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Peng X, Feng J, Yang H, Xia P, Pu F. Nrf2: A key regulator in chemoradiotherapy resistance of osteosarcoma. Genes Dis 2025; 12:101335. [PMID: 40242036 PMCID: PMC12000747 DOI: 10.1016/j.gendis.2024.101335] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 01/24/2024] [Accepted: 04/03/2024] [Indexed: 04/18/2025] Open
Abstract
Osteosarcoma (OS), frequently observed in children and adolescents, is one of the most common primary malignant tumors of the bone known to be associated with a high capacity for invasion and metastasis. The incidence of osteosarcoma in children and adolescents is growing annually, although improvements in survival remain limited. With the clinical application of neoadjuvant chemotherapy, chemotherapy combined with limb-preserving surgery has gained momentum as a major intervention. However, certain patients with OS experience treatment failure owing to chemoradiotherapy resistance or metastasis. Nuclear factor E2-related factor 2 (Nrf2), a key antioxidant factor in organisms, plays a crucial role in maintaining cellular physiological homeostasis; however, its overactivation in cancer cells restricts reactive oxygen species production, promotes DNA repair and drug efflux, and ultimately leads to chemoradiotherapy resistance. Recent studies have also identified the functions of Nrf2 beyond its antioxidative function, including the promotion of proliferation, metastasis, and regulation of metabolism. The current review describes the multiple mechanisms of chemoradiotherapy resistance in OS and the substantial role of Nrf2 in the signaling regulatory network to elucidate the function of Nrf2 in promoting OS chemoradiotherapy resistance and formulating relevant therapeutic strategies.
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Affiliation(s)
- Xianglin Peng
- Department of Orthopedics, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Department of Orthopedics, Wuhan No.1 Hospital, Wuhan 430022, China
| | - Jing Feng
- Department of Orthopedics, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Department of Orthopedics, Wuhan No.1 Hospital, Wuhan 430022, China
| | - Han Yang
- Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Zunyi Medical University, Zunyi 563000, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Ping Xia
- Department of Orthopedics, Wuhan Fourth Hospital, Wuhan 430030, China
| | - Feifei Pu
- Department of Orthopedics, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Department of Orthopedics, Wuhan No.1 Hospital, Wuhan 430022, China
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Su Y, Mei L, Wu Y, Li C, Jiang T, Zhao Y, Feng X, Sun T, Li Y, Wang Z, Ji Y. Xenotropic and polytropic retrovirus receptor 1 (XPR1) promotes progression of papillary thyroid carcinoma via the BRAF-ERK1/2-P53 signaling pathway. J Endocrinol Invest 2025; 48:633-652. [PMID: 39487939 DOI: 10.1007/s40618-024-02481-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 10/19/2024] [Indexed: 11/04/2024]
Abstract
BACKGROUND Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Xenotropic and polytropic retrovirus receptor 1 (XPR1), identified as a cellular receptor, plays roles in many pathophysiological processes. However, the underlying function and molecular mechanisms of XPR1 in PTC remain unclear. Therefore, this study aimed to elucidate the role of XPR1 in the process of PTC and the potential mechanisms. METHODS RNA-sequencing was performed for gene differential expression analysis in PTC patients' tissues. Immunohistochemical assay, real-time PCR, and western blotting assay were used to determine the expression of XPR1, BRAF, and P53 in PTC tissues. The function of XPR1 on the progression of PTC was explored using in vitro and in vivo experiments. The molecular mechanism of XPR1 was investigated using gene silencing, ELISA, immunofluorescence, western blotting, and real-time PCR assays. RESULTS We found that XPR1 was markedly upregulated in PTC tissues compared to adjacent noncancerous tissues, suggesting that high expression of XPR1 could be correlated with poor patient disease-free survival in PTC. In addition, the expression of BRAF and P53 in PTC tissues was substantially higher than in adjacent noncancerous tissues. Silencing of XPR1 reduced the proliferation, migration, and invasion capacities of TPC-1 cells in vitro and effectively inhibited the tumorigenecity of PTC in vivo. More importantly, silencing of XPR1 in TPC-1 cells significantly decreased the expression of XPR1, BRAF, and P53 both in vitro and in vivo. Interestingly, we demonstrated that XPR1 may positively activate the BRAF-ERK-P53 signaling pathway, further promoting PTC progression. CONCLUSION The findings reveal a crucial role of XPR1 in PTC progression and prognosis via the BRAF-ERK1/2-P53 signaling pathway, providing potential therapeutic targets for treating PTC.
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Affiliation(s)
- Yuanhao Su
- Department of Geriatric General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Lin Mei
- Scientific Research Center and Precision Medical Institute, The Second Affiliated Hospital, Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, Shaanxi, China
| | - Yongke Wu
- Department of Geriatric General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Cheng Li
- Department of Geriatric General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Tiantian Jiang
- Department of Geriatric General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Yiyuan Zhao
- Department of Geriatric General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Xin Feng
- Department of Geriatric General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Tingkai Sun
- Department of Geriatric General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Yunhao Li
- Department of Geriatric General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Zhidong Wang
- Department of Geriatric General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China.
| | - Yuanyuan Ji
- Scientific Research Center and Precision Medical Institute, The Second Affiliated Hospital, Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, Shaanxi, China.
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Khaled Z, Ilia G, Watz C, Macașoi I, Drăghici G, Simulescu V, Merghes PE, Varan NI, Dehelean CA, Vlaia L, Sima L. The Biological Impact of Some Phosphonic and Phosphinic Acid Derivatives on Human Osteosarcoma. Curr Issues Mol Biol 2024; 46:4815-4831. [PMID: 38785558 PMCID: PMC11120618 DOI: 10.3390/cimb46050290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 05/10/2024] [Accepted: 05/14/2024] [Indexed: 05/25/2024] Open
Abstract
Osteosarcoma malignancy currently represents a major health problem; therefore, the need for new therapy approaches is of great interest. In this regard, the current study aims to evaluate the anti-neoplastic potential of a newly developed phosphinic acid derivative (2-carboxyethylphenylphosphinic acid) and, subsequently, to outline its pharmaco-toxicological profile by employing two different in vitro human cell cultures (keratinocytes-HaCaT-and osteosarcoma SAOS-2 cells), employing different techniques (MTT assay, cell morphology assessment, LDH assay, Hoechst staining and RT-PCR). Additionally, the results obtained are compared with three commercially available phosphorus-containing compounds (P1, P2, P3). The results recorded for the newly developed compound (P4) revealed good biocompatibility (cell viability of 77%) when concentrations up to 5 mM were used on HaCaT cells for 24 h. Also, the HaCaT cultures showed no significant morphological alterations or gene modulation, thus achieving a biosafety profile even superior to some of the commercial products tested herein. Moreover, in terms of anti-osteosarcoma activity, 2-carboxyethylphenylphosphinic acid expressed promising activity on SAOS-2 monolayers, the cells showing viability of only 55%, as well as apoptosis features and important gene expression modulation, especially Bid downregulation. Therefore, the newly developed compound should be considered a promising candidate for further in vitro and in vivo research related to osteosarcoma therapy.
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Affiliation(s)
- Zakzak Khaled
- Pharmaceutical Technology, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timisoara, Romania; (Z.K.); (L.V.)
- Formulation and Technology of Drugs Research Center, “Victor Babeş” University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timisoara, Romania
| | - Gheorghe Ilia
- Department of Biology-Chemistry, Faculty of Chemistry, Biology, Geography, West University Timisoara, 16 Pestalozzi Street, 300115 Timisoara, Romania; (G.I.); (V.S.)
| | - Claudia Watz
- Department of Pharmaceutical Physics, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy of Timisoara, 2nd Eftimie Murgu Square, 300041 Timisoara, Romania
- Research Center for Pharmaco-Toxicological Evaluation, “Victor Babeş” University of Medicine and Pharmacy Timisoara, 2nd Eftimie Murgu Square, 300041 Timisoara, Romania; (I.M.); (G.D.); (C.A.D.)
| | - Ioana Macașoi
- Research Center for Pharmaco-Toxicological Evaluation, “Victor Babeş” University of Medicine and Pharmacy Timisoara, 2nd Eftimie Murgu Square, 300041 Timisoara, Romania; (I.M.); (G.D.); (C.A.D.)
- Department of Toxicology and Drug Industry, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy Timisoara, 2nd Eftimie Murgu Square, 300041 Timisoara, Romania
| | - George Drăghici
- Research Center for Pharmaco-Toxicological Evaluation, “Victor Babeş” University of Medicine and Pharmacy Timisoara, 2nd Eftimie Murgu Square, 300041 Timisoara, Romania; (I.M.); (G.D.); (C.A.D.)
- Department of Toxicology and Drug Industry, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy Timisoara, 2nd Eftimie Murgu Square, 300041 Timisoara, Romania
| | - Vasile Simulescu
- Department of Biology-Chemistry, Faculty of Chemistry, Biology, Geography, West University Timisoara, 16 Pestalozzi Street, 300115 Timisoara, Romania; (G.I.); (V.S.)
| | - Petru Eugen Merghes
- Department of Physical Education and Sport, “King Mihai I” University of Life Sciences from Timisoara, Calea Aradului 119, 300645 Timisoara, Romania; (P.E.M.); (N.I.V.)
| | - Narcis Ion Varan
- Department of Physical Education and Sport, “King Mihai I” University of Life Sciences from Timisoara, Calea Aradului 119, 300645 Timisoara, Romania; (P.E.M.); (N.I.V.)
| | - Cristina Adriana Dehelean
- Research Center for Pharmaco-Toxicological Evaluation, “Victor Babeş” University of Medicine and Pharmacy Timisoara, 2nd Eftimie Murgu Square, 300041 Timisoara, Romania; (I.M.); (G.D.); (C.A.D.)
