang
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; (X.D.); (G.W.); (Y.Z.); (X.Z.); (R.Y.); (T.J.)
- Open Studio for Druggability Research of Marine Natural Products, Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China
| | - Ruijuan Yin
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; (X.D.); (G.W.); (Y.Z.); (X.Z.); (R.Y.); (T.J.)
| | - Xin Qi
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; (X.D.); (G.W.); (Y.Z.); (X.Z.); (R.Y.); (T.J.)
| | - Jing Li
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; (X.D.); (G.W.); (Y.Z.); (X.Z.); (R.Y.); (T.J.)
- Open Studio for Druggability Research of Marine Natural Products, Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China
| | - Tao Jiang
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; (X.D.); (G.W.); (Y.Z.); (X.Z.); (R.Y.); (T.J.)
- Open Studio for Druggability Research of Marine Natural Products, Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China
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7
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Adamopoulos PG, Tsiakanikas P, Adam EE, Scorilas A. Unraveling novel survivin mRNA transcripts in cancer cells using an in-house developed targeted high-throughput sequencing approach. Genomics 2020; 113:573-581. [PMID: 32980523 DOI: 10.1016/j.ygeno.2020.09.053] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 09/03/2020] [Accepted: 09/22/2020] [Indexed: 12/17/2022]
Abstract
The human baculoviral IAP repeat containing 5 (BIRC5), also known as survivin, is a conserved member of the inhibitor of apoptosis protein (IAPs) family, which is normally expressed during embryonic and fetal development. Although the expression levels of survivin are low in terminally differentiated cells and/or tissues, they can be found notably increased in certain pathological conditions including malignant tumors. Conventional cloning and sequencing techniques have already confirmed that alternative splicing events of the survivin pre-mRNA result in five distinct alternative transcript variants. In the present study, however, we implemented an innovative, in-house developed, targeted DNA-seq assay to identify novel survivin alternative transcript variants with increased depth and coverage that high-throughput sequencing approaches offer. Bioinformatics analysis of the derived NGS datasets unveiled several novel splice junctions between annotated exons of survivin gene as well as the existence of a novel exon of 117 nt, spanning between the annotated exons 3 and 3B. Validation of the NGS findings with PCR-based assays, using variant-specific primers, led to the identification of fourteen novel survivin alternative splice variants (BIRC5 v.4 - v.17), which demonstrate wide expression profiles in a broad established panel of human cell lines. Although the presented novel findings provide a crystal-clear overview of the survivin mRNAs that are actually generated from the pre-mRNA, future studies should focus on the impending necessity of characterizing the biological function of all novel alternative transcript variants as well as the putative protein isoforms. Such studies will further contribute to our understanding of how the balance between survivin isoforms regulate malignant cell proliferation and apoptosis, providing novel diagnostic, prognostic and predictive biomarkers as well as therapeutic targets.
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Affiliation(s)
- Panagiotis G Adamopoulos
- Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Tsiakanikas
- Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Eleni E Adam
- Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Andreas Scorilas
- Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece.
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Zhang Y, Yin R, Wu G, Yu M, Liu J, Wang X, Liu X, Guan H, Yu R, Jiang T. Self-assembling nanoparticles of dually hydrophobic prodrugs constructed from camptothecin analogue for cancer therapy. Eur J Med Chem 2020; 200:112365. [PMID: 32460113 DOI: 10.1016/j.ejmech.2020.112365] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 04/17/2020] [Accepted: 04/18/2020] [Indexed: 11/19/2022]
Abstract
Nanomedicines have shown success in cancer therapy in recent years because of their excellent solubility in aqueous solution and drug accumulation through controlled release in tumor tissues, but the preparation of most nanomedicines still requires ionic materials, surfactants or the amphiphilic structure to maintain nanoparticle stability and function. In this study, we developed a couple of novel dually hydrophobic prodrugs (DHPs) by combining two hydrophobic compounds through different linkers and elaborated their self-assembly mechanisms by virtue of computational simulation. Importantly, without using any excipients, FL-2 NPs exhibited significantly prolonged retention in blood circulation and displayed a remarkable anti-tumor effect at very low concentration in vivo. Both DHPs consisted of camptothecin structural analogue(FL118) and a marine natural product (ES-285). Comparative experiments proved that these compounds could quickly form nanoparticles by way of simple preparation and remained relatively stable for long periods in PBS. FL-2 NPs linked with a disulphide bond could rapidly release bioactive FL118 after being triggered by endogenous reductive stimulus to exert anti-cancer effects. Overall, this study provides a new strategy for design of therapeutic nanomedicines consisting of dually hydrophobic molecules for cancer therapy.
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Affiliation(s)
- Yixuan Zhang
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Ruijuan Yin
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Guanzhao Wu
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Mingming Yu
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Jiannan Liu
- Department of Pharmacy, Qingdao Hiserve Medical Center, Qingdao, 266003, China
| | - Xueting Wang
- Center for High Performance Computing & System Simulation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266100, China
| | - Xuemeng Liu
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Huashi Guan
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China
| | - Rilei Yu
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China.
| | - Tao Jiang
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China.
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9
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Galloway NR, Ball KF, Stiff T, Wall NR. Yin Yang 1 (YY1): Regulation of Survivin and Its Role In Invasion and Metastasis. Crit Rev Oncog 2019; 22:23-36. [PMID: 29604934 DOI: 10.1615/critrevoncog.2017020836] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Despite significant clinical and basic science advancements, cancer remains a devastating disease that affects people of all ages, races, and backgrounds. The pathogenesis of cancer has recently been described to result from eight biological capabilities or hallmarks and two enabling characteristics. These eight hallmarks are: deregulation of cellular energetics, avoiding immune destruction, enabling replicative immortality, inducing angiogenesis, sustaining proliferative signaling, evading growth suppressors, resisting cell death, and activating invasion and metastasis. The enabling characteristics are: genome instability and mutation and tumor-promoting inflammation. Survivin, the fourth most common transcript found in cancer cells, is a protein that is thought to be involved in the enhanced proliferation, survival, and metastasis and possibly other key hallmarks of cancer cells. Understanding how this gene is turned on and off is vitally important for attempt improving cancer management and therapy. Our work has identified a novel transcriptional regulator of survivin called Yin Yang 1 (YY1), which has been observed to activate some gene promoters and repress others and is gaining increasing interest as a target of cancer therapy. Our work shows for the first time that YY1 represses survivin transcription by physically interacting with the survivin promoter. Furthermore, YY1 appears to contribute to basal survivin transcriptional activity, indicating that disruption of its binding may in part contribute to survivin overexpression after cellular stress events including chemotherapy and radiotherapy.
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Affiliation(s)
- Nicholas R Galloway
- Department of Basic Science and Division of Biochemistry, Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, California 92350
| | - Kathryn F Ball
- Department of Basic Science and Division of Biochemistry, Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, California 92350
| | - TessaRae Stiff
- Department of Basic Science and Division of Biochemistry, Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, California 92350
| | - Nathan R Wall
- Department of Basic Science and Division of Biochemistry, Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, California 92350
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10
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Kamra M, Maiti B, Dixit A, Karande AA, Bhattacharya S. Tumor Chemosensitization through Oncogene Knockdown Mediated by Unique α-Tocopherylated Cationic Geminis. Biomacromolecules 2019; 20:1555-1566. [DOI: 10.1021/acs.biomac.8b01751] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- Mohini Kamra
- Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
| | - Bappa Maiti
- Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
- School of Applied and Interdisciplinary Sciences, Indian Association for the Cultivation of Science, Kolkata 700 032, India
| | - Akanksha Dixit
- Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India
| | - Anjali A. Karande
- Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India
| | - Santanu Bhattacharya
- Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
- School of Applied and Interdisciplinary Sciences, Indian Association for the Cultivation of Science, Kolkata 700 032, India
- Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560064, India
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11
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Wu G, Mai X, Liu F, Lin M, Dong X, Xu Q, Hao C, Zhang L, Yu R, Jiang T. Synthesis of novel 10,11-methylenedioxy-camptothecin glycoside derivatives and investigation of their anti-tumor effects in vivo. RSC Adv 2019; 9:11142-11150. [PMID: 35520228 PMCID: PMC9063016 DOI: 10.1039/c9ra00315k] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 03/21/2019] [Indexed: 11/21/2022] Open
Abstract
10,11-Methylenedioxy-camptothecin (FL118) is a novel camptothecin analogue that possesses exceptional antitumor efficacy in human tumor xenograft models. The aim of the current study was to develop novel 20-substituted FL118 derivatives coupled with glycosyl-succinic acid esters with improved antitumor efficacy. These FL118 glycoside derivatives were designed, synthesized and their cytotoxicity evaluated in three tumor cell lines (A-549, MDA-MB-231 and RM-1). All of the derivatives showed superior in vitro cytotoxic activity and were more potent than irinotecan in A549 and MDA-MB-231 cells. In mouse prostate cancer cells RM-1, 10,11-methylenedioxy-camptothecin rhamnoside 11b displayed significant activities with IC50 of 48.27 nM. Western blot analysis demonstrated that 11b inhibited survivin expression and induced cancer cells apoptosis. Further cell cycle analyses clearly showed 11b induced G2/M phase cell cycle arrest. Molecule docking studies suggested that the binding mode of 11b was different from that of the crystal complex of ligand topotecan in Top1/DNA. Importantly, 11b showed high in vivo antitumor efficacy in the RM-1 mouse model with transplantation of prostate cancer (TGI = 44.9%) at dose of 9 mg kg−1 without apparent toxicity. In a RM-1 xenograft model, 11b had superior in vivo antitumor efficacy (TGI = 44.9%) at a dose of 9 mg kg−1.![]()
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12
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Liang Z, Xin R, Yu Y, Wang R, Wang C, Liu X. Diagnostic value of urinary survivin as a biomarker for bladder cancer: a systematic review and meta-analysis of published studies. World J Urol 2018; 36:1373-1381. [PMID: 29610963 DOI: 10.1007/s00345-018-2285-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 03/28/2018] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE This study is a meta-analysis and aims to determine the value of urinary survivin for detecting bladder cancer (BC) on the basis of preceding statistical performance and to compare their diagnostic value. MATERIALS AND METHODS Considering that the urinary survivin data were from both RNA and protein levels, the key words "bladder cancer" AND "survivin" and "bladder cancer" AND "survivin RNA" were used; and PubMed, Web of Science, and Cochrane Library were systematically searched to identify relevant articles. The methodological quality of each study was assessed by QUADAS-2. Data were analyzed by STATA 12.0 and Meta-disc v.1.4 software package. A random-effects model was used and subgroup analysis was carried out to identify possible sources of heterogeneity. RESULTS Nine articles for survivin protein test with 789 patients and 684 controls, and 12 articles for survivin RNA test with 880 patients and 922 controls were identified. The results showed that the pooled sensitivity was 0.79 (95% CI 0.73, 0.84), specificity was 0.87 (95% CI 0.79, 0.92) of the survivin protein test for bladder cancer, and the sensitivity and specificity was 0.84 (95% CI 0.79, 0.88) and 0.94 (95% CI 0.89, 0.97) of the survivin RNA test. The AUC of the two approaches was 0.89 (95% CI 0.86, 0.91) and 0.94 (95% CI 0.92, 0.96), respectively. CONCLUSIONS The survivin protein and survivin RNA both had great potential as biomarkers for BC detection, and survivin RNA showed higher accuracy than survivin protein on BC diagnosis.