- Department of Toxicology and Drug Industry, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy Timisoara, 2nd Eftimie Murgu Square, 300041 Timisoara, Romania
| | - Lavinia Vlaia
- Pharmaceutical Technology, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timisoara, Romania; (Z.K.); (L.V.)
- Formulation and Technology of Drugs Research Center, “Victor Babeş” University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timisoara, Romania
| | - Laurențiu Sima
- Department of Surgery I, “Victor Babeş” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
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Green spectrofluorimetric determination of alendronate sodium using nano switchable probe; Water-soluble carbon dots synthesized from a natural source. TALANTA OPEN 2022. [DOI: 10.1016/j.talo.2022.100127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Fu Y, Yuan P, Zheng Y, Gao L, Wei Y, Chen Y, Li P, Ruan Y, Zheng X, Feng W. Ephedra herb reduces adriamycin-induced testicular toxicity by upregulating the gonadotropin-releasing hormone signalling pathway. Biomed Pharmacother 2022; 150:113061. [PMID: 35658231 DOI: 10.1016/j.biopha.2022.113061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 04/26/2022] [Accepted: 04/26/2022] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVE We investigated the protective effects of ephedra herb (HEPH) on adriamycin-induced testicular toxicity in rats and explored the potential mechanisms underlying these effects. METHODS A rat model of adriamycin injury was established, and sperm motility-related indicator and oxidative stress levels in the testis were evaluated. Serum levels of sex hormones and levels of testicular cell apoptosis were detected by enzyme-linked immunosorbent assay and flow cytometry, respectively. Western blotting (WB), immunofluorescence analyses, and reverse transcription-polymerase chain reaction (RT-PCR) were performed to evaluate the gonadotropin-releasing hormone (GnRH) signalling pathway- and meiosis-related genes and proteins. In subsequent in vitro experiments, adriamycin was used to stimulate GC-1 cells, which were treated with HEPH, ephedrine, or pseudoephedrine. Cell viability was assessed using flow cytometry to detect apoptosis and reactive oxygen species, whereas the GnRH signalling pathway and levels of meiosis-related genes and proteins were evaluated by InCell WB, a high-content imaging system, and RT-PCR. RESULTS Per in vivo experiments, HEPH restored testicular weight and function, sperm characteristics, serum and tissue hormonal levels, and antioxidant defences and significantly activated the GnRH signalling pathway- and meiosis-related protein levels. All protective effects of HEPH against adriamycin-induced injury were antagonised by the GnRH antagonist cetrorelix. In vitro, HEPH, ephedrine, and pseudoephedrine significantly reduced adriamycin-induced GC-1 cell apoptosis and reactive oxygen species levels and increased the expression of GnRH signalling pathway- and meiosis-related proteins. The effect of pseudoephedrine was greater than that of ephedrine, and these findings may be an important basis for understanding the effects of HEPH.
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Affiliation(s)
- Yang Fu
- Department of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China; The Engineering and Technology Center for Chinese Medicine Development of Henan Province, Zhengzhou 450046, China
| | - PeiPei Yuan
- Department of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China; The Engineering and Technology Center for Chinese Medicine Development of Henan Province, Zhengzhou 450046, China
| | - Yajuan Zheng
- Department of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Liyuan Gao
- Department of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Yaxin Wei
- Department of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Yi Chen
- Department of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Panying Li
- Department of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Yuan Ruan
- Department of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Xiaoke Zheng
- Department of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China; The Engineering and Technology Center for Chinese Medicine Development of Henan Province, Zhengzhou 450046, China.
| | - Weisheng Feng
- Department of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China; The Engineering and Technology Center for Chinese Medicine Development of Henan Province, Zhengzhou 450046, China.
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Shanti A, Al Adem K, Stefanini C, Lee S. Hydrogen phosphate selectively induces MDA MB 231 triple negative breast cancer cell death in vitro. Sci Rep 2022; 12:5333. [PMID: 35351930 PMCID: PMC8964734 DOI: 10.1038/s41598-022-09299-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 02/28/2022] [Indexed: 12/03/2022] Open
Abstract
Phosphate ions are the most abundant anions inside the cells, and they are increasingly gaining attention as key modulators of cellular function and gene expression. However, little is known about the effect of inorganic phosphate ions on cancer cells, particularly breast cancer cells. Here, we investigated the toxicity of different phosphate compounds to triple-negative human breast cancer cells, particularly, MDA-MB-231, and compared it to that of human monocytes, THP-1. We found that, unlike dihydrogen phosphate (H2PO4−), hydrogen phosphate (HPO42−) at 20 mM or lower concentrations induced breast cancer cell death more than immune cell death, mainly via apoptosis. We correlate this effect to the fact that phosphate in the form of HPO42− raises pH levels to alkaline levels which are not optimum for transport of phosphate into cancer cells. The results in this study highlight the importance of further exploring hydrogen phosphate (HPO42−) as a potential therapeutic for the treatment of breast cancer.
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Affiliation(s)
- Aya Shanti
- Department of Biomedical Engineering, Healthcare Engineering Innovation Center, Khalifa University of Science and Technology, 127788, Abu Dhabi, United Arab Emirates
| | - Kenana Al Adem
- Department of Biomedical Engineering, Healthcare Engineering Innovation Center, Khalifa University of Science and Technology, 127788, Abu Dhabi, United Arab Emirates
| | - Cesare Stefanini
- Department of Biomedical Engineering, Healthcare Engineering Innovation Center, Khalifa University of Science and Technology, 127788, Abu Dhabi, United Arab Emirates
| | - Sungmun Lee
- Department of Biomedical Engineering, Healthcare Engineering Innovation Center, Khalifa University of Science and Technology, 127788, Abu Dhabi, United Arab Emirates. .,Khalifa University's Center for Biotechnology, Khalifa University of Science and Technology, 127788, Abu Dhabi, United Arab Emirates.
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7
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Zhang B, Yang L, Wang X, Fu D. Identification of a survival-related signature for sarcoma patients through integrated transcriptomic and proteomic profiling analyses. Gene 2021; 764:145105. [PMID: 32882333 DOI: 10.1016/j.gene.2020.145105] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 08/18/2020] [Accepted: 08/26/2020] [Indexed: 02/06/2023]
Abstract
Sarcoma (SARC) represents a group of highly histological and molecular heterogeneous rare malignant tumors with poor prognosis. There are few proposed classifiers for predicting patient's outcome. The Cancer Proteome Atlas (TPCA) and The Cancer Genome Atlas (TCGA) databases provide multi-omics datasets that enable a comprehensive investigation for this disease. The proteomic expression profile of SARC patients along with the clinical information was downloaded. 55 proteins were found to be associated with overall survival (OS) of patients using univariate Cox regression analysis. We developed a prognostic risk signature that comprises seven proteins (AMPKALPHA, CHK1, S6, ARID1A, RBM15, ACETYLATUBULINLYS40, and MSH6) with robust predictive performance using multivariate Cox stepwise regression analysis. Additionally, the signature could be an independent prognostic predictor after adjusting for clinicopathological parameters. Patients in high-risk group also have worse progression free intervals (PFI) than that of patients in low-risk group, but not for disease free intervals (DFI). The signature was validated using transcriptomic profile of SARC patients from TCGA. Potential mechanisms between high- and low-risk groups were identified using differentially expressed genes (DEGs) analysis. These DEGs were primarily enriched in RAS and MPAK signaling pathways. The signature protein molecules are candidate biomarkers for SARC, and the analysis of computational biology in tumor infiltrating lymphocytes and immune checkpoint molecules revealed distinctly immune landscapes of high- and low-risk patients. Together, we constructed a prognostic signature for predicting outcomes for SARC integrating proteomic and transcriptomic profiles, this might have value in guiding clinical practice.
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Affiliation(s)
- Biyu Zhang
- School of Pharmacy and Life Science, Jiujiang University, Jiujiang, Jiangxi 332005, China
| | - Lei Yang
- School of Basic Medicine, Jiujiang University, Jiujiang, Jiangxi 332005, China
| | - Xin Wang
- School of Basic Medicine, Jiujiang University, Jiujiang, Jiangxi 332005, China
| | - Denggang Fu
- School of Basic Medicine, Jiujiang University, Jiujiang, Jiangxi 332005, China; School of Medicine, Indiana University, Indianapolis, IN 46202, USA.
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Arnst JL, Beck GR. Modulating phosphate consumption, a novel therapeutic approach for the control of cancer cell proliferation and tumorigenesis. Biochem Pharmacol 2020; 183:114305. [PMID: 33129806 DOI: 10.1016/j.bcp.2020.114305] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/22/2020] [Accepted: 10/23/2020] [Indexed: 01/30/2023]
Abstract
Phosphorus, often in the form of inorganic phosphate (Pi), is critical to cellular function on many levels; it is required as an integral component of kinase signaling, in the formation and function of DNA and lipids, and energy metabolism in the form of ATP. Accordingly, crucial aspects of cell mitosis - such as DNA synthesis and ATP energy generation - elevate the cellular requirement for Pi, with rapidly dividing cells consuming increased levels. Mechanisms to sense, respond, acquire, accumulate, and potentially seek Pi have evolved to support highly proliferative cellular states such as injury and malignant transformation. As such, manipulating Pi availability to target rapidly dividing cells presents a novel strategy to reduce or prevent unrestrained cell growth. Currently, limited knowledge exists regarding how modulating Pi consumption by pre-cancerous cells might influence the initiation of aberrant growth during malignant transformation, and if reducing the bioavailability or suppressing Pi consumption by malignant cells could alter tumorigenesis. The concept of targeting Pi-regulated pathways and/or consumption by pre-cancerous or tumor cells represents a novel approach to cancer prevention and control, although current data remains insufficient as to rigorously assess the therapeutic value and physiological relevance of this strategy. With this review, we present a critical evaluation of the paradox of how an element critical to essential cellular functions can, when available in excess, influence and promote a cancer phenotype. Further, we conjecture how Pi manipulation could be utilized as a therapeutic intervention, either systemically or at the cell level, to ultimately suppress or treat cancer initiation and/or progression.
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Affiliation(s)
- Jamie L Arnst
- Emory University, Department of Medicine, Division of Endocrinology, Metabolism, and Lipids, Atlanta, GA 30322, United States
| | - George R Beck
- The Atlanta Department of Veterans Affairs Medical Center, Decatur, GA 30033, United States; Emory University, Department of Medicine, Division of Endocrinology, Metabolism, and Lipids, Atlanta, GA 30322, United States; The Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, United States.
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Wang F, Zhang Z, Li Q, Yu T, Ma C. Untargeted LC-MS/MS analysis reveals metabolomics feature of osteosarcoma stem cell response to methotrexate. Cancer Cell Int 2020; 20:269. [PMID: 32587477 PMCID: PMC7313215 DOI: 10.1186/s12935-020-01356-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 06/16/2020] [Indexed: 02/08/2023] Open
Abstract
Background Cancer stem cell (CSC) is identified in osteosarcoma (OS) and considered resistant to chemotherapeutic agents. However, the mechanism of osteosarcoma stem cell (OSC) resistant to chemotherapy remains debatable and vague, and the metabolomics feature of OSC is not clarified. Materials and methods OSC was isolated by using sphere forming assay and identified. Untargeted LC-MS/MS analysis was performed to reveal the metabolomics feature of OSC and underlying mechanisms of OSC resistant to methotrexate (MTX). Results OSC was efficiently isolated and identified from human OS 143B and MG63 cell lines with enhanced chemo-resistance to MTX. The untargeted LC-MS analysis revealed that OSC showed differential metabolites and perturbed signaling pathways, mainly involved in metabolisms of fatty acid, amino acid, carbohydrate metabolism and nucleic acid. After treated with MTX, metabolomics feature of OSC was mainly involved metabolisms of amino acid, fatty acid, energy and nucleic acid. Moreover, compared with their parental OS cells response to MTX, the differential metabolites and perturbed signaling pathways were mainly involved in metabolism of amino acid, fatty acid and nucleic acid. What's more, Rap1 signaling pathway and Ras signaling pathway were involved in OS cells and their SCs response to MTX. Conclusion Sphere-forming assay was able to efficiently isolate OSC from human OS cell lines and the untargeted LC-MS/MS analysis was suggested a sufficient methodology to investigate metabolomics features of OS cells and OSCs. Moreover, the metabolomics features of OSCs response to MTX might reveal a further understanding of chemotherapeutic resistance in OS.
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Affiliation(s)
- Feng Wang
- Department of Orthopedics, the Fourth Affiliated Hospital of China Medical University, Chongshan Road, Shenyang, 110032 Liaoning People's Republic of China
| | - Zhiyu Zhang
- Department of Orthopedics, the Fourth Affiliated Hospital of China Medical University, Chongshan Road, Shenyang, 110032 Liaoning People's Republic of China
| | - Qin Li
- Center for Translational Medicine, the Fourth Affiliated Hospital of China Medical University, Chongshan Road, Shenyang, 110032 Liaoning People's Republic of China
| | - Tao Yu
- Center for Translational Medicine, the Fourth Affiliated Hospital of China Medical University, Chongshan Road, Shenyang, 110032 Liaoning People's Republic of China
| | - Chengbin Ma
- Department of Orthopedics, the Fourth Affiliated Hospital of China Medical University, Chongshan Road, Shenyang, 110032 Liaoning People's Republic of China
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Affiliation(s)
- Yanyan Liu
- Department of Materials ScienceFudan University Shanghai P. R. China
- Shanghai Key Laboratory of Green Chemistry and Chemical ProcessesCollege of Chemistry and Molecular EngineeringEast China Normal University Shanghai P. R. China
| | - Meng Zhang
- State Key Laboratory of High Performance Ceramics and Superfine MicrostructuresShanghai Institute of CeramicsChinese Academy of Sciences Shanghai P. R. China
| | - Wenbo Bu
- Department of Materials ScienceFudan University Shanghai P. R. China
- Shanghai Key Laboratory of Green Chemistry and Chemical ProcessesCollege of Chemistry and Molecular EngineeringEast China Normal University Shanghai P. R. China
- State Key Laboratory of High Performance Ceramics and Superfine MicrostructuresShanghai Institute of CeramicsChinese Academy of Sciences Shanghai P. R. China
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He J, Zhou M, Li X, Gu S, Cao Y, Xing T, Chen W, Chu C, Gu F, Zhou J, Jin Y, Ma J, Ma D, Zou Q. SLC34A2 simultaneously promotes papillary thyroid carcinoma growth and invasion through distinct mechanisms. Oncogene 2020; 39:2658-2675. [PMID: 32005974 DOI: 10.1038/s41388-020-1181-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Revised: 01/13/2020] [Accepted: 01/22/2020] [Indexed: 02/06/2023]
Abstract
Thyroid cancer is the fastest growing cancer among all solid tumors in recent decades. Papillary thyroid carcinoma (PTC) is the most predominant type of thyroid cancer. Around 30% of PTC patients with distant metastases and local invasion receive poor prognosis. Thus, the identification of new druggable biological targets is of great importance. Accumulating evidence indicates that solute carrier family numbers have emerged as obligate effectors during the progression of multiple malignancies. Here, we uncovered the functional significance, molecular mechanisms, and clinical impact of solute carrier family 34 member A2 (SLC34A2) in PTC. SLC34A2 was markedly overexpressed in PTC tissues at both mRNA and protein levels compared with matched adjacent normal tissues due to promoter hypomethylation mediated by the DNA methyltransferase 3 beta (DNMT3B). Furthermore, a series of in vivo and in vitro gain- or loss-of-functional assays elucidated the role of SLC34A2 in boosting cell proliferation, cell cycle progression, migration, invasion, and adhesion of PTC cells. Using immunoprecipitation and mass spectrometry, we discovered that SLC34A2 bound to the actin-binding repeats domain of Cortactin (CTTN), thereby inducing the invadopodia formation of PTC cells to promote the metastasis potential of PTC cells. Besides, our mechanistic studies, as well as gene set enrichment analysis (GSEA), have pinpointed the PTEN/AKT/FOXO3a pathway as a major signaling functioning downstream of SLC34A2 regulated cell growth. Taken together, our results highlighted that SLC34A2 plays a pivotal oncogenic role during carcinogenesis and metastasis through distinct mechanisms in PTC.
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Affiliation(s)
- Jing He
- Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Middle Road, Shanghai, 200040, China
| | - Mingxia Zhou
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Xiaoyan Li
- Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Middle Road, Shanghai, 200040, China
| | - Siwen Gu
- Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Middle Road, Shanghai, 200040, China
| | - Yun Cao
- Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Middle Road, Shanghai, 200040, China
| | - Tengfei Xing
- Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Middle Road, Shanghai, 200040, China
| | - Wei Chen
- Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Middle Road, Shanghai, 200040, China
| | - Chengyu Chu
- Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Middle Road, Shanghai, 200040, China
| | - Fei Gu
- Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Middle Road, Shanghai, 200040, China
| | - Jian Zhou
- Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Middle Road, Shanghai, 200040, China
| | - Yiting Jin
- Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Middle Road, Shanghai, 200040, China
| | - Jing Ma
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Institute of Biomedical Sciences, Fudan University, 130 Dong'an Road, Shanghai, 200032, China
| | - Duan Ma
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Institute of Biomedical Sciences, Fudan University, 130 Dong'an Road, Shanghai, 200032, China.
| | - Qiang Zou
- Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Middle Road, Shanghai, 200040, China.
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12
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Pang KL, Chin KY. Emerging Anticancer Potentials of Selenium on Osteosarcoma. Int J Mol Sci 2019; 20:E5318. [PMID: 31731474 PMCID: PMC6862058 DOI: 10.3390/ijms20215318] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 10/05/2019] [Accepted: 10/22/2019] [Indexed: 02/07/2023] Open
Abstract
Selenium is a trace element essential to humans and forms complexes with proteins, which exert physiological functions in the body. In vitro studies suggested that selenium possesses anticancer effects and may be effective against osteosarcoma. This review aims to summarise current evidence on the anticancer activity of inorganic and organic selenium on osteosarcoma. Cellular studies revealed that inorganic and organic selenium shows cytotoxicity, anti-proliferative and pro-apoptotic effects on various osteosarcoma cell lines. These actions may be mediated by oxidative stress induced by selenium compounds, leading to the activation of p53, proapoptotic proteins and caspases. Inorganic selenium is selective towards cancer cells, but can cause non-selective cell death at a high dose. This condition challenges the controlled release of selenium from biomaterials. Selenium treatment in animals inoculated with osteosarcoma reduced the tumour size, but did not eliminate the incidence of osteosarcoma. Only one study investigated the relationship between selenium and osteosarcoma in humans, but the results were inconclusive. In summary, although selenium may exert anticancer properties on osteosarcoma in experimental model systems, its effects in humans require further investigation.