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Affiliation(s)
- Zhenzhen Liang
- Epidemiology and Statistics, School of Public Health, Jilin University, Changchun, 130021, China
| | - Rui Xin
- Department Radiology, The 2nd Hospital Affiliated to Jilin University, Changchun, China
| | - Yinghui Yu
- Epidemiology and Statistics, School of Public Health, Jilin University, Changchun, 130021, China
| | - Rui Wang
- Epidemiology and Statistics, School of Public Health, Jilin University, Changchun, 130021, China
| | - Chunpeng Wang
- School of Mathematics and Statistics, Northeast Normal University, Changchun, Jilin, China
| | - Xin Liu
- Epidemiology and Statistics, School of Public Health, Jilin University, Changchun, 130021, China.
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13
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14
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Tzankov A, Went P, Dirnhofer S. Prognostic Significance of in situ Phenotypic Marker Expression in Diffuse Large B-cell Lymphomas. Biomark Insights 2017. [DOI: 10.1177/117727190700200009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Diffuse large B-cell lymphomas (DLBCL) are the most common lymphoid malignancies, and encompass all malignant lymphomas characterized by large neoplastic cells and B-cell derivation. In the last decade, DLBCL has been subjected to intense clinical, phenotypic and molecular studies, and were found to represent a heterogeneous group of tumors. These studies suggested new disease subtypes and variants with distinct clinical characteristics, morphologies, immunophenotypes, genotypes or gene expression profiles, associated with distinct prognoses or unique sensitivities to particular therapy regimens. Unfortunately, the reliability and reproducibility of the molecular results remains unclear due to contradictory reports in the literature resulting from small sample sizes, referral and selection biases, and variable methodologies and cut-off levels used to determine positivity. Here, we review phenotypic studies on the prognostic significance of protein expression profiles in DLBCL and reconsider our own retrospective data on 301 primary DLBCL cases obtained on a previously validated tissue microarray in light of powerful statistical methods of determining optimal cut-off values of phenotypic factors for prediction of outcome.
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Affiliation(s)
| | - Philip Went
- Department of Pathology, University Hospital Basel, Switzerland
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15
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Tastekin E, Caloglu VY, Durankus NK, Sut N, Turkkan G, Can N, Puyan FO, Caloglu M. Survivin expression, HPV positivity and microvessel density in oropharyngeal carcinomas and relationship with survival time. Arch Med Sci 2017; 13:1467-1473. [PMID: 29181079 PMCID: PMC5701673 DOI: 10.5114/aoms.2015.56616] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 10/11/2015] [Indexed: 12/22/2022] Open
Abstract
INTRODUCTION Among head and neck cancers, those of the oral cavity and oropharynx are the second most prevalent following the larynx. This study aimed to research immunohistochemical expression of survivin, HPV positivity and microvessel density in tumors and their relationships with prognosis. MATERIAL AND METHODS Pathological materials and demographic properties of 46 patients were retrospectively evaluated. Survivin, HPV and CD34 (for microvessel density evaluation) antibodies were applied tumoral tissues. Survival times, clinical stage and differentiation were evaluated. RESULTS In univariate analysis, we observed that survivin, microvessel density and stage were significantly associated with survival time (p < 0.05). In multivariate analysis, only survivin and microvessel density were associated with survival time (p < 0.05). But we did not find significant correlation between neither tumor differentiation nor HPV positivity and survival (p > 0.05). CONCLUSIONS Survivin levels and microvessel density were found to be effective prognostic factors and were related to survival in oral cavity and oropharyngeal cancers. Treatments targeting survivin expression and angiogenesis might be employed against these tumor groups.
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Affiliation(s)
- Ebru Tastekin
- Department of Pathology, Medical Faculty, Trakya University, Edirne, Turkey
| | - Vuslat Yurut Caloglu
- Department of Radiation Oncology, Faculty of Medicine, Trakya University, Edirne, Turkey
| | - Nilufer Kilic Durankus
- Department of Radiation Oncology, Faculty of Medicine, Trakya University, Edirne, Turkey
| | - Necdet Sut
- Department of Biostatistics, Faculty of Medicine, Trakya University, Edirne, Turkey
| | - Gorkem Turkkan
- Department of Radiation Oncology, Faculty of Medicine, Trakya University, Edirne, Turkey
| | - Nuray Can
- Department of Pathology, Medical Faculty, Trakya University, Edirne, Turkey
| | - Fulya Oz Puyan
- Department of Pathology, Medical Faculty, Trakya University, Edirne, Turkey
| | - Murat Caloglu
- Department of Radiation Oncology, Faculty of Medicine, Trakya University, Edirne, Turkey
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16
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Wang J, Liu Z, Zhang D, Liu R, Lin Q, Liu J, Yang Z, Ma Q, Sun D, Zhou X, Jiang G. FL118, a novel survivin inhibitor, wins the battle against drug-resistant and metastatic lung cancers through inhibition of cancer stem cell-like properties. Am J Transl Res 2017; 9:3676-3686. [PMID: 28861158 PMCID: PMC5575181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Accepted: 07/22/2017] [Indexed: 06/07/2023]
Abstract
Failure of cancer treatment caused by drug resistance and metastasis is mainly due to existence of cancer stem cells (CSCs). Therefore, targeting CSCs to overcome cancers is a challenging issue in clinic. In this report, in view of the important role of survivin in tumor growth and CSCs maintaining, we aimed to confirm that FL118, as a novel survivin inhibitor, may effectively inhibit lung cancer stem cells. We showed that lung cancer stem cells have the obviously higher expression of survivin than their parental cells. After treated with FL118, the survivin level in CSCs was suppressed. Consistently, lung cancer stem cells displayed significantly growth inhibition over time. Here, we compared the antitumor efficacy between FL118 and cisplatin. The data revealed that CSCs are more sensitive to FL118 than cisplatin. To further demonstrate the inhibitory effect of FL118 on CSCs, we found that FL118 down-regulated the expression of CSCs markers (ABCG2, ALDH1A1, Oct4) and drug resistant proteins (P-gp, ERCC1), suggesting that FL118 may change CSCs phenotype and improve drug-sensitivity of tumor cells. Moreover, FL118 effectively decreased the invasive ability of CSCs. These findings expand the uniqueness of FL118 as an attractive therapeutic option for cancers with drug-resistant or metastatic potential.
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Affiliation(s)
- Jin Wang
- School of Basic Medicine, Qingdao UniversityQingdao 266021, China
| | - Zhantao Liu
- School of Pharmacy, Qingdao UniversityQingdao 266021, China
| | - Dandan Zhang
- School of Pharmacy, Qingdao UniversityQingdao 266021, China
| | - Ranran Liu
- School of Pharmacy, Qingdao UniversityQingdao 266021, China
| | - Qian Lin
- School of Pharmacy, Qingdao UniversityQingdao 266021, China
| | - Jia Liu
- School of Pharmacy, Qingdao UniversityQingdao 266021, China
| | - Zhihong Yang
- School of Pharmacy, Qingdao UniversityQingdao 266021, China
| | - Qingxia Ma
- School of Pharmacy, Qingdao UniversityQingdao 266021, China
| | - Dantong Sun
- School of Basic Medicine, Qingdao UniversityQingdao 266021, China
| | - Xin Zhou
- School of Basic Medicine, Qingdao UniversityQingdao 266021, China
| | - Guohui Jiang
- School of Pharmacy, Qingdao UniversityQingdao 266021, China
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17
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Chang Y, Xu J, Zhang Q. Microplate magnetic chemiluminescence immunoassay for detecting urinary survivin in bladder cancer. Oncol Lett 2017; 14:4043-4052. [PMID: 28943911 PMCID: PMC5605963 DOI: 10.3892/ol.2017.6675] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 07/20/2017] [Indexed: 02/07/2023] Open
Abstract
Survivin is a tumor marker for bladder cancer; however the role of urinary survivin levels has not been fully elucidated due to the limitations of current detection methods. Based on two survivin-specific monoclonal antibodies (McAbs) already confirmed through enzyme linked immunosorbent assays, the present study aimed to establish a microplate magnetic chemiluminescence immunoassay (CLIA) for the detection of urinary survivin levels and evaluate its application for the diagnosis of patients with bladder cancer. Horseradish peroxidase and biotin conjugates were used to label two different anti-survivin McAbs, respectively. The labeled antibodies combined with survivin to form a sandwiched immune complex. The streptavidin magnetic particles (MPs) served as the solid phase and the separator. The relevant parameters involved in the immunoassay, including the immunoassay reagents used and the physicochemical parameters were optimized. Then, urine samples from 130 patients with bladder cancer and 113 healthy controls were detected, and analyzed using the established method. The method was linear to 1,000 ng/ml survivin with a detection limit of 0.83 ng/ml. The intra- and inter-assay coefficients of variation were <8, and <11%, respectively. The concentration of diluted survivin and the dilution ratios gave a linear correlation of 0.9989. The results demonstrated that the urinary survivin levels in patients with bladder cancer were significantly higher (P<0.001) compared with that in healthy controls. At a survivin concentration of 2.0884 ng/ml, the sensitivity and specificity were 86.9 and 61.9%, respectively. Furthermore, the urinary survivin levels were positively correlated with metastatic stage, histological stage and recurrence (P<0.01). In conclusion, the present study preliminarily proposed a microplate magnetic CLIA for survivin detection and further evaluated the value of urinary survivin as a diagnostic marker for bladder cancer.