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Affiliation(s)
| | - Kok-Yong Chin
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia;
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13
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Chen WC, Li QL, Pan Q, Zhang HY, Fu XY, Yao F, Wang JN, Yang AK. Xenotropic and polytropic retrovirus receptor 1 (XPR1) promotes progression of tongue squamous cell carcinoma (TSCC) via activation of NF-κB signaling. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:167. [PMID: 30995931 PMCID: PMC6469095 DOI: 10.1186/s13046-019-1155-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Accepted: 03/27/2019] [Indexed: 01/15/2023]
Abstract
Background Xenotropic and polytropic retrovirus receptor 1 (XPR1), a previously identified cellular receptor for several murine leukemia viruses, plays a role in many pathophysiological processes. However, the role of XPR1 in human cancers has not yet been characterized. Methods Real-time PCR and western blotting assay were used to measure the expression of XPR1 in tongue squamous cell carcinoma (TSCC) tissues. Expression of XPR1 and p65 in clinical specimens was analyzed using immunohistochemical assay. The function of XPR1 on progression of TSCC was explored using in vitro and in vivo experiments. The molecular mechanism by which XPR1 helps to cancer progression was investigated by luciferase reporter activity, ELISA, PKA activity assay, immunofluorescence, western blotting and qPCR assay. Results Herein, we find that XPR1 is markedly upregulated in TSCC tissues compared to normal tongue tissues. High expression of XPR1 significantly correlates with the malignant features and poor patient survival in TSCC. Ectopic expression of XPR1 increases, while silencing of XPR1 reduces the proliferation, invasion and anti-apoptosis capacities of TSCC cells. Importantly, silencing of XPR1 effectively inhibits the tumorigenecity of TSCC cells. Moreover, we identified that XPR1 increased the concentration of intracellular cAMP and activated PKA. Thus, XPR1 promoted phosphorylation and activation of NF-κB signaling, which is required for XPR1-mediated oncogenic roles and significantly correlates with XPR1 expression in clinical specimens. Conclusions These findings uncover a critical role of XPR1 in TSCC progression via activation of NF-κB, and suggest that XPR1 might be a potential prognostic marker or therapeutic target. Electronic supplementary material The online version of this article (10.1186/s13046-019-1155-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Wei-Chao Chen
- Department of Head and Neck, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510060, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Qiu-Li Li
- Department of Head and Neck, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510060, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Qimei Pan
- Guangzhou Yousheng Biotech Co., Ltd., Guangzhou, Guangdong, 510060, People's Republic of China
| | - Hua-Yong Zhang
- Department of Head and Neck, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510060, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Xiao-Yan Fu
- Department of Head and Neck, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510060, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Fan Yao
- Department of Head and Neck, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510060, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Jian-Ning Wang
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong Province, 510055, People's Republic of China.
| | - An-Kui Yang
- Department of Head and Neck, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, People's Republic of China. .,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510060, People's Republic of China. .,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China.
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14
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Catauro M, Tranquillo E, Salzillo A, Capasso L, Illiano M, Sapio L, Naviglio S. Silica/Polyethylene Glycol Hybrid Materials Prepared by a Sol-Gel Method and Containing Chlorogenic Acid. Molecules 2018; 23:2447. [PMID: 30257424 PMCID: PMC6222366 DOI: 10.3390/molecules23102447] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 09/19/2018] [Accepted: 09/21/2018] [Indexed: 12/13/2022] Open
Abstract
Chlorogenic acid (CGA) is a very common dietary polyphenolic compound. CGA is becoming very attractive due to its potential use as preventive and therapeutic agent in many diseases, including cancer. Inorganic/organic hybrid materials are gaining considerable attention in the biomedical field. The sol-gel process provides a useful way to obtain functional organic/inorganic hybrids. The aim of this study was to synthesize silica/polyethylene glycol (PEG) hybrids with different percentages of CGA by sol-gel technique and to investigate their impact on the cancer cell proliferation. Synthesized materials have been chemically characterized through the FTIR spectroscopy and their bioactivity evaluated looking by SEM at their ability to produce a hydroxyapatite layer on their surface upon incubation with simulated body fluid (SBF). Finally, their effects on cell proliferation were studied in cell lines by direct cell number counting, MTT, flow cytometry-based cell-cycle and cell death assays, and immunoblotting experiments. Notably, we found that SiO₂/PEG/CGA hybrids exhibit clear antiproliferative effects in different tumor, including breast cancer and osteosarcoma, cell lines in a CGA dependent manner, but not in normal cells. Overall, our results increase the evidence of CGA as a possible anticancer agent and illustrate the potential for clinical applications of sol-gel synthesized SiO₂/PEG/CGA materials.
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Affiliation(s)
- Michelina Catauro
- Department of Engineering, University of Campania "Luigi Vanvitelli", Via Roma 29, I-81031 Aversa, Italy.
| | - Elisabetta Tranquillo
- Department of Engineering, University of Campania "Luigi Vanvitelli", Via Roma 29, I-81031 Aversa, Italy.
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli" Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Alessia Salzillo
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli" Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Lucia Capasso
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli" Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Michela Illiano
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli" Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Luigi Sapio
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli" Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Silvio Naviglio
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli" Via L. De Crecchio 7, 80138 Naples, Italy.
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15
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Zheng Y, Dai Y, Liu W, Wang N, Cai Y, Wang S, Zhang F, Liu P, Chen Q, Wang Z. Astragaloside IV enhances taxol chemosensitivity of breast cancer via caveolin-1-targeting oxidant damage. J Cell Physiol 2018; 234:4277-4290. [PMID: 30146689 DOI: 10.1002/jcp.27196] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 07/17/2018] [Indexed: 01/09/2023]
Abstract
Accumulating evidence suggests that caveolin-1 (CAV-1) is a stress-related oncotarget and closely correlated to chemoresistance. Targeting CAV-1 might be a promising strategy to improve chemosensitivity for breast cancer treatment. Astragaloside IV (AS-IV), a bioactive compound purified from Astragalus membranaceus, has been shown to exhibit multiple bioactivities, including anticancer. However, the involved molecular targets are still ambiguous. In this study, we investigated the critical role of CAV-1 in mediating the chemosensitizing effects of AS-IV to Taxol on breast cancer. We found that AS-IV could enhance the chemosensitivity of Taxol with minimal direct cytotoxicity on breast cancer cell lines MCF-7 and MDA-MB-231, as well as the nontumor mammary epithelial cell line MCF-10A. AS-IV was further demonstrated to aggravate Taxol-induced apoptosis and G2/M checkpoint arrest. The phosphorylation of mitogen-activated protein kinase (MAPK) signaling extracellular signal-regulated kinase (ERK) and c-Jun N-terminal Kinase (JNK), except p38, was also abrogated by a synergistic interaction between AS-IV and Taxol. Moreover, AS-IV inhibited CAV-1 expression in a dose-dependent manner and reversed CAV-1 upregulation induced by Taxol administration. Mechanism study further demonstrated that AS-IV treatment triggered the eNOS/NO/ONOO- pathway via inhibiting CAV-1, which led to intense oxidant damage. CAV-1 overexpression abolished the chemosensitizing effects of AS-IV to Taxol by inhibiting oxidative stress. In vivo experiments further validated that AS-IV increased Taxol chemosensitivity on breast cancer via inhibiting CAV-1 expression, followed by activation of the eNOS/NO/ONOO- pathway. Taken together, our findings not only suggested the potential of AS-IV as a promising candidate to enhance chemosensitivity, but also highlighted the significance of CAV-1 as the target to reverse cancer drug resistance.
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Affiliation(s)
- Yifeng Zheng
- Guangzhou University of Chinese Medicine, Integrative Research Laboratory of Breast Cancer, The Research Centre of Integrative Medicine, Discipline of Integrated Chinese and Western Medicine & The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.,Translational Research Laboratory of Chinese Medicine & Cancer Stress Signaling, College of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yan Dai
- Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Weiping Liu
- Guangzhou University of Chinese Medicine, Integrative Research Laboratory of Breast Cancer, The Research Centre of Integrative Medicine, Discipline of Integrated Chinese and Western Medicine & The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Neng Wang
- Guangzhou University of Chinese Medicine, Integrative Research Laboratory of Breast Cancer, The Research Centre of Integrative Medicine, Discipline of Integrated Chinese and Western Medicine & The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Translational Research Laboratory of Chinese Medicine & Cancer Stress Signaling, College of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.,Discipline of Integrated Chinese and Western Medicine, Post-Doctoral Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Youli Cai
- Guangzhou University of Chinese Medicine, Integrative Research Laboratory of Breast Cancer, The Research Centre of Integrative Medicine, Discipline of Integrated Chinese and Western Medicine & The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Discipline of Integrated Chinese and Western Medicine, Post-Doctoral Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shengqi Wang
- Guangzhou University of Chinese Medicine, Integrative Research Laboratory of Breast Cancer, The Research Centre of Integrative Medicine, Discipline of Integrated Chinese and Western Medicine & The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.,Translational Research Laboratory of Chinese Medicine & Cancer Stress Signaling, College of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Fengxue Zhang
- Guangzhou University of Chinese Medicine, Integrative Research Laboratory of Breast Cancer, The Research Centre of Integrative Medicine, Discipline of Integrated Chinese and Western Medicine & The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Translational Research Laboratory of Chinese Medicine & Cancer Stress Signaling, College of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.,Discipline of Integrated Chinese and Western Medicine, Post-Doctoral Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Pengxi Liu
- Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.,Translational Research Laboratory of Chinese Medicine & Cancer Stress Signaling, College of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qianjun Chen
- Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Zhiyu Wang
- Guangzhou University of Chinese Medicine, Integrative Research Laboratory of Breast Cancer, The Research Centre of Integrative Medicine, Discipline of Integrated Chinese and Western Medicine & The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.,Translational Research Laboratory of Chinese Medicine & Cancer Stress Signaling, College of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.,Discipline of Integrated Chinese and Western Medicine, Post-Doctoral Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
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16
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Amin N, Afkhami A, Hosseinzadeh L, Madrakian T. Green and cost-effective synthesis of carbon dots from date kernel and their application as a novel switchable fluorescence probe for sensitive assay of Zoledronic acid drug in human serum and cellular imaging. Anal Chim Acta 2018; 1030:183-193. [PMID: 30032768 DOI: 10.1016/j.aca.2018.05.014] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 04/28/2018] [Accepted: 05/03/2018] [Indexed: 10/17/2022]
Abstract
A new label-free, sensitive and selective off and on signaling fluorescence platform for assay of trace levels of Zoledronic acid (ZA) drug in human biological samples based on nitrogen doped carbon dots (N-CDs) - ferric ions (Fe3+) was designed. The fluorescence probe, N-CDs, was synthesized for the first time through a facile, eco-friendly and one-step hydrothermal treatment using date kernel as the precursor without any need to use chemical reagents. These CDs exhibited excellent water solubility, ionic and photo stability in various circumstances and a highly relative quantum yield of 12.5%. In the presence of Fe3+, the fluorescence intensity (FL) for N-CDs was strongly quenched due to the interaction between ferric ions and the functional groups at the N-CDs (switch off). Afterwards, by the addition of ZA, the fluorescence sensor status turned to "ON" (switch on) due to the dominance of ZA in the competition between functional groups on the surface of N-CDs and phosphate groups in ZA in the interaction with Fe3+ results in removing Fe3+ from the surface of N-CDs. Under the optimized conditions, the proposed fluorescence probe (N-CDs-Fe3+) exhibited good sensing performance for ZA assay with a linearity from 0.1 μM to 10.0 μM, a detection limit of 0.04 μM and the precision of 2.70%. The developed N-CDs-Fe3+ sensor was successfully used for the assay of ZA contents with good recoveries and selectivity in human serum samples. Meanwhile, the in vitro cytotoxic activity and cellular uptake of N-CDs were investigated on human osteosarcoma (MG-63) cell line.
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Affiliation(s)
- Niloufar Amin
- Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
| | - Abbas Afkhami
- Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran.
| | - Leila Hosseinzadeh
- Pharmaceutical Sciences Research Center, School of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran
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17
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Wang X, Zhang C, Ma Q, Xiao W, Guo L, Wu Y. An effective method for bisphosphonate moiety inserting into O–H bond of carboxylic acids by Cu (II) catalyst. Tetrahedron Lett 2018. [DOI: 10.1016/j.tetlet.2017.12.038] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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18
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Fakhry M, Skafi N, Fayyad-Kazan M, Kobeissy F, Hamade E, Mebarek S, Habib A, Borghol N, Zeidan A, Magne D, Fayyad-Kazan H, Badran B. Characterization and assessment of potential microRNAs involved in phosphate-induced aortic calcification. J Cell Physiol 2017; 233:4056-4067. [PMID: 28776684 DOI: 10.1002/jcp.26121] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Accepted: 08/01/2017] [Indexed: 02/01/2023]
Abstract
Medial artery calcification, a hallmark of type 2 diabetes mellitus and chronic kidney disease (CKD), is known as an independent risk factor for cardiovascular mortality and morbidity. Hyperphosphatemia associated with CKD is a strong stimulator of vascular calcification but the molecular mechanisms regulating this process remain not fully understood. We showed that calcification was induced after exposing Sprague-Dawley rat aortic explants to high inorganic phosphate level (Pi , 6 mM) as examined by Alizarin red and Von Kossa staining. This calcification was associated with high Tissue-Nonspecific Alkaline Phosphatase (TNAP) activity, vascular smooth muscle cells de-differentiation, manifested by downregulation of smooth muscle 22 alpha (SM22α) protein expression which was assessed by immunoblot analysis, immunofluorescence, and trans-differentiation into osteo-chondrocyte-like cells revealed by upregulation of Runt related transcription factor 2 (Runx2), TNAP, osteocalcin, and osteopontin mRNA levels which were determined by quantitative real-time PCR. To unravel the possible mechanism(s) involved in this process, microRNA (miR) expression profile, which was assessed using TLDA technique and thereafter confirmed by individual qRT-PCR, revealed differential expression 10 miRs, five at day 3 and 5 at day 6 post Pi treatment versus control untreated aortas. At day 3, miR-200c, -155, 322 were upregulated and miR-708 and 331 were downregulated. After 6 days of treatment, miR-328, -546, -301a were upregulated while miR-409 and miR-542 were downregulated. Our results indicate that high Pi levels trigger aortic calcification and modulation of certain miRs. These observations suggest that mechanisms regulating aortic calcification might involve miRs, which warrant further investigations in future studies.
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Affiliation(s)
- Maya Fakhry
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath, Beirut, Lebanon.,Institute of Molecular and Supramolecular Chemistry and Biochemistry (ICBMS), UMR CNRS 5246, University of Lyon 1, Bâtiment Raulin, Villeurbanne Cedex, France
| | - Najwa Skafi
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath, Beirut, Lebanon.,Institute of Molecular and Supramolecular Chemistry and Biochemistry (ICBMS), UMR CNRS 5246, University of Lyon 1, Bâtiment Raulin, Villeurbanne Cedex, France
| | - Mohammad Fayyad-Kazan
- Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, Gosselies, Belgium
| | - Firas Kobeissy
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Eva Hamade
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath, Beirut, Lebanon
| | - Saida Mebarek
- Institute of Molecular and Supramolecular Chemistry and Biochemistry (ICBMS), UMR CNRS 5246, University of Lyon 1, Bâtiment Raulin, Villeurbanne Cedex, France
| | - Aida Habib
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.,INSERM-U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation, and the Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Université Paris Diderot, Paris, France
| | - Nada Borghol
- Institute of Molecular and Supramolecular Chemistry and Biochemistry (ICBMS), UMR CNRS 5246, University of Lyon 1, Bâtiment Raulin, Villeurbanne Cedex, France
| | - Asad Zeidan
- Cardiovascular Physiology Lab, Department of Anatomy, Cell Biology and Physiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.,College of Medicine, Qatar University, Doha, Qatar
| | - David Magne
- Institute of Molecular and Supramolecular Chemistry and Biochemistry (ICBMS), UMR CNRS 5246, University of Lyon 1, Bâtiment Raulin, Villeurbanne Cedex, France
| | - Hussein Fayyad-Kazan
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath, Beirut, Lebanon
| | - Bassam Badran
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath, Beirut, Lebanon
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19
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Cappetta D, De Angelis A, Sapio L, Prezioso L, Illiano M, Quaini F, Rossi F, Berrino L, Naviglio S, Urbanek K. Oxidative Stress and Cellular Response to Doxorubicin: A Common Factor in the Complex Milieu of Anthracycline Cardiotoxicity. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:1521020. [PMID: 29181122 PMCID: PMC5664340 DOI: 10.1155/2017/1521020] [Citation(s) in RCA: 252] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 09/18/2017] [Indexed: 12/11/2022]
Abstract
The production of reactive species is a core of the redox cycling profile of anthracyclines. However, these molecular characteristics can be viewed as a double-edged sword acting not only on neoplastic cells but also on multiple cellular targets throughout the body. This phenomenon translates into anthracycline cardiotoxicity that is a serious problem in the growing population of paediatric and adult cancer survivors. Therefore, better understanding of cellular processes that operate within but also go beyond cardiomyocytes is a necessary step to develop more effective tools for the prevention and treatment of progressive and often severe cardiomyopathy experienced by otherwise successfully treated oncologic patients. In this review, we focus on oxidative stress-triggered cellular events such as DNA damage, senescence, and cell death implicated in anthracycline cardiovascular toxicity. The involvement of progenitor cells of cardiac and extracardiac origin as well as different cardiac cell types is discussed, pointing to molecular signals that impact on cell longevity and functional competence.
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Affiliation(s)
- Donato Cappetta
- Department of Experimental Medicine, Section of Pharmacology, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Antonella De Angelis
- Department of Experimental Medicine, Section of Pharmacology, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Luigi Sapio
- Department of Biochemistry, Biophysics and General Pathology, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Lucia Prezioso
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Michela Illiano
- Department of Biochemistry, Biophysics and General Pathology, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Federico Quaini
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Francesco Rossi
- Department of Experimental Medicine, Section of Pharmacology, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Liberato Berrino
- Department of Experimental Medicine, Section of Pharmacology, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Silvio Naviglio
- Department of Biochemistry, Biophysics and General Pathology, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Konrad Urbanek
- Department of Experimental Medicine, Section of Pharmacology, University of Campania Luigi Vanvitelli, Naples, Italy
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20
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Catauro M, Tranquillo E, Illiano M, Sapio L, Spina A, Naviglio S. The Influence of the Polymer Amount on the Biological Properties of PCL/ZrO₂ Hybrid Materials Synthesized via Sol-Gel Technique. MATERIALS (BASEL, SWITZERLAND) 2017; 10:1186. [PMID: 29039803 PMCID: PMC5666992 DOI: 10.3390/ma10101186] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 10/10/2017] [Accepted: 10/13/2017] [Indexed: 12/11/2022]
Abstract
Organic/inorganic hybrid materials are attracting considerable attention in the biomedical area. The sol-gel process provides a convenient way to produce many bioactive organic-inorganic hybrids. Among those, poly(e-caprolactone)/zirconia (PCL/ZrO₂) hybrids have proved to be bioactive with no toxic materials. The aim of this study was to investigate the effects of these materials on the cellular response as a function of the PCL content, in order to evaluate their potential use in the biomedical field. For this purpose, PCL/ZrO₂ hybrids containing 6, 12, 24, and 50 wt % of PCL were synthesized by the sol-gel method. The effects of their presence on the NIH-3T3 fibroblast cell line carrying out direct cell number counting, MTT, cell damage assays, flow cytometry-based analysis of cell-cycle progression, and immunoblotting experiments. The results confirm and extend the findings that PCL/ZrO₂ hybrids are free from toxicity. The hybrids containing 12 and 24 wt % PCL, (more than 6 and 50 wt % ones) enhance cell proliferation when compared to pure ZrO₂ by affecting cell cycle progression. The finding that the content of PCL in PCL/ZrO₂ hybrids differently supports cell proliferation suggests that PCL/ZrO₂ hybrids could be useful tools with different potential clinical applications.