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Affiliation(s)
- Yanli Chang
- Department of Clinical Laboratory, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Jianjun Xu
- Department of Clinical Laboratory, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Qingyun Zhang
- Department of Clinical Laboratory, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
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18
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Shintani M, Tashiro A, Sangawa A, Yamao N, Kamoshida S. Expression of chromosomal regional maintenance protein-1 may be associated with subcellular survivin expression in human gastric and colorectal carcinoma. Oncol Lett 2017; 12:4630-4634. [PMID: 28105170 DOI: 10.3892/ol.2016.5220] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Accepted: 04/22/2016] [Indexed: 11/06/2022] Open
Abstract
Survivin, a member of the inhibitor of apoptosis protein family, is a potential prognostic marker and molecular target for anticancer therapies. Chromosomal regional maintenance protein-1 (CRM-1) mediates the nuclear export of proteins such as survivin. The aims of the present study were to compare the expression and subcellular localization of CRM-1 in human gastric and colorectal carcinomas and to assess the association between CRM-1 and survivin expression in these tumor types. The nuclear and cytoplasmic CRM-1 expression rates in gastric carcinoma were 61% (42/69) and 29% (20/69), respectively, while the nuclear and cytoplasmic CRM-1 expression rates in colorectal carcinoma were 55% (43/78) and 37% (29/78), respectively. Nuclear and cytoplasmic CRM-1 expression was found to be significantly correlated with nuclear and cytoplasmic survivin expression in colorectal carcinoma, but not gastric carcinoma. These results indicate that CRM-1 expression patterns differ between gastric and colorectal carcinomas and thus, we hypothesize that CRM-1-mediated nuclear export of survivin may be deregulated in gastric carcinoma. Therefore, CRM-1 may exhibit different functions in gastric and colorectal carcinoma.
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Affiliation(s)
- Michiko Shintani
- Laboratory of Pathology, Division of Medical Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Hyogo 654-0142, Japan
| | - Akito Tashiro
- Laboratory of Pathology, Division of Medical Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Hyogo 654-0142, Japan
| | - Akiko Sangawa
- Department of Diagnostic Pathology, Osaka Red Cross Hospital, Osaka 543-8555, Japan
| | - Naoki Yamao
- Department of Clinical Laboratory, Kuma Hospital, Kobe, Hyogo 650-0011, Japan
| | - Shingo Kamoshida
- Laboratory of Pathology, Division of Medical Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Hyogo 654-0142, Japan
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19
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Yue B, Lin Y, Ma X, Zhang G, Chen B. Effect of Survivin gene therapy via lentivirus vector on the course of intervertebral disc degeneration in an in vivo rabbit model. Mol Med Rep 2016; 14:4593-4598. [PMID: 27748828 PMCID: PMC5102010 DOI: 10.3892/mmr.2016.5830] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 10/03/2016] [Indexed: 01/28/2023] Open
Abstract
The aim of the current study was to use gene therapy to attenuate or reverse the degenerative process within the intervertabral disc. The effect of survivin gene therapy via lentiviral vector transfection on the course of intervertebral disc degeneration was investigated in the current study in an in vivo rabbit model. A total of 15 skeletally mature female New Zealand White rabbits were randomly divided into three groups: Punctured blank control group (group A, n=5), punctured empty vector control group (group B, n=5) and the treatment group (group C, n=5). Computed tomography‑guided puncture was performed at the L3‑L4 and L4‑L5 discs, in accordance with a previously validated rabbit annulotomy model for intervertebral disc degeneration. After 3 weeks, a lentiviral vector (LV) carrying survivin was injected into the nucleus pulposus. The results demonstrated that through magnetic resonance imaging, histology, gene expression, protein content and apoptosis analyses, group A and B were observed to exhibit disc degeneration, which increased over time, and no significant difference was observed between the two groups (P>0.05). However, there was reduced disc degeneration in group C compared with the punctured control groups, and the difference was statistically significant (P<0.05). Overall, the results of the present study demonstrated that injection of the LV carrying survivin into punctured rabbit intervertebral discs acted to delay changes associated with the degeneration of the discs. Although data from animal models should be extrapolated to the human condition with caution, the present study suggests potential for the use of gene therapy to decelerate disc degeneration.
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Affiliation(s)
- Bin Yue
- Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Yazhou Lin
- Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Xuexiao Ma
- Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Guoqing Zhang
- Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Bohua Chen
- Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
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20
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Xu Q, Liu M, Zhang J, Xue L, Zhang G, Hu C, Wang Z, He S, Chen L, Ma K, Liu X, Zhao Y, Lv N, Liang S, Zhu H, Xu N. Overexpression of KLF4 promotes cell senescence through microRNA-203-survivin-p21 pathway. Oncotarget 2016; 7:60290-60302. [PMID: 27531889 PMCID: PMC5312384 DOI: 10.18632/oncotarget.11200] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Accepted: 07/26/2016] [Indexed: 02/05/2023] Open
Abstract
Krüppel-like factor 4 (KLF4) is a transcription factor and functions as a tumor suppressor or tumor promoter in different cancer types. KLF4 regulates many gene expression, thus affects the process of cell proliferation, differentiation, and apoptosis. Recently, KLF4 was reported to induce senescence during the generation of induced pluripotent stem (iPS) cells, but the exact mechanism is still unclear. In this study, we constructed two doxycycline-inducing KLF4 cell models, and demonstrated overexpression of KLF4 could promote cell senescence, detected by senescence-associated β-galactosidase activity assay. Then we confirmed that p21, a key effector of senescence, was directly induced by KLF4. KLF4 could also inhibit survivin, which could indirectly induce p21. By miRNA microarray, we found a series of miRNAs regulated by KLF4 and involved in senescence. We demonstrated that KLF4 could upregulate miR-203, and miR-203 contributed to senescence through miR-203-survivin-p21 pathway. Our results suggest that KLF4 could promote cell senescence through a complex network: miR-203, survivin, and p21, which were all regulated by overexpression of KLF4 and contributed to cell senescence.
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Affiliation(s)
- Qing Xu
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mei Liu
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ju Zhang
- Division of Proteomics, Beijing Institute of Genomics, Chinese Academy of Science, Beijing, China
| | - Liyan Xue
- Department of Pathology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guo Zhang
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chenfei Hu
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zaozao Wang
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shun He
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lechuang Chen
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Kai Ma
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xianghe Liu
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yahui Zhao
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ning Lv
- Department of Pathology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shufang Liang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, P. R. China
| | - Hongxia Zhu
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ningzhi Xu
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, P. R. China
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Suganya G, Bavle RM, Paremala K, Makarla S, Sudhakar M, Reshma V. Survivin expression in oral lichen planus: Role in malignant transformation. J Oral Maxillofac Pathol 2016; 20:234-8. [PMID: 27601815 PMCID: PMC4989553 DOI: 10.4103/0973-029x.185912] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Context: Oral lichen planus (OLP) is a potentially malignant disease with a prevalence rate of 0.5–2.2%. It is a T-cell-mediated autoimmune disease, in which cytotoxic CD8+ T-cells trigger apoptosis of the basal cells of oral epithelium. The reported progression of OLP to oral squamous cell carcinoma (OSCC) ranges from 0.4% to 6.5%. Apoptosis plays a major role in the maintenance of tissue homeostasis. The evasion of apoptosis in the form of dysregulation of inhibitors of apoptosis proteins (IAPs) may lead to malignant transformation. Survivin belongs to the second gene family of IAPs, which is overexpressed in many tumors such as OSCC and gastric carcinomas, and its expression is widely involved in apoptosis as well as in tumor metastasis. Materials and Methods: Sections were obtained from the paraffin-embedded archival blocks of patients diagnosed histologically as OLP, and cases with normal epithelium were used for comparison whereas cases with OSCC were used as positive control. Results: We analyzed the expression of survivin in OLP and normal epithelium. Survivin expression with moderate intensity was seen in the cells of basal layer with nuclear positivity in cases of OLP, whereas mild to nil expression was seen in normal epithelium with nuclear and cytoplasmic positivity in different layers. Conclusions: Survivin positivity was seen predominantly in the basal cells of OLP suggesting increased longevity of these cells which in turn might acquire dysplastic changes leading to increased risk of malignant transformation of this premalignant condition. Although the conversion rate may be low, the potential exists in the indolent course of the disease.
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Affiliation(s)
- G Suganya
- Department of Oral and Maxillofacial Pathology, M R Ambedkar Dental College and Hospital, Bengaluru, Karnataka, India
| | - Radhika M Bavle
- Department of Oral and Maxillofacial Pathology, Krishnadevaraya College of Dental Sciences, Bengaluru, Karnataka, India
| | - K Paremala
- Department of Oral and Maxillofacial Pathology, Krishnadevaraya College of Dental Sciences, Bengaluru, Karnataka, India
| | - Soumya Makarla
- Department of Oral and Maxillofacial Pathology, Krishnadevaraya College of Dental Sciences, Bengaluru, Karnataka, India
| | - M Sudhakar
- Department of Oral and Maxillofacial Pathology, Krishnadevaraya College of Dental Sciences, Bengaluru, Karnataka, India
| | - V Reshma
- Department of Oral and Maxillofacial Pathology, Krishnadevaraya College of Dental Sciences, Bengaluru, Karnataka, India
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22
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Yenkejeh RA, Sam MR, Esmaeillou M. Targeting survivin with prodigiosin isolated from cell wall of Serratia marcescens induces apoptosis in hepatocellular carcinoma cells. Hum Exp Toxicol 2016; 36:402-411. [PMID: 27334973 DOI: 10.1177/0960327116651122] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND Abnormal activation of the Wnt/β-catenin signaling pathway increases survivin expression that is involved in hepatocarcinogenesis. Therefore, downregulation of survivin may provide an attractive strategy for treatment of hepatocellular carcinoma. In this regard, little is known about the anticancer effects of prodigiosin isolated from cell wall of Serratia marcescens on the survivin expression and induction of apoptosis in hepatocellular carcinoma cells. METHODS Human hepatocellular carcinoma (HepG2) cells were treated with 100-, 200-, 400-, and 600-nM prodigiosin after which morphology of cells, cell number, growth inhibition, survivin expression, caspase-3 activation, and apoptotic rate were evaluated by inverted microscope, hemocytometer, MTT assay, RT-PCR, fluorometric immunosorbent enzyme assay, and flow cytometric analysis, respectively. RESULTS Prodigiosin changed morphology of cells to apoptotic forms and disrupted cell connections. This compound significantly increased growth inhibition rate and decreased metabolic activity of HepG2 cells in a dose- and time-dependent manner. After 24-, 48-, and 72-h treatments with prodigiosin at concentrations ranging from 100 nM to 600 nM, growth inhibition rates were measured to be 1.5-10%, 24-47.5%, and 55.5-72.5%, respectively, compared to untreated cells. At the same conditions, metabolic activities were measured to be 91-83%, 74-53%, and 47-31% for indicated concentrations of prodigiosin, respectively, compared to untreated cells. We also found that treatment of HepG2 cells for 48 h decreased significantly cell number and survivin expression and increased caspase-3 activation in a dose-dependent manner. Specifically, treatment with 600-nM prodigiosin resulted in 77% decrease in cell number, 88.5% decrease in survivin messenger RNA level, and 330% increase in caspase-3 activation level compared to untreated cells. An increase in the number of apoptotic cells (late apoptosis) ranging from 36.9% to 97.4% was observed with increasing prodigiosin concentrations. CONCLUSION From our data, prodigiosin is an attractive compound that turns the profile of high-level survivin expression in hepatocellular carcinoma cells into that of normal cells and may provide a novel approach to the hepatocellular carcinoma-targeted therapy.
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Affiliation(s)
- R A Yenkejeh
- 1 Department of Cellular and Molecular Biotechnology, Institute of Biotechnology, Urmia University, Urmia, Islamic Republic of Iran
| | - M R Sam
- 1 Department of Cellular and Molecular Biotechnology, Institute of Biotechnology, Urmia University, Urmia, Islamic Republic of Iran.,2 Department of Histology and Embryology, Faculty of Science, Urmia University, Urmia, Islamic Republic of Iran
| | - M Esmaeillou
- 1 Department of Cellular and Molecular Biotechnology, Institute of Biotechnology, Urmia University, Urmia, Islamic Republic of Iran
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Survivin-TGFB3-TIMP1 Gene Therapy Via Lentivirus Vector Slows the Course of Intervertebral Disc Degeneration in an In Vivo Rabbit Model. Spine (Phila Pa 1976) 2016; 41:926-934. [PMID: 26839993 DOI: 10.1097/brs.0000000000001474] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN The ability of lentivirus vector (LV) survivin-transforming growth factor beta 3 (TGFB3)-tissue inhibitor of metalloproteinases 1 (TIMP1) on slowing disc degeneration was evaluated by an animal experiment. OBJECTIVE The aim of the study was to investigate the effect of LV survivin-TGFB3-TIMP1 on slowing disc degeneration in an in vivo rabbit model. SUMMARY OF BACKGROUND DATA Cell apoptosis, increase of catabolic activity, and decrease of anabolic activity were the mechanisms of disc degeneration. Meanwhile, survivin, TGFB3, and TIMP1 can influence above process, respectively. However, there were no researches conducted to evaluate the effect of an LV containing all three proteins (referred to as LV-survivin-TGFB3-TIMP1) on slowing disc degeneration in vivo. METHODS Twenty skeletally mature female New Zealand White rabbits were randomly divided into four groups: nonpunctured sham surgical group (group A, n = 5), punctured blank control group (group B, n = 5), punctured empty vector control group (group C, n = 5), and the treatment group (group D, n = 5). Computed tomography-guided puncture was performed at the L3-L4 and L4-L5 discs, in accordance with a previously validated rabbit annulotomy model for intervertebral disc degeneration. After 3 weeks, LV-carrying survivin, TGFB3, and TIMP1 were injected into the nucleus pulposus. Serial magnetic resonance imaging studies at 0, 3, and 12 weeks were performed. The rabbits were sacrificed at 12 weeks, and the histology, immunofluorescence, quantitative real-time polymerase chain reaction, Western blot, and caspase-3 activity was used for evaluation. RESULTS Magnetic resonance imaging, histology, gene expression, protein content, and apoptosis analyses of group A showed no disc degeneration. Groups B and C showed disc degeneration, which increased over time, and no significant difference was observed between the two groups (P > 0.05). In group D, there was less disc degeneration compared to the punctured control groups and the difference was statistically significant (P < 0.05). CONCLUSION The injection of LV-carrying survivin-TGFB3-TIMP1 into punctured rabbit intervertebral discs helps delay degenerative disc changes. Although data from animal models should be extrapolated to the human condition with caution, this study shows promise for gene therapy to decelerate disc degeneration. LEVEL OF EVIDENCE N/A.
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Bhat A, Mokou M, Zoidakis J, Jankowski V, Vlahou A, Mischak H. BcCluster: A Bladder Cancer Database at the Molecular Level. Bladder Cancer 2016; 2:65-76. [PMID: 27376128 PMCID: PMC4927921 DOI: 10.3233/blc-150024] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Bladder Cancer (BC) has two clearly distinct phenotypes. Non-muscle invasive BC has good prognosis and is treated with tumor resection and intravesical therapy whereas muscle invasive BC has poor prognosis and requires usually systemic cisplatin based chemotherapy either prior to or after radical cystectomy. Neoadjuvant chemotherapy is not often used for patients undergoing cystectomy. High-throughput analytical omics techniques are now available that allow the identification of individual molecular signatures to characterize the invasive phenotype. However, a large amount of data produced by omics experiments is not easily accessible since it is often scattered over many publications or stored in supplementary files. OBJECTIVE To develop a novel open-source database, BcCluster (http://www.bccluster.org/), dedicated to the comprehensive molecular characterization of muscle invasive bladder carcinoma. MATERIALS A database was created containing all reported molecular features significant in invasive BC. The query interface was developed in Ruby programming language (version 1.9.3) using the web-framework Rails (version 4.1.5) (http://rubyonrails.org/). RESULTS BcCluster contains the data from 112 published references, providing 1,559 statistically significant features relative to BC invasion. The database also holds 435 protein-protein interaction data and 92 molecular pathways significant in BC invasion. The database can be used to retrieve binding partners and pathways for any protein of interest. We illustrate this possibility using survivin, a known BC biomarker. CONCLUSIONS BcCluster is an online database for retrieving molecular signatures relative to BC invasion. This application offers a comprehensive view of BC invasiveness at the molecular level and allows formulation of research hypotheses relevant to this phenotype.
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Affiliation(s)
- Akshay Bhat
- Charité-Universitätsmedizin Berlin, Berlin, Germany; Mosaiques diagnostics GmbH, Hannover, Germany
| | - Marika Mokou
- Biomedical Research Foundation Academy of Athens , Biotechnology Division, Athens, Greece
| | - Jerome Zoidakis
- Biomedical Research Foundation Academy of Athens , Biotechnology Division, Athens, Greece
| | - Vera Jankowski
- Institute for Molecular Cardiovascular Research (IMCAR) , Aachen, Germany
| | - Antonia Vlahou
- Biomedical Research Foundation Academy of Athens , Biotechnology Division, Athens, Greece
| | - Harald Mischak
- Mosaiques diagnostics GmbH, Hannover, Germany; BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
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Sam MR, Ahangar P, Nejati V, Habibian R. Treatment of LS174T colorectal cancer stem-like cells with n-3 PUFAs induces growth suppression through inhibition of survivin expression and induction of caspase-3 activation. Cell Oncol (Dordr) 2015; 39:69-77. [PMID: 26671842 DOI: 10.1007/s13402-015-0254-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/03/2015] [Indexed: 01/05/2023] Open
Abstract
PURPOSE Colorectal cancer stem cells (CCSCs) are thought to contribute to tumor initiation, progression, metastasis, chemo-resistance and therapy failure. Therefore, assessment of the effectiveness of agents with anti-proliferative activities against CCSCs is warranted. Several studies have shown that different tumorigenic steps, ranging from initiation to metastasis, can be affected by n-3 polyunsaturated fatty acids (PUFAs). Here, we evaluated the effects of the PUFA components docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), alone or in combination, on LS174T cells that serve as a model for colorectal cancer initiating cells with stem cell-like properties. METHODS LS174T cells were treated with 50, 100 and 150 μM DHA and EPA, or equal mixtures of DHA/EPA (i.e., 25/25, 50/50 and 75/75 μM), after which cell number, viability, growth inhibition, survivin expression, caspase-3 activation and apoptotic rate were evaluated. RESULTS We found that treatment of LS174T cells with increasing PUFA concentrations significantly increased growth inhibition in a dose- and time-dependent manner. After a 72 h treatment with 150 μM DHA and EPA, or their combination (75/75 μM), growth rates were inhibited by 80.3 ± 5.5%, 79.3 ± 5% and 71.1 ± 1%, respectively, compared to untreated cells. We also found that treatment for 48 h with 100 μM DHA and EPA, or their combination (50/50 μM), resulted in 2.9-, 3- and 2.6-fold increases in caspase-3 activation, as well as 54, 62.4 and 100% decreases in survivin mRNA expression levels, respectively, compared to untreated cells. Low survivin mRNA levels combined with high caspase-3 activity levels were found to correlate with a higher growth inhibition in PUFA-treated cells. DHA appears to be a more potent growth inhibitor than EPA and the DHA/EPA combination. An increase in the number of apoptotic cells (early + late), ranging from 12.9 to 44.7%, was observed with increasing DHA doses. CONCLUSION From our data we conclude that PUFAs induce growth inhibition via targeting survivin expression in LS174T cells, which serve as a model for CCSCs.