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Affiliation(s)
- Michelina Catauro
- Department of Industrial and Information Engineering, University of Campania "Luigi Vanvitelli", Via Roma 29, 81031 Aversa, Italy.
| | - Elisabetta Tranquillo
- Department of Industrial and Information Engineering, University of Campania "Luigi Vanvitelli", Via Roma 29, 81031 Aversa, Italy.
- Department of Biochemistry, Biophysics and General Pathology, Medical School, University of Campania "Luigi Vanvitelli", Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Michela Illiano
- Department of Biochemistry, Biophysics and General Pathology, Medical School, University of Campania "Luigi Vanvitelli", Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Luigi Sapio
- Department of Biochemistry, Biophysics and General Pathology, Medical School, University of Campania "Luigi Vanvitelli", Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Annamaria Spina
- Department of Biochemistry, Biophysics and General Pathology, Medical School, University of Campania "Luigi Vanvitelli", Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Silvio Naviglio
- Department of Biochemistry, Biophysics and General Pathology, Medical School, University of Campania "Luigi Vanvitelli", Via L. De Crecchio 7, 80138 Naples, Italy.
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21
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Clauzure M, Valdivieso ÁG, Massip-Copiz MM, Mori C, Dugour AV, Figueroa JM, Santa-Coloma TA. Intracellular Chloride Concentration Changes Modulate IL-1β Expression and Secretion in Human Bronchial Epithelial Cultured Cells. J Cell Biochem 2017; 118:2131-2140. [DOI: 10.1002/jcb.25850] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 12/19/2016] [Indexed: 11/10/2022]
Affiliation(s)
- Mariángeles Clauzure
- Laboratory of Cellular and Molecular Biology, National Scientific and Technical Research Council (CONICET) and School of Medical Sciences, Institute for Biomedical Research (BIOMED); Pontifical Catholic University of Argentina (UCA); Buenos Aires Argentina
| | - Ángel G. Valdivieso
- Laboratory of Cellular and Molecular Biology, National Scientific and Technical Research Council (CONICET) and School of Medical Sciences, Institute for Biomedical Research (BIOMED); Pontifical Catholic University of Argentina (UCA); Buenos Aires Argentina
| | - María M. Massip-Copiz
- Laboratory of Cellular and Molecular Biology, National Scientific and Technical Research Council (CONICET) and School of Medical Sciences, Institute for Biomedical Research (BIOMED); Pontifical Catholic University of Argentina (UCA); Buenos Aires Argentina
| | - Consuelo Mori
- Laboratory of Cellular and Molecular Biology, National Scientific and Technical Research Council (CONICET) and School of Medical Sciences, Institute for Biomedical Research (BIOMED); Pontifical Catholic University of Argentina (UCA); Buenos Aires Argentina
| | | | | | - Tomás A. Santa-Coloma
- Laboratory of Cellular and Molecular Biology, National Scientific and Technical Research Council (CONICET) and School of Medical Sciences, Institute for Biomedical Research (BIOMED); Pontifical Catholic University of Argentina (UCA); Buenos Aires Argentina
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22
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Rudnick-Glick S, Corem-Salkmon E, Grinberg I, Margel S. Targeted drug delivery of near IR fluorescent doxorubicin-conjugated poly(ethylene glycol) bisphosphonate nanoparticles for diagnosis and therapy of primary and metastatic bone cancer in a mouse model. J Nanobiotechnology 2016; 14:80. [PMID: 27919267 PMCID: PMC5139040 DOI: 10.1186/s12951-016-0233-6] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 11/26/2016] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Most primary and metastatic bone tumors demonstrate increased osteoclast activity and bone resorption. Current treatment is based on a combination of surgery, radiotherapy and chemotherapy. Severe side effects are associated with chemotherapy due to use of high dosage and nonspecific uptake. Bisphosphonates have a strong affinity to Ca2+ ions and are widely used in the treatment of bone disorders. RESULTS We have engineered a unique biodegradable bisphosphonate nanoparticle (NPs) bearing two functional surface groups: (1) primary amine groups for covalent attachment of a dye/drug (e.g. NIR dye Cy 7 or doxorubicin); (2) bisphosphonate groups for targeting and chelation to bone hydroxyapatite. In addition, these engineered NPs contain high polyethyleneglycol (PEG) concentration in order to increase their blood half life time. In vitro experiments on Saos-2 human osteosarcoma cell line, demonstrated that at a tenth of the concentration, doxorubicin-conjugated bisphosphonate NPs achieved a similar uptake to free doxorubicin. In vivo targeting experiments using the NIR fluorescence bisphosphonate NPs on both Soas-2 human osteosarcoma xenograft mouse model and orthotopic bone metastases mCherry-labeled 4T1 breast cancer mouse model confirmed specific targeting. In addition, therapeutic in vivo experiments using doxorubicin-conjugated bisphosphonate NPs demonstrated a 40% greater inhibition of tumor growth in Saos-2 human osteosarcoma xenograft mouse model when compared to free doxorubicin. CONCLUSIONS In this research we have shown the potential use of doxorubicin-conjugated BP NPs for the targeting and treatment of primary and metastatic bone tumors. The targeted delivery of doxorubicin to the tumor significantly increased the efficacy of the anti-cancer drug, thus enabling the effective use of a lower concentration of doxorubicin. Furthermore, the targeting ability of the BP NPs in an orthotopic xenograft mouse model reinforced our findings that these BP NPs have the potential to be used for the treatment of primary and metastatic bone cancer.
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Affiliation(s)
- S. Rudnick-Glick
- Department of Chemistry, The Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, 52900 Ramat Gan, Israel
| | - E. Corem-Salkmon
- Department of Chemistry, The Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, 52900 Ramat Gan, Israel
| | - I. Grinberg
- Department of Chemistry, The Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, 52900 Ramat Gan, Israel
| | - S. Margel
- Department of Chemistry, The Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, 52900 Ramat Gan, Israel
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Yang K, Gao K, Hu G, Wen Y, Lin C, Li X. CTGF enhances resistance to 5-FU-mediating cell apoptosis through FAK/MEK/ERK signal pathway in colorectal cancer. Onco Targets Ther 2016; 9:7285-7295. [PMID: 27942222 PMCID: PMC5138041 DOI: 10.2147/ott.s108929] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers among both males and females; the chemotherapy drug 5-fluorouracil (5-FU) is one of a doctors’ first lines of defense against CRC. However, therapeutic failures are common because of the emergence of drug resistance. Connective tissue growth factor (CTGF) is a secreted protein that binds to integrins, and regulates the invasiveness and metastasis of certain carcinoma cells. Here, we found that CTGF was upregulated in drug-resistant phenotype of human CRC cells. Overexpression of CTGF enhanced the resistance to 5-FU-induced cell apoptosis. Moreover, downregulating the expression of CTGF promoted the curative effect of chemotherapy and blocked the cell cycle in the G1 phase. We also found that CTGF facilitated resistance to 5-FU-induced apoptosis by increasing the expression of B-cell lymphoma-extra large (Bcl-xL) and survivin. Then we pharmacologically blocked MEK/ERK signal pathway and assessed 5-FU response by MTT assays. Our current results indicate that the expression of phosphorylated forms of MEK/ERK increased in high CTGF expression cells and MEK inhibited increases in 5-FU-mediated apoptosis of resistant CRC cells. Therefore, our data suggest that MEK/ERK signaling contributes to 5-FU resistance through upstream of CTGF, and supports CRC cell growth. Comprehending the molecular mechanism underlying 5-FU resistance may ultimately aid the fight against CRC.
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Affiliation(s)
- Kai Yang
- Department of General Surgery, The Third Affiliated Hospital of Central South University, Central South University, Changsha, Hunan, People's Republic of China
| | - Kai Gao
- Department of General Surgery, The Third Affiliated Hospital of Central South University, Central South University, Changsha, Hunan, People's Republic of China
| | - Gui Hu
- Department of General Surgery, The Third Affiliated Hospital of Central South University, Central South University, Changsha, Hunan, People's Republic of China
| | - Yanguang Wen
- Department of General Surgery, The Third Affiliated Hospital of Central South University, Central South University, Changsha, Hunan, People's Republic of China
| | - Changwei Lin
- Department of General Surgery, The Third Affiliated Hospital of Central South University, Central South University, Changsha, Hunan, People's Republic of China
| | - Xiaorong Li
- Department of General Surgery, The Third Affiliated Hospital of Central South University, Central South University, Changsha, Hunan, People's Republic of China
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24
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Catauro M, Papale F, Sapio L, Naviglio S. Biological influence of Ca/P ratio on calcium phosphate coatings by sol-gel processing. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2016; 65:188-193. [PMID: 27157742 DOI: 10.1016/j.msec.2016.03.110] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 03/11/2016] [Accepted: 03/23/2016] [Indexed: 12/13/2022]
Abstract
The objective of this work has been to develop low temperature sol-gel glass coatings to modify the substrate surface and to evaluate their bioactivity and biocompatibility. Glasses, based on SiO2·CaO·P2O5, were synthesized by the sol-gel technique using tetraethyl orthosilicate, calcium nitrate tetrahydrate and triethyl phosphate as precursors of SiO2, CaO and P2O5, respectively. Those materials, still in the sol phase, have been used to coat substrates by means of the dip-coating technique. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) has been used for characterize coatings and a microstructural analysis has been obtained using scanning electron microscopy (SEM). The potential applications of the coatings in the biomedical field were evaluated by bioactivity and biocompatibility tests. The coated substrate was immersed in simulated body fluid (SBF) for 21days and the hydroxyapatite deposition on its surface was subsequently evaluated via SEM-EDXS analysis, as an index of bone-bonding capability. In order to study the cell behavior and response to our silica based materials, prepared via the sol-gel method, with various Ca/P ratio and coating substrate, we have used the human osteoblast-like U2OS cell line.