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Affiliation(s)
- Mohammad Reza Sam
- Department of Histology and Embryology, Faculty of Science, Urmia University, Urmia, Iran. .,Department of Cellular and Molecular Biotechnology, Institute of Biotechnology, Urmia University, Urmia, Iran, P.O. Box: 165. .,Royan Stem Cell Technology Company, West Azerbaijan Cord Blood Bank, Urmia, Iran.
| | - Parinaz Ahangar
- Department of Histology and Embryology, Faculty of Science, Urmia University, Urmia, Iran.,Department of Cellular and Molecular Biotechnology, Institute of Biotechnology, Urmia University, Urmia, Iran, P.O. Box: 165
| | - Vahid Nejati
- Department of Histology and Embryology, Faculty of Science, Urmia University, Urmia, Iran
| | - Reza Habibian
- Department of Microbiology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
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Lin Y, Yue B, Xiang H, Liu Y, Ma X, Chen B. Survivin is expressed in degenerated nucleus pulposus cells and is involved in proliferation and the prevention of apoptosis in vitro. Mol Med Rep 2015; 13:1026-32. [PMID: 26648308 PMCID: PMC4686112 DOI: 10.3892/mmr.2015.4605] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2014] [Accepted: 11/05/2015] [Indexed: 01/08/2023] Open
Abstract
Survivin is a unique inhibitor of apoptosis, which is frequently present within degenerated human nucleus pulposus (NP) cells. Survivin has been extensively investigated using proliferation and apoptosis assays in tumor cells; however, studies conducted on survivin in degenerative NP cells remain limited to date. The aim of the present study was to investigate survivin expression and its effects on the proliferation and apoptosis of degenerated NP cells in vitro. The expression levels of survivin in the NP cells of patients (>45 years) with lumbar disc degenerative disease and the NP cells of patients (<25 years) with lumbar vertebra fracture were assessed by reverse transcription‑quantitative polymerase chain reaction. The effects on in vitro proliferation and apoptosis were investigated through transfection with a specific small interfering (si)RNA. The results of the present study demonstrated that survivin was expressed in the degenerated NP cells, but was undetectable in normal NP cells at the mRNA level. Survivin suppression following transfection with a specific survivin‑siRNA reduced the proliferation rate of NP cells and enhanced sensitization to pro‑apoptotic stimuli. Therefore, survivin was shown to be expressed and exhibit an important role in the proliferation and prevention of apoptosis of degenerated NP cells. Studies on survivin in NP cells may aid in increasing the understanding of the complex processes underlying NP cell degeneration, and could provide fundamental information for gene therapy to inhibit this degeneration in vitro.
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Affiliation(s)
- Yazhou Lin
- Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Bin Yue
- Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Hongfei Xiang
- Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Yong Liu
- Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Xuexiao Ma
- Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Bohua Chen
- Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
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Zhang M, Zhang X, Zhao S, Wang Y, Di W, Zhao G, Yang M, Zhang Q. Prognostic value of survivin and EGFR protein expression in triple-negative breast cancer (TNBC) patients. Target Oncol 2015; 9:349-57. [PMID: 24233638 DOI: 10.1007/s11523-013-0300-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Accepted: 10/30/2013] [Indexed: 12/12/2022]
Abstract
Triple-negative breast cancer (TNBC) is a particular type of breast cancer which is characterized by its biological aggressiveness, worse prognosis, and lack of prognostic markers or therapeutic targets in contrast with hormonal receptor-positive and human epidermal growth factor receptor 2-positive (HER2+) breast cancers. We aimed to evaluate survivin and epidermal growth factor receptor (EGFR) expression and their prognostic value and determine their relationships with the clinicopathological parameters of TNBC. A total of 136 patients who had undergone a resection of primary TNBC were enrolled at the Third Affiliated Hospital of Harbin Medical University from March 2003 to September 2005. Expression of ER, PR, HER2, EGFR, and survivin was assessed by immunohistochemistry. The association of TNBC and other clinicopathological variables and the prognostic value of survivin and EGFR expression were evaluated. Survivin was expressed in 62 (45.6 %) cases and EGFR was expressed in 82 (60.3 %) cases. Survivin expression was associated with menopausal status (P = 0.011), tumor size (P = 0.037), and lymph node status (P = 0.001). EGFR expression was associated with menopausal status (P = 0.029), lymph node status (P = 0.004), P53 expression (P = 0.001), Ki-67 expression (P = 0.028), and lymphatic vascular invasion (P = 0.037). A multivariate analysis demonstrated that tumor size (hazard ratio (HR) 1.587, 95 % confidence interval (CI) 1.081–2.330, P = 0.018 for disease-free survival (DFS); HR 1.606, 95%CI 1.096–2.354, P = 0.015 for overall survival (OS)), lymph node status (HR 2.873, 95%CI 1.544–5.344, P = 0.001 for DFS; HR 2.915, 95%CI 1.553–5.471, P = 0.001 for OS), tumor grade (HR 1.914, 95%CI 1.218–3.007, P = 0.005 for DFS; HR 1.983, 95%CI 1.228–3.203, P = 0.005 for OS), EGFR (HR 3.008, 95%CI 1.331–6.792, P = 0.008 for DFS; HR 3.151, 95%CI 1.374–7.226, P = 0.007 for OS), and survivin (HR 1.573, 95%CI 1.087–2.277, P = 0.016 for DFS; HR 1.607, 95%CI 1.088–2.374, P = 0.017 for OS) were of prognostic significance for disease-free and overall survival. We draw a conclusion from the present study that survivin and EGFR expression are useful prognostic markers of TNBC and might be useful for molecular targeting therapy of TNBC treatment.
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Sah NK, Seniya C. Survivin splice variants and their diagnostic significance. Tumour Biol 2015; 36:6623-31. [PMID: 26245993 DOI: 10.1007/s13277-015-3865-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Accepted: 07/29/2015] [Indexed: 12/12/2022] Open
Abstract
Survivin plays a crucial role in cell division particularly during the development of the fetus, in the onset and progression of most tumors and is found expressed in a few terminally differentiated cells. Altogether, there are ten splice variants of survivin, some of which are not yet satisfactorily characterized. Several isoforms may undergo homo/heterodimerization, particularly with the wild-type survivin to elicit a variety of biological functions. The detection of survivin and its splice variants not only suggests the onset, maintenance, and progression of cancer, but also the stage of certain cancers. Recent studies demonstrate that the presence of survivin in urine and blood samples of patients may suggest urogenital and bladder cancer hematologic malignancies, respectively. The expression of the survivin-3α splice variant is indicative of the onset and progression of breast cancer. Several companies have developed cancer diagnostic kits using survivin for detection of cancer. Some are also engaged in fine-tuning the type and stage-specific diagnosis of cancer based on survivin, its splice variants with and without other markers, such as hyaluronidase. Briefly, survivin and its splice variants hold a great biological significance, particularly in the diagnosis of cancer.
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Affiliation(s)
- Nand K Sah
- Department of Life Sciences (Botany), T. N. B. College, Bhagalpur (T M Bhagalpur University, Bhagalpur), Bhagalpur, 812007, India.
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Khan S, Ferguson Bennit H, Asuncion Valenzuela MM, Turay D, Diaz Osterman CJ, Moyron RB, Esebanmen GE, Ashok A, Wall NR. Localization and upregulation of survivin in cancer health disparities: a clinical perspective. Biologics 2015; 9:57-67. [PMID: 26185415 PMCID: PMC4501680 DOI: 10.2147/btt.s83864] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Survivin is one of the most important members of the inhibitors of apoptosis protein family, as it is expressed in most human cancers but is absent in normal, differentiated tissues. Lending to its importance, survivin has proven associations with apoptosis and cell cycle control, and has more recently been shown to modulate the tumor microenvironment and immune evasion as a result of its extracellular localization. Upregulation of survivin has been found in many cancers including breast, prostate, pancreatic, and hematological malignancies, and it may prove to be associated with the advanced presentation, poorer prognosis, and lower survival rates observed in ethnically diverse populations.
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Affiliation(s)
- Salma Khan
- Department of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA ; Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Heather Ferguson Bennit
- Department of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA ; Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Malyn May Asuncion Valenzuela
- Department of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA ; Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - David Turay
- Department of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA ; Department of Anatomy, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Carlos J Diaz Osterman
- Department of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA ; Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Ron B Moyron
- Department of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA ; Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Grace E Esebanmen
- Department of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA ; Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Arjun Ashok
- Department of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA ; Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Nathan R Wall
- Department of Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA ; Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA
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Survivin expression in lung cancer: Association with smoking, histological types and pathological stages. Oncol Lett 2015; 10:1456-1462. [PMID: 26622690 DOI: 10.3892/ol.2015.3374] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Accepted: 04/14/2015] [Indexed: 02/03/2023] Open
Abstract
Survivin is expressed in the nucleus and/or cytoplasm of various malignant cells. Nuclear survivin is critical for the completion of mitosis, while cytoplasmic survivin functions as an inhibitor of apoptosis. The expression of survivin has been reported to be associated with the aggressiveness of certain types of cancer. The present study examined the association between cigarette smoking history and the expression of survivin and Ki-67 in lung adenocarcinomas of pathological (p) stages I, II and III. The expression of survivin and Ki-67 in adenocarcinomas was also compared with that of other p-stage I lung cancers, including squamous cell carcinoma (SqCC), large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SmCCs), of patients with a smoking history. In adenocarcinomas at p-stage I, labeling indices (LIs) of nuclear survivin and Ki-67 were significantly higher in tissue samples from smokers than those from non-smokers; however, the nuclear survivin and Ki-67 LIs in p-stage II and III adenocarcinomas from non-smokers and smokers were similar to those in p-stage I adenocarcinomas of smokers. The nuclear survivin and Ki-67 LIs in adenocarcinomas of smokers at p-stage I were lower than those in SqCCs, LCNECs and SmCCs of smokers at the same stage. Smokers with adenocarcinoma also exhibited a higher survival rate compared with that of smokers with SqCCs, LCNECs and SmCCs. The present results indicated that a history of smoking is associated with increased nuclear survivin and Ki-67 expression in lung adenocarcinomas of p-stage I, but not p-stages II or III. In addition it was revealed that, in smokers, the nuclear survivin and Ki-67 expression in p-stage I adenocarcinomas was lower than that of other p-stage I lung cancer types, and was associated with an enhanced survival rate. In conclusion, smoking is associated with the histogenesis of lung adenocarcinoma but not with the development of lung adenocarcinoma, based on the nuclear expression levels of Ki-67 and survivin.
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Tsao CY, Sabbatino F, Cheung NKV, Hsu JCF, Villani V, Wang X, Ferrone S. Anti-proliferative and pro-apoptotic activity of GD2 ganglioside-specific monoclonal antibody 3F8 in human melanoma cells. Oncoimmunology 2015; 4:e1023975. [PMID: 26405581 DOI: 10.1080/2162402x.2015.1023975] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 02/20/2015] [Accepted: 02/20/2015] [Indexed: 12/21/2022] Open
Abstract
The beneficial clinical effects of immunotherapy with GD2-specific monoclonal antibodies (mAbs) in melanoma and neuroblastoma patients have stimulated interest in characterizing the mechanisms underlying their antitumor effects. Previous studies have shown that GD2-specific mAbs mediate complement- and cell-dependent cytotoxicity and induce caspase-dependent apoptosis of tumor cells. In this study, we showed that GD2-specific mAb 3F8, which is undergoing clinical evaluation, inhibited the in vitro growth and induced apoptosis of melanoma cells. This effect was dose- and time-dependent, mediated by the interaction of mAb 3F8 combining site with GD2 ganglioside, associated with GD2 expression level on the cell surface, mAb internalization and increase of GD2 containing endosomes triggered by mAb 3F8. The induction of apoptosis by mAb 3F8 was mediated by caspase 3-, 7-, and 8-dependent pathways, downregulation of the anti-apoptotic molecules survivin and cytochrome c, and caspase 9 independent-AIF release from mitochondria. In addition, analyses of signaling pathway components demonstrated that mAb 3F8 strongly inhibited AKT and FAK activation and increased cleaved PARP expression. These results indicated that multiple mechanisms played a role in the antitumor activity of mAb 3F8 in melanoma cells. This information should provide a mechanistic basis for the optimization of the rational design of immunotherapeutic strategies in the mAb-based treatment of GD2 positive tumors.
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Affiliation(s)
- Chun-Yen Tsao
- Department of Surgery; Massachusetts General Hospital; Harvard Medical School ; Boston, MA USA
| | - Francesco Sabbatino
- Department of Surgery; Massachusetts General Hospital; Harvard Medical School ; Boston, MA USA
| | - Nai-Kong V Cheung
- Department of Pediatrics; Memorial Sloan-Kettering Cancer Center ; New York, NY USA
| | - Jeff Chi-Feng Hsu
- Department of Surgery; Massachusetts General Hospital; Harvard Medical School ; Boston, MA USA
| | - Vincenzo Villani
- Department of Surgery; Massachusetts General Hospital; Harvard Medical School ; Boston, MA USA
| | - Xinhui Wang
- Department of Surgery; Massachusetts General Hospital; Harvard Medical School ; Boston, MA USA
| | - Soldano Ferrone
- Department of Surgery; Massachusetts General Hospital; Harvard Medical School ; Boston, MA USA
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Hernández-Bringas O, Ortiz-Hidalgo C. [Histopathological and immunohistochemical features of cardiac myxomas]. ARCHIVOS DE CARDIOLOGIA DE MEXICO 2015; 83:199-208. [PMID: 23663893 DOI: 10.1016/j.acmx.2013.02.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2012] [Revised: 02/14/2013] [Accepted: 02/21/2013] [Indexed: 12/16/2022] Open
Abstract
Mixomas are the most common primary cardiac tumors with an estimate incidence of 0,5-1 per 10(6) individuals per year. These tumors have generated interest due to their unique location (left side of the atrial septum near the fossa ovalis), variable clinical presentation and undefined histogenesis. Most cardiac myxomas occur sporadically while approximately 10% of diagnosed cases develop as part of Carney complex. This neoplasm is of uncertain histogenesis, however, endothelial, neurogenic, fibroblastic, and cardiac and smooth muscle cells differentiation has been proposed, and rarely glandular differentiation has been observed. Recently, due to the expression of certain cardiomyocyte-specific factors, an origin of mesenchymal cardiomyocytes progenitor cells has been suggested. Histologically cardiac myxomas are mainly composed of stellated, fusiform and polygonal cells, immersed in an amorphous myxoid matrix. Immunohistochemically some endothelial markers, such as CD31, CD34, FVIIIAg, are present. Positive staining has also been reported for S-100 protein, calretinin, vimentin, desmin, smooth muscle myosin, CD56, α1 antitrypsin and α 1antichymotrypsin. Surgical resection is currently the only treatment of choice. We present in this article a histopathological and immunohistochemical review of cardiac myxomas.
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Hassankhani R, Sam MR, Esmaeilou M, Ahangar P. Prodigiosin isolated from cell wall of Serratia marcescens alters expression of apoptosis-related genes and increases apoptosis in colorectal cancer cells. Med Oncol 2014; 32:366. [DOI: 10.1007/s12032-014-0366-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2014] [Accepted: 11/13/2014] [Indexed: 10/24/2022]
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Paramita R, Sadikin M, Sutandyo N, Wanandi SI. Effect of hypoxia-inducible factor-1α induction by CoCl<sub>2</sub> on breast cancer cells survival: influence of cytochrome-c and survivin. MEDICAL JOURNAL OF INDONESIA 2014. [DOI: 10.13181/mji.v23i3.933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
Abstract
Background: Tumor tissue usually became hypoxic due to disruption of oxygen supply. Adaptation response to hypoxia is mediated by transcription factor, hypoxia- inducible factor-1α (HIF-1α). HIF-1α signaling is known to increase the expression of pro-apoptotic protein cytochrome-c, and anti- apoptotic survivin. In this study we wanted to analyze the role of HIF-1α on breast cancer cells survival through pro-apoptosis cytohrome-c and anti-apoptosis survivin regulation.Methods: Breast cancer cell lines T47D were induced by CoCl2 then harvested to analyze the expression of HIF-1α, protein cytochrome-c, mRNA survivin and cell viabilities.Results: HIF-1α induction by CoCl2 causes the increase of protein and mRNA of HIF-1α, cytochrome-c protein, and survivin mRNA, but does not cause the changes in cell viability.Conclusion: HIF-1α induction have no effects on breast cancer cell line T47D viabilities due to the balance regulation between pro-apoptosis expression cytochrome-c and anti-apoptosis survivin.
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Xu Q, Liu M, Xu N, Zhu H. Variation in Sp1 binding sites correlates with expression of survivin in breast cancer. Mol Med Rep 2014; 10:1395-9. [PMID: 25018047 DOI: 10.3892/mmr.2014.2371] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Accepted: 11/26/2013] [Indexed: 11/06/2022] Open
Abstract
Survivin is the smallest member of the inhibitor of apoptosis (IAP) family and is deregulated in breast cancer, where it is associated with a poor overall prognosis. It is well established that survivin overexpression predominately occurs at the transcriptional level. Numerous transcription factors bind to specific sequences in the promoter regions of genes and are involved in transcriptional regulation. Specificity protein (Sp) 1 binding sites have been found in the promoter region of the survivin gene. The present study aimed to investigate whether variations in Sp1 binding sites affect survivin expression. Nested polymerase chain reaction followed by DNA sequencing were performed to analyze the survivin gene promoter region in 42 breast cancer tissue samples. Furthermore, survivin expression was assessed using immunohistochemistry. High survivin protein expression was found in 66.7% (28/42) of breast cancer tissue samples. In addition, 15 variations in seven Sp1 binding sites were detected in 12 samples and Sp1 binding site variation was found to be associated with low survivin expression in the 42 samples. These findings suggested that variations in Sp1 binding sites may be associated with survivin expression.
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Affiliation(s)
- Qing Xu
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Mei Liu
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Ningzhi Xu
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Hongxia Zhu
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
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The expression of HER-2/neu (c-erbB2), survivin and cycline D1 in serous ovarian neoplasms: their correlation with clinicopathological variables. J Mol Histol 2014; 45:679-87. [DOI: 10.1007/s10735-014-9591-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Accepted: 07/29/2014] [Indexed: 11/25/2022]
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Arora R, Yates C, Gary BD, McClellan S, Tan M, Xi Y, Reed E, Piazza GA, Owen LB, Dean-Colomb W. Panepoxydone targets NF-kB and FOXM1 to inhibit proliferation, induce apoptosis and reverse epithelial to mesenchymal transition in breast cancer. PLoS One 2014; 9:e98370. [PMID: 24896091 PMCID: PMC4045585 DOI: 10.1371/journal.pone.0098370] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Accepted: 05/01/2014] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) is a highly diverse group that is associated with an aggressive phenotype. Its treatment has been challenging due to its heterogeneity and absence of well-defined molecular targets. Thus, there is an urgent need to identify novel agents with therapeutic application. NF-κB is over-expressed in many breast cancers; thus, inactivation of the NF-κB pathway could serve as a therapeutic target. Here we report for the first time the anti-tumor activity of panepoxydone (PP), a NF-κB inhibitor isolated from an edible mushroom, in several breast cancer cell lines. METHODS We investigated the effects of PP on cell growth, migration-invasion, apoptosis and EMT-related proteins expression in MCF-7 and TNBC cell lines MDA-MB-231, MDA-MB-468 and MDA-MB-453. RESULTS Significant antitumor activity was seen in all cell lines, with differential responses noted in cell-line specific manner. Treatment with PP resulted in significant cytotoxicity, decreased invasion, migration and increased apoptosis in all cell lines tested. Up-regulation of Bax and cleaved PARP and down-regulation of Bcl-2, survivin, cyclin D1 and caspase 3 were noted in PP-treated breast cancer cells. The antitumor effect of PP appeared related to its ability to inhibit the phosphorylation of inhibitor of NF-κB (IκBα) with cytoplasmic accumulation. PP treatment also down-regulated FOXM1 which resulted in a reversal of EMT. Similar results were obtained after silencing of NF-kB and FOXM1. CONCLUSION Altogether, these studies show, for the first time the antitumor activity of PP against breast cancer cells, in particular TNBC cells. Furthermore, it highlights the concept that optimal treatment of TNBC warrants attention to the differential sensitivity of various TNBC subtypes to therapeutic agents. These results suggest that the PP may be a potentially effective chemopreventive or therapeutic agent against breast cancer. However, additional studies are required to more fully elucidate the mechanism of antitumor effect of PP.
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Affiliation(s)
- Ritu Arora
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, United States of America
| | - Clayton Yates
- Department of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, Alabama, United States of America
| | - Bernard D. Gary
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, United States of America
| | - Steven McClellan
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, United States of America
| | - Ming Tan
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, United States of America
| | - Yaguang Xi
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, United States of America
| | - Eddie Reed
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, United States of America
| | - Gary A. Piazza
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, United States of America
| | - Laurie B. Owen
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, United States of America
| | - Windy Dean-Colomb
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, United States of America
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Li X, Zhang X, Li X, Ding F, Ding J. The role of survivin in podocyte injury induced by puromycin aminonucleoside. Int J Mol Sci 2014; 15:6657-73. [PMID: 24747598 PMCID: PMC4013653 DOI: 10.3390/ijms15046657] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Revised: 04/04/2014] [Accepted: 04/08/2014] [Indexed: 11/29/2022] Open
Abstract
Objective Survivin is a member of the inhibitor of apoptosis protein family, which uniquely promotes mitosis and regulates apoptosis in cancer cells. Recent studies have demonstrated that survivin also expresses in several normal adult cells. In the present study, we aimed to investigate the function of survivin in the terminally differentiated epithelial cells, podocytes. Methods Survivin expression and location were detected by Quantitative Real-Time PCR, western blot and fluorescence confocal microscopy methods in normal and injured mouse podocytes. Cyto-protection function of survivin was also studied in cultured podocyte injured by puromycin aminonucleoside (PAN), transfected with survivin siRNA to down-regulate survivin expression, or with survivin plasmid to transiently over-express survivin. Results In podocytes, PAN stimulated expressions of survivin and the apoptosis related molecule caspase 3. Knockdown of survivin expression by siRNA increased the activation of caspase 3, induced podocyte apoptosis and remarkable rearrangement of actin cytoskeleton. Moreover, over-expression of survivin inhibited PAN-induced podocyte apoptosis and cytoskeleton rearrangement. Conclusion Our data provides the evidence that survivin plays an important role in protecting podocytes from apoptosis induced by PAN. The mechanism of survivin related anti-apoptosis may, at least partially, be through the activation of caspase 3.