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Affiliation(s)
- M Catauro
- Department of Industrial and Information Engineering, Second University of Naples, Via Roma 29, Italy.
| | - F Papale
- Department of Industrial and Information Engineering, Second University of Naples, Via Roma 29, Italy
| | - L Sapio
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Via L. De Crecchio 7, 80138 Naples, Italy
| | - S Naviglio
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Via L. De Crecchio 7, 80138 Naples, Italy
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25
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Ilisso CP, Sapio L, Delle Cave D, Illiano M, Spina A, Cacciapuoti G, Naviglio S, Porcelli M. S-Adenosylmethionine Affects ERK1/2 and Stat3 Pathways and Induces Apotosis in Osteosarcoma Cells. J Cell Physiol 2016; 231:428-435. [PMID: 26174106 DOI: 10.1002/jcp.25089] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Accepted: 07/07/2015] [Indexed: 01/06/2023]
Abstract
Osteosarcoma is a very aggressive bone tumor. Its clinical outcome remains discouraging despite intensive surgery, radiotherapy, and chemotherapy. Thus, novel therapeutic approaches are demanded. S-Adenosylmethionine (AdoMet) is a naturally occurring molecule that is synthesized in our body by methionine adenosyltransferase isoenzymes and is also available as a nutritional supplement. AdoMet is the principal methyl donor in numerous methylation reactions and is involved in many biological functions. Interestingly, AdoMet has been shown to exert antiproliferative action in various cancer cells. However, the underlying molecular mechanisms are just starting to be studied. Here, we investigated the effects of AdoMet on the proliferation of osteosarcoma U2OS cells and the underlying mechanisms. We carried out direct cell number counting, MTT and flow cytometry-based assays, and immunoblotting experiments in response to AdoMet treatment. We found that AdoMet strongly inhibits proliferation of U2OS cells by slowing-down cell cycle progression and by inducing apoptosis. We also report that AdoMet consistently causes an increase of p53 and p21 cell-cycle inhibitor, a decrease of cyclin A and cyclin E protein levels, and a marked increase of pro-apoptotic Bax/Bcl-2 ratio, with caspase-3 activation and PARP cleavage. Moreover, the AdoMet-induced antiproliferative effects were dynamically accompanied by profound changes in ERK1/2 and STAT3 protein and phosphorylation levels. Altogether, our data enforce the evidence of AdoMet acting as a biomolecule with antiproliferative action in osteosarcoma cells, capable of down-regulating ERK1/2 and STAT3 pathways leading to cell cycle inhibition and apoptosis, and provide a rationale for the possible use of AdoMet in osteosarcoma therapy.
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Affiliation(s)
- Concetta Paola Ilisso
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy
| | - Luigi Sapio
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy
| | - Donatella Delle Cave
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy
| | - Michela Illiano
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy
| | - Annamaria Spina
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy
| | - Giovanna Cacciapuoti
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy
| | - Silvio Naviglio
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy
| | - Marina Porcelli
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy
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26
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Sapio L, Naviglio S. Inorganic phosphate in the development and treatment of cancer: A Janus Bifrons? World J Clin Oncol 2015; 6:198-201. [PMID: 26677430 PMCID: PMC4675902 DOI: 10.5306/wjco.v6.i6.198] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 08/06/2015] [Accepted: 09/29/2015] [Indexed: 02/06/2023] Open
Abstract
Inorganic phosphate (Pi) is an essential nutrient to living organisms. It is required as a component of the energy metabolism, kinase/phosphatase signaling and in the formation and function of lipids, carbohydrates and nucleic acids and, at systemic level, it plays a key role for normal skeletal and dentin mineralization. Pi represents an abundant dietary element and its intestinal absorption is efficient, minimally regulated and typically extends to approximately 70%. Maintenance of proper Pi homeostasis is a critical event and serum Pi level is maintained within a narrow range through an elaborate network of humoral interactions and feedback loops involving intestine, kidney, parathyroid gland and bone, and depends on the activity of a number of hormones, including parathyroid hormone, 1,25-dihydroxy vitamin D, and fibroblast growth factor 23 as major regulators of Pi homeostasis. Notably, Pi intake seemingly continues to increase as a consequence of chronic high-phosphorus (P) diets deriving from the growing consumption of highly processed foods, especially restaurant meals, fast foods, and convenience foods. Several recent reports have generated significant associations between high-P intake or high-serum Pi concentration and morbidity and mortality. Many chronic diseases, including cardiovascular diseases, obesity and even cancer have been proposed to be associated with high-P intakes and high-serum Pi concentrations. On the other hand, there is also evidence that Pi can have antiproliferative effects on some cancer cell types, depending on cell status and genetic background and achieve additive cytotoxic effects when combined with doxorubicin, illustrating its potential for clinical applications and suggesting that up-regulating Pi levels at local sites for brief times, might contribute to the development of novel and cheap modalities for therapeutic intervention in some tumours. Overall, the influence of Pi on cell function and the possible relationship to cancer have to be fully understood and investigated further.
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27
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Chen H, Shen J, Choy E, Hornicek FJ, Duan Z. Targeting protein kinases to reverse multidrug resistance in sarcoma. Cancer Treat Rev 2015; 43:8-18. [PMID: 26827688 DOI: 10.1016/j.ctrv.2015.11.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Revised: 11/27/2015] [Accepted: 11/30/2015] [Indexed: 12/28/2022]
Abstract
Sarcomas are a group of cancers that arise from transformed cells of mesenchymal origin. They can be classified into over 50 subtypes, accounting for approximately 1% of adult and 15% of pediatric cancers. Wide surgical resection, radiotherapy, and chemotherapy are the most common treatments for the majority of sarcomas. Among these therapies, chemotherapy can palliate symptoms and prolong life for some sarcoma patients. However, sarcoma cells can have intrinsic or acquired resistance after treatment with chemotherapeutics drugs, leading to the development of multidrug resistance (MDR). MDR attenuates the efficacy of anticancer drugs and results in treatment failure for sarcomas. Therefore, overcoming MDR is an unmet need for sarcoma therapy. Certain protein kinases demonstrate aberrant expression and/or activity in sarcoma cells, which have been found to be involved in the regulation of sarcoma cell progression, such as cell cycle, apoptosis, and survival. Inhibiting these protein kinases may not only decrease the proliferation and growth of sarcoma cells, but also reverse their resistance to chemotherapeutic drugs to subsequently reduce the doses of anticancer drugs and decrease drug side-effects. The discovery of novel strategies targeting protein kinases opens a door to a new area of sarcoma research and provides insight into the mechanisms of MDR in chemotherapy. This review will focus on the recent studies in targeting protein kinase to reverse chemotherapeutic drug resistance in sarcoma.
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Affiliation(s)
- Hua Chen
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, MA 02114, United States; Department of Emergency Surgery, ShenZhen People's Hospital, 2nd Clinical Medical College of Jinan University, No. 1017 Dongmenbei Road, Shenzhen, Guangdong Province 518020, China
| | - Jacson Shen
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, MA 02114, United States
| | - Edwin Choy
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, MA 02114, United States
| | - Francis J Hornicek
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, MA 02114, United States
| | - Zhenfeng Duan
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, MA 02114, United States.
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28
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Sapio L, Sorvillo L, Illiano M, Chiosi E, Spina A, Naviglio S. Inorganic Phosphate Prevents Erk1/2 and Stat3 Activation and Improves Sensitivity to Doxorubicin of MDA-MB-231 Breast Cancer Cells. Molecules 2015; 20:15910-15928. [PMID: 26340617 PMCID: PMC6332303 DOI: 10.3390/molecules200915910] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Revised: 08/19/2015] [Accepted: 08/26/2015] [Indexed: 02/06/2023] Open
Abstract
Due to its expression profile, triple-negative breast cancer (TNBC) is refractory to the most effective targeted therapies available for breast cancer treatment. Thus, cytotoxic chemotherapy represents the mainstay of treatment for early and metastatic TNBC. Therefore, it would be greatly beneficial to develop therapeutic approaches that cause TNBC cells to increase their sensitivity to cytotoxic drugs. Inorganic phosphate (Pi) is emerging as an important signaling molecule in many cell types. Interestingly, it has been shown that Pi greatly enhances the sensitivity of human osteosarcoma cell line (U2OS) to doxorubicin. We investigated the effects of Pi on the sensitivity of TNBC cells to doxorubicin and the underlying molecular mechanisms, carrying out flow cytometry-based assays of cell-cycle progression and cell death, MTT assays, direct cell number counting and immunoblotting experiments. We report that Pi inhibits the proliferation of triple-negative MDA-MB-231 breast cancer cells mainly by slowing down cell cycle progression. Interestingly, we found that Pi strongly increases doxorubicin-induced cytotoxicity in MDA-MB-231 cells by apoptosis induction, as revealed by a marked increase of sub-G1 population, Bcl-2 downregulation, caspase-3 activation and PARP cleavage. Remarkably, Pi/doxorubicin combination-induced cytotoxicity was dynamically accompanied by profound changes in Erk1/2 and Stat3 protein and phosphorylation levels. Altogether, our data enforce the evidence of Pi acting as a signaling molecule in MDA-MB-231 cells, capable of inhibiting Erk and Stat3 pathways and inducing sensitization to doxorubicin of TNBC cells, and suggest that targeting Pi levels at local sites might represent the rationale for developing effective and inexpensive strategies for improving triple-negative breast cancer therapy.