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Affiliation(s)
- Xuejuan Li
- Department of Pediatrics, Peking University First Hospital, No.1 Xi An Men Da Jie, Beijing 100034, China.
| | - Xiaoyan Zhang
- Department of Pediatrics, Peking University First Hospital, No.1 Xi An Men Da Jie, Beijing 100034, China.
| | - Xiaoyan Li
- Department of Pediatrics, Peking University First Hospital, No.1 Xi An Men Da Jie, Beijing 100034, China.
| | - Fangrui Ding
- Department of Pediatrics, Peking University First Hospital, No.1 Xi An Men Da Jie, Beijing 100034, China.
| | - Jie Ding
- Department of Pediatrics, Peking University First Hospital, No.1 Xi An Men Da Jie, Beijing 100034, China.
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Zhao J, Ling X, Cao S, Liu X, Wan S, Jiang T, Li F. Antitumor activity of FL118, a survivin, Mcl-1, XIAP, and cIAP2 selective inhibitor, is highly dependent on its primary structure and steric configuration. Mol Pharm 2014; 11:457-67. [PMID: 24329001 DOI: 10.1021/mp4004282] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
We recently reported the identification and characterization of a novel small chemical molecule designated FL118. FL118 selectively inhibits multiple cancer survival and proliferation-associated antiapoptotic proteins (survivin, Mcl-1, XIAP, cIAP2) and eliminates small and large human tumor xenografts in animal models (Ling et al., PLoS One 2012, 7, e45571). Here, we report a follow-up study on the structure-activity relationship (SAR) of the hydroxyl group in the lactone ring of FL118. We found that the superior antitumor efficacy of FL118 heavily depends on its steric configuration through comparing the antitumor activity of FL118 with FL113 (the racemic mixture of FL118). Consistently, FL118 proved much more effective in inhibiting the expression of survivin, Mcl-1, and cIAP2, both in vitro and in vivo, compared to FL113. Additionally, Tet-on controlled induction of survivin or forced expression of Mcl-1 protects cancer cells from FL118-mediated growth inhibition and cell death. To further explore the SAR, we synthesized seven position 20-esterifiable FL118 and FL113 derivatives. Studies on these seven new compounds revealed that keeping a free hydroxyl group of FL118 is also important for high antitumor efficacy. Together, these studies confirm the superior anticancer activity of FL118 and narrow the window for further SAR studies to generate novel analogues based on FL118 core structure on its other potential chemical positions.
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Affiliation(s)
- Jiuyang Zhao
- Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China , 5 Yushan Road, Qingdao, Shandong 266003 China
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Shintani M, Sangawa A, Yamao N, Kamoshida S. Immunohistochemical expression of nuclear and cytoplasmic survivin in gastrointestinal carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2013; 6:2919-2927. [PMID: 24294379 PMCID: PMC3843273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Accepted: 10/22/2013] [Indexed: 06/02/2023]
Abstract
Survivin is a protein that is highly expressed in many embryonic tissues, as well as most human tumors. Prior studies have reported both positive and negative correlations between survivin expression and cancer prognosis, but these associations remain controversial. In the present study, we assessed the expression of nuclear and cytoplasmic survivin in gastrointestinal carcinomas. Using these data, we determined the correlation between nuclear and cytoplasmic survivin and, further, investigated correlations between survivin expression and clinicopathological parameters. Seventy-two advanced gastric adenocarcinomas and 78 colorectal adenocarcinomas were analyzed for survivin expression by immunohistochemistry. Expression of both nuclear and cytoplasmic survivin was significantly higher in colorectal carcinomas than in gastric carcinomas (P < 0.01). There was a positive correlation between nuclear and cytoplasmic expression of survivin (r = 0.42, P < 0.001). In gastric carcinomas, the level of survivin protein expression was associated with tumor differentiation, patient age, and lymphatic invasion (P < 0.05, 0.01, and 0.01, respectively). In colorectal carcinomas, the level of nuclear survivin expression was significantly higher in females than in males (P < 0.05). There were no significant associations between survivin expression and most of the clinicopathological parameters. Nevertheless, there was a trend towards an inverse correlation between nuclear survivin expression and tumor aggressiveness in gastric carcinoma; there was a similar trend for cytoplasmic survivin expression. In summary, our results suggest that levels of nuclear and cytoplasmic survivin expression differ between gastric carcinoma and colorectal carcinoma.
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Affiliation(s)
- Michiko Shintani
- Laboratory of Pathology, Division of Medical Biophysics, Kobe University Graduate School of Health SciencesKobe, Japan
| | - Akiko Sangawa
- Laboratory of Pathology, Division of Medical Biophysics, Kobe University Graduate School of Health SciencesKobe, Japan
- Department of Diagnostic Pathology, Osaka Red Cross HospitalOsaka, Japan
| | - Naoki Yamao
- Department of Clinical Laboratory, Kuma HospitalKobe, Japan
| | - Shingo Kamoshida
- Laboratory of Pathology, Division of Medical Biophysics, Kobe University Graduate School of Health SciencesKobe, Japan
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Hirano H, Maeda H, Takeuchi Y, Susaki Y, Kobayashi R, Hayashi A, Ose N, Nakazawa Y, Yamaguchi T, Yokota S, Mori M. Association of cigarette smoking with the expression of nuclear survivin in pathological Stage IA lung adenocarcinomas. Med Mol Morphol 2013; 47:196-200. [PMID: 24213518 DOI: 10.1007/s00795-013-0061-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2013] [Accepted: 09/30/2013] [Indexed: 10/26/2022]
Abstract
Survivin is expressed in the cytoplasm and/or nucleus of various types of malignant tumor cells. Cytoplasmic survivin functions as an apoptosis inhibitor, while nuclear survivin is indispensable for complete mitosis completion. To investigate the effect of cigarette smoking on the survivin expression in lung adenocarcinomas at the early developmental stage, we examined the expression of nuclear and cytoplasmic survivin in pathological Stage IA lung adenocarcinomas resected from 38 non-smokers and 44 smokers (current smokers and ex-smokers) using an immunohistochemical method. Labeling indices of nuclear survivin in tumors of smokers were significantly greater than those of non-smokers. The labeling index of nuclear survivin was above 3 % in only 1 (2.6 %) of the 38 tumors of the non-smokers, while the labeling indices in 19 (43.2 %) of 44 tumors of the smokers were above 3 % with a significantly greater frequency. There was no significant difference in the labeling index of nuclear survivin between current smokers and ex-smokers. There was no significant difference in the labeling index of cytoplasmic survivin between tumors of the non-smokers and the smokers. The present results show that cigarette smoking is associated with the higher nuclear surviving expression in lung adenocarcinomas at the early stage, suggesting that cigarette smoking affects the nuclear survivin expression in lung adenocarcinomas at the early developmental stage.
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Affiliation(s)
- Hiroshi Hirano
- Department of Pathology, Toneyama National Hospital, Toyonaka, Osaka, Japan,
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Jeon C, Kim M, Kwak C, Kim HH, Ku JH. Prognostic role of survivin in bladder cancer: a systematic review and meta-analysis. PLoS One 2013; 8:e76719. [PMID: 24204662 PMCID: PMC3799942 DOI: 10.1371/journal.pone.0076719] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2013] [Accepted: 08/24/2013] [Indexed: 01/19/2023] Open
Abstract
PURPOSE The objective of the present study was to conduct a systematic review and meta-analysis of published literature investigating the survivin expression and its effects on bladder cancer prognosis. MATERIALS AND METHODS We carefully searched online Pubmed, Cochrane Library and SCOPUS database from August 1997 to May 2013. RESULTS A total of 14 articles met the eligibility criteria for this systematic review. The eligible studies included a total of 2,165 patients with a median number of 155 patients per study (range: 17-726). Of the 14 studies, nine evaluated immunohistochemistry in formalin-fixed paraffin-embedded tissue blocks. In non-muscle invasive bladder tumor, the pooled hazard ratio (HR) was statistically significant for recurrence-free survival (pooled HR, 1.81; 95% confidence interval [CI], 1.30-2.52), progression-free survival (pooled HR, 2.12; 95% CI, 1.60-2.82), cancer-specific survival (pooled HR, 2.01; 95% CI, 1.32-3.06), and overall survival (pooled HR, 1.53; 95% CI, 1.02-2.29). The overall HRs by survivin status were robust across advanced stages. When only adjusted survival data were included, statistically significant differences were identified for all survival subgroup analyses. There was no between-study heterogeneity in the effect of survivin status on the majority of meta-analyses. There was no clear evidence of publication bias in this meta-analysis. CONCLUSIONS Survivin expression indicates worse prognosis in patients with bladder cancer but the results should be interpreted with caution. It is necessary that better-designed studies with standardized assays need to provide a better conclusion about the relationship between survivin expression and the outcome of patients with bladder cancer.
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Affiliation(s)
- Chanhoo Jeon
- Department of Urology, Seoul National University College of Medicine, Seoul, Korea
| | - Myong Kim
- Department of Urology, Seoul National University College of Medicine, Seoul, Korea
| | - Cheol Kwak
- Department of Urology, Seoul National University College of Medicine, Seoul, Korea
| | - Hyeon Hoe Kim
- Department of Urology, Seoul National University College of Medicine, Seoul, Korea
| | - Ja Hyeon Ku
- Department of Urology, Seoul National University College of Medicine, Seoul, Korea
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Weng Y, Fei B, Chi AL, Cai M. Inhibition of gastric cancer cell growth in vivo by overexpression of adeno-associated virus-mediated survivin mutant C84A. Oncol Res 2013; 20:411-7. [PMID: 23924925 DOI: 10.3727/096504013x13657689383094] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Survivin is overexpressed in most of human cancer cells and tissues. Its overexpression is associated with apoptosis inhibition, drug resistance, and poor prognosis. In this study, we investigated the effect of adeno-associated virus (AAV)-mediated survivin mutant Cys84Ala [rAAV-Sur-Mut(C84A)] on gastric cancer growth. Sur-Mut(C84A) was subcloned into the AAV expression vector pAM/CAG to generate recombinant (r)AAV-Sur-Mut(C84A) virus. Cell survival was determined by the MTT method. Apoptosis was measured by FACS analysis and TUNEL. Tumor growth was assessed using a xenograft mouse model. Results showed that treatment of rAAV-Sur-Mut(C84A) virus significantly reduced cell survival, induced apoptosis, and sensitized gastric cancer cells to 5-fluorouracil in vitro. Furthermore, treatment of rAAV-Sur-Mut(C84A) virus markedly induced apoptosis and inhibited gastric cancer growth in vivo. Moreover, rAAV-Sur-Mut(C84A) treatment strongly enhanced the antitumor activity of 5-fluorouracil. Our results suggest that the combination of rAAV-Sur-Mut(C84A) with chemotherapy may be a promising strategy for gastric cancer therapy.
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Affiliation(s)
- Yuan Weng
- Department of Thoracic and Cardiovascular Surgery, No. 4 People's Hospital of Wuxi City, Wuxi City, PR China
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Chen J, Cui X, Zhou H, Qin C, Cao Q, Ju X, Li P, Cai H, Zhu J, Meng X, Wang M, Zhang Z, Shao P, Li J, Yin C. Functional promoter -31G/C variant of Survivin gene predict prostate cancer susceptibility among Chinese: a case control study. BMC Cancer 2013; 13:356. [PMID: 23883402 PMCID: PMC3765859 DOI: 10.1186/1471-2407-13-356] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Accepted: 06/24/2013] [Indexed: 11/17/2022] Open
Abstract
Background Abnormal expression of Baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5, also called as survivin), a novel member of the inhibitor of apoptosis protein (IAP) family, has implications in many types of cancer and is considered as a new therapeutic target. We suppose that genetic variant rs9904341 in the 5′ UTR region of survivin gene may be associated with the development and progression of prostate cancer (PCa) in Chinese population. Methods TaqMan assay method was used to genotype the polymorphism in the hospital-based case–control analysis of 665 patients with PCa and 710 age-matched cancer-free controls. The genetic associations with the occurrence and progression of PCa were calculated by logistic regression. Results Our results indicated that compared with GG genotypes, there was a statistically significant increased risk of PCa associated with those with CC genotypes [odds ratios (ORs) = 1.57, 95%confidence intervals (CIs) = 1.17-2.13, P = 0.004]. Moreover, stratification analysis revealed that the association was more pronounced in subgroups of nondrinkers, nonsmokers and those without a family history of cancer (all P < 0.05). In addition, we observed that PSA ≥ 20 was more frequent in patients carrying GC/CC genotypes than in those with a wild type genotype. Conclusion The functional survivin rs9904341 genetic variant may have a substantial influence on the PCa susceptibility and evolution.
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Affiliation(s)
- Jiawei Chen
- State Key Laboratory of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 300 Guangzhou Road, Nanjing 210029, China.
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Necochea-Campion RD, Chen CS, Mirshahidi S, Howard FD, Wall NR. Clinico-pathologic relevance of Survivin splice variant expression in cancer. Cancer Lett 2013; 339:167-74. [PMID: 23791888 DOI: 10.1016/j.canlet.2013.06.007] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2013] [Revised: 05/13/2013] [Accepted: 06/08/2013] [Indexed: 01/28/2023]
Abstract
Survivin is a member of the inhibitor of apoptosis (IAP) family and has multifunctional properties that include aspects of proliferation, invasion and cell survival control. Survivin is a promising candidate for targeted cancer therapy as its expression is associated with poor clinical outcome, more aggressive clinico-pathologic features, and resistance to radiation and chemotherapy. In the present review the different properties of the Survivin splice variants are discussed and their activities correlated with different aspects of cancer cell biology, to include subcellular location. Special emphasis is placed on our current understanding of these Survivin splice variants influence on each other and on the phenotypic responses to therapy that they may control.
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Affiliation(s)
- Rosalia de Necochea-Campion
- Cancer Center & Department of Internal Medicine, Division of Hematology and Medical Oncology & Biospecimen Laboratory, Loma Linda University, Loma Linda, CA 92350, United States
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Li W, Chen YQ, Shen YB, Shu HM, Wang XJ, Zhao CL, Chen CJ. HIF-1α knockdown by miRNA decreases survivin expression and inhibits A549 cell growth in vitro and in vivo. Int J Mol Med 2013; 32:271-80. [PMID: 23732337 PMCID: PMC3776716 DOI: 10.3892/ijmm.2013.1405] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2013] [Accepted: 03/19/2013] [Indexed: 12/31/2022] Open
Abstract
The present study examined the downregulation of survivin expression by hypoxia-inducible factor-1α (HIF-1α) miRNA and its effect in the inhibition of A549 cell growth in vitro and in vivo. Survivin expression, apoptosis, proliferation and migration under normoxic and hypoxic conditions were assessed by standard methods. Cotransfection and chromatin immunoprecipitation were used to observe the effects of HIF-1α on survivin transcription. HIF-1α knockdown in A549 cells were injected into nude mice to examine survivin expression and suppression of tumorigenicity. Transfection of A549 cells with HIF-1α miRNA led to decreased expression of HIF-1α and survivin mRNA and protein. Survivin overexpression is mediated by HIF-1α by direct binding to a putative binding site in the survivin core promoter. HIF-1α-miRNA induced apoptosis and inhibited proliferation of A549 cells under hypoxic, but not normoxic, conditions, whereas transfection by survivin expression vectors partly rescued the apoptotic phenotype and revived cell proliferation under hypoxic conditions. However, cell migration was substantially suppressed by HIF-1α silencing under normoxic and hypoxic conditions. After A549 cells were xenografted in nude mice, survivin expression in mice treated with HIF-1α miRNA was downregulated, and tumor growth was significantly inhibited. Silenced HIF-1α gene expression induced apoptosis and suppressed growth of A549 cells by downregulating survivin expression in vitro and in vivo. Our results also provide a basis to target the HIF-1α pathway in lung cancer therapy.
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Affiliation(s)
- Wei Li
- Department of Respiration, First Affiliated Hospital, Bengbu Medical College, Provincial Key Laboratory of Respiratory disease in Anhui, Bengbu, Anhui 233004, P.R. China
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Moniri Javadhesari S, Gharechahi J, Hosseinpour Feizi MA, Montazeri V, Halimi M. Transcriptional Expression Analysis of Survivin Splice Variants Reveals Differential Expression of Survivin-3α in Breast Cancer. Genet Test Mol Biomarkers 2013; 17:314-20. [DOI: 10.1089/gtmb.2012.0411] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
| | - Javad Gharechahi
- Department of Molecular Genetics, National Institute for Genetic Engineering and Biotechnology, Tehran, Iran
- Department of Genetics, Iranian Center for Breast Cancer, Academic Center for Education, Culture and Research, Tehran, Iran
| | | | - Vahid Montazeri
- Department of Surgery, School of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Monireh Halimi
- Department of Pathology, School of Medicine, Tabriz University of Medical Science, Tabriz, Iran
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Ling X, Li F. An intravenous (i.v.) route-compatible formulation of FL118, a survivin, Mcl-1, XIAP, and cIAP2 selective inhibitor, improves FL118 antitumor efficacy and therapeutic index (TI). Am J Transl Res 2013; 5:139-154. [PMID: 23573360 PMCID: PMC3612511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2013] [Accepted: 02/28/2013] [Indexed: 06/02/2023]
Abstract
We recently reported a novel anticancer small molecule, designated FL118, which was discovered via high throughput screening (HTS), and followed by hit-lead in vitro and in vivo analysis. FL118 selectively inhibits the expression of four major cancer survival-associated gene products (survivin, Mcl-1, XIAP, and cIAP2) and shows promising antitumor activity in animal models of human cancers when administered using a weekly x 4 schedule (Ling et al., PLOS ONE. 2012, 7: e45571). Here, we compared the antitumor efficacy and therapeutic index (TI) of FL118 in a newly developed Tween 80-free formulation that can be delivered intravenously (i.v.) and intraperitoneally (i.p.) against the previous Tween 80-containing formulation that can only be delivered via an i.p. route. We found that the maximum tolerated dose (MTD) for FL118 in the i.v. formulation increases 3-7 fold in comparison with the MTD of FL118 in the i.p. formulation. FL118 in the i.v. recipe was able to eliminate human tumor xenografts in all three major schedules tested (daily x 5, q2 x 5 and weekly x 5). In contrast, FL118 was able to eliminate human tumor xenografts in the i.p. formulation only with the weekly x 4 schedule previously reported. The TI of FL118 in the i.v. formulation reached 5-6 in the most effective schedule, while the TI of FL118 in the i.p. formulation was only 1.3 - 2. These findings overcome several clinical challenges including FL118 formulation to realize clinically compatible drug administration routes, and expanding effective treatment schedules. The striking improvement of the TI makes FL118 a much safer drug for further development toward clinical trials.
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Affiliation(s)
- Xiang Ling
- Departments of Pharmacology & Therapeutics, Roswell Park Cancer Institute (RPCI)Buffalo, New York 14263, USA
| | - Fengzhi Li
- Departments of Pharmacology & Therapeutics, Roswell Park Cancer Institute (RPCI)Buffalo, New York 14263, USA
- NCI CCSG-supported Experimental Therapeutics (ET) Program, Roswell Park Cancer Institute (RPCI)Buffalo, New York 14263, USA
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The association between the Survivin A9194G exon polymorphisms and papillary thyroid carcinoma risk in the Han Chinese population. Pathol Res Pract 2013; 209:151-4. [DOI: 10.1016/j.prp.2013.01.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2012] [Revised: 01/03/2013] [Accepted: 01/04/2013] [Indexed: 11/23/2022]
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Sheikh H, Abdulghani J, Ali S, Sinha R, Lipton A. Impact of Genetic Targets on Prostate Cancer Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2013; 779:359-83. [DOI: 10.1007/978-1-4614-6176-0_17] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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