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Affiliation(s)
- Luigi Sapio
- Department of Biochemistry, Biophysics and General Pathology, Medical School, Second University of Naples, via L. De Crecchio 7, 80138 Naples, Italy.
| | - Luca Sorvillo
- Department of Biochemistry, Biophysics and General Pathology, Medical School, Second University of Naples, via L. De Crecchio 7, 80138 Naples, Italy.
| | - Michela Illiano
- Department of Biochemistry, Biophysics and General Pathology, Medical School, Second University of Naples, via L. De Crecchio 7, 80138 Naples, Italy.
| | - Emilio Chiosi
- Department of Biochemistry, Biophysics and General Pathology, Medical School, Second University of Naples, via L. De Crecchio 7, 80138 Naples, Italy.
| | - Annamaria Spina
- Department of Biochemistry, Biophysics and General Pathology, Medical School, Second University of Naples, via L. De Crecchio 7, 80138 Naples, Italy.
| | - Silvio Naviglio
- Department of Biochemistry, Biophysics and General Pathology, Medical School, Second University of Naples, via L. De Crecchio 7, 80138 Naples, Italy.
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29
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Jing Z, Heng W, Xia L, Ning W, Yafei Q, Yao Z, Shulan Z. Downregulation of phosphoglycerate dehydrogenase inhibits proliferation and enhances cisplatin sensitivity in cervical adenocarcinoma cells by regulating Bcl-2 and caspase-3. Cancer Biol Ther 2015; 16:541-8. [PMID: 25719555 DOI: 10.1080/15384047.2015.1017690] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
Phosphoglycerate dehydrogenase (PHGDH) is the key enzyme of de novo serine biosynthesis. Previous reports have demonstrated that PHGDH plays an important role in some malignancies. However, the biological role of PHGDH in human cervical adenocarcinoma has not been explored. We examined the expression of PHGDH in 54 cervical adenocarcinoma samples by immunohistochemistry and evaluated the association with clinicopathological parameters and prognosis. We performed shRNA transfection to knock down PHGDH gene expression in HeLa cells. A cell proliferation test, cisplatin cytotoxicity test and apoptosis test examined the HeLa cell line after PHGDH knockdown in vitro. In vivo tumorigenesis was assessed using a mouse xenograft model. Moreover, we examined the effects on Bcl-2 and cleaved caspase-3 expression after knockdown of PHGDH and treatment of cisplatin for 48h by Western blot. In this study, we demonstrated that elevated PHGDH expression was found in cervical adenocarcinoma and was associated with tumor size and prognosis. Knocking down PHGDH in HeLa cells significantly inhibited cell proliferation and increased cisplatin chemotherapy sensitivity. Silencing PHGDH resulted in inhibition of tumorigenesis in vivo. Furthermore, PHGDH knockdown reduced Bcl-2 and increased cleaved caspase-3 expression. Collectively, our study indicates the novel roles of PHGDH in cervical adenocarcinoma and identifies PHGDH as a new anticancer target.
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Key Words
- Bcl-2
- Bcl-2, B cell leukemia/lymphoma-2
- CCK-8, cell counting kit-8
- Caspase, Cysteinyl aspartate specific proteinase
- DMEM, Dulbecco's Modified Eagle Medium
- FBS, fetal calf serum
- G418, Geneticin
- GAPDH, Glyceraldehyde-3-phosphate dehydrogenase
- HPV, human papilloma virus
- ICC, immuocytochemistry
- IHC, immunohistochemistry
- PHGDH
- PHGDH, phosphoglycerate dehydrogenase
- caspase-3
- cervical adenocarcinoma
- chemotherapy sensitivity
- metabolism
- proliferation
- shRNA, short hairpin RNA
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Affiliation(s)
- Zhang Jing
- a Department of Obstetrics and Gynecology; Shengjing Hospital; China Medical University ; Shenyang , Liaoning , China
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Zhao D, Yuan H, Yi F, Meng C, Zhu Q. Autophagy prevents doxorubicin‑induced apoptosis in osteosarcoma. Mol Med Rep 2014; 9:1975-81. [PMID: 24639013 DOI: 10.3892/mmr.2014.2055] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2013] [Accepted: 02/10/2014] [Indexed: 11/05/2022] Open
Abstract
Autophagy is a process of selective degradation of cellular components. Autophagy is an adaptive process in the majority of tumor cells; it provides sufficient nutrients by degrading cellular components to enhance the survival of tumors. Osteosarcoma is the most common type of primary malignant bone tumor in children and adolescents. Identification of an improved therapeutic strategy for the treatment of osteosarcoma is urgently required. Osteosarcoma has been primarily treated by chemotherapy and the phenomena of resistance to the therapy has become increasingly common. Doxorubicin (Dox) is a classic chemotherapeutic drug for the treatment of osteosarcoma, and certain studies have suggested that Dox induces autophagy. On the basis of the protective effect of autophagy for tumors, the present study investigated whether U2OS and Saos-2 osteosarcoma cells activate autophagy to reduce Dox-induced apoptosis. Dox was observed to inhibit the growth of U2OS and Saos-2 osteosarcoma cells in a concentration-dependent manner. The results of the western blot analysis demonstrated that Dox induced increased expression levels of the apoptosis-related proteins cleaved caspase-3 and cytochrome c and loss of mitochondrial membrane potential (MMP) in the U2OS and Saos-2 osteosarcoma cells. Furthermore, the results of the western blot analysis also revealed that Dox increased the expression levels of the autophagy-related protein microtubule-associated protein 1 light chain 3 and reduced those of p62 in the U2OS and Saos-2 osteosarcoma cells. In order to determine the effect of autophagy on the apoptosis induced by Dox in the U2OS and Saos-2 osteosarcoma cells, autophagy-related protein (Atg)7 small interfering (si) RNA or the autophagy inhibitor 3-methyladenine (3-MA) alone or combined with Dox was used in U2OS and Saos-2 osteosarcoma cells. The results identified that Atg7 siRNA and the autophagy inhibitor 3-MA significantly elevated the levels of growth inhibition by Dox and markedly increased the expression levels of the apoptosis‑related proteins cleaved caspase-3 and cytochrome c, and reduced the levels of MMP in the U2OS and Saos-2 osteosarcoma cells, which were treated with Dox. These results indicated that autophagy was the protective mechanism used by U2OS and Saos-2 osteosarcoma against Dox-induced apoptosis. The inhibition of autophagy notably increases the levels of apoptosis induced by Dox. This suggested that Dox used in combination with autophagy inhibitors may effectively treat osteosarcoma.
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Affiliation(s)
- Dongxu Zhao
- Department of Spine Surgery, The First Bethune Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Hongping Yuan
- Department of Nephrology, The Fourth Bethune Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Fei Yi
- Department of Spine Surgery, The First Bethune Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Chunyang Meng
- Department of Spine Surgery, The First Bethune Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Qingsan Zhu
- Department of Spine Surgery, The First Bethune Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
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Tsai HC, Huang CY, Su HL, Tang CH. CCN2 enhances resistance to cisplatin-mediating cell apoptosis in human osteosarcoma. PLoS One 2014; 9:e90159. [PMID: 24637722 PMCID: PMC3956456 DOI: 10.1371/journal.pone.0090159] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2013] [Accepted: 01/26/2014] [Indexed: 01/16/2023] Open
Abstract
Osteosarcoma (OS) is the most common form of malignant bone tumor and is an aggressive malignant neoplasm exhibiting osteoblastic differentiation. Cisplatin is one of the most efficacious antitumor drugs for osteosarcoma patients. However, treatment failures are common due to the development of chemoresistance. CCN2 (also known as CTGF), is a secreted protein that binds to integrins, modulates the invasive behavior of certain human cancer cells. However, the effect of CCN2 in cisplatin-mediated chemotherapy is still unknown. Here, we found that CCN2 was upregulated in human osteosarcoma cells after treatment with cisplatin. Moreover, overexpression of CCN2 increased the resistance to cisplatin-mediated cell apoptosis. In contrast, reduction of CCN2 by CCN2 shRNA promoted the chemotherapeutic effect of cisplatin. We also found that CCN2 provided resistance to cisplatin-induced apoptosis through upregulation of Bcl-xL and survivin. Knockdown of Bcl-xL or survivin removed the CCN2-mediated resistance to apoptosis induced by cisplatin. On the other hand, CCN2 also promoted FAK, MEK, and ERK survival signaling pathways to enhance tumor survival during cisplatin treatment. In a mouse xenograft model, overexpression of CCN2 promoted resistance to cisplatin. However, knockdown of CCN2 increased the therapeutic effect of cisplatin. Therefore, our data suggest that CCN2 might be a critical oncogene of human osteosarcoma for cisplatin-resistance and supported osteosarcoma cell growth in vivo and in vitro.
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Affiliation(s)
- Hsiao-Chi Tsai
- Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Chun-Yin Huang
- Department of Orthopaedic Surgery, China Medical University Beigang Hospital, Yun-Lin County, Taiwan
- Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
| | - Hong-Lin Su
- Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
- * E-mail: (HLS); (CHT)
| | - Chih-Hsin Tang
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
- Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
- Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
- * E-mail: (HLS); (CHT)
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Park J, Lin YS, Tsantrizos YS, Berghuis AM. Structure of human farnesyl pyrophosphate synthase in complex with an aminopyridine bisphosphonate and two molecules of inorganic phosphate. Acta Crystallogr F Struct Biol Commun 2014; 70:299-304. [PMID: 24598914 PMCID: PMC3944689 DOI: 10.1107/s2053230x14002106] [Citation(s) in RCA: 9] [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: 12/18/2013] [Accepted: 01/29/2014] [Indexed: 12/12/2022] Open
Abstract
Human farnesyl pyrophosphate synthase (hFPPS) produces farnesyl pyrophosphate, an isoprenoid essential for a variety of cellular processes. The enzyme has been well established as the molecular target of the nitrogen-containing bisphosphonates (N-BPs), which are best known for their antiresorptive effects in bone but are also known for their anticancer properties. Crystal structures of hFPPS in ternary complexes with a novel bisphosphonate, YS0470, and the secondary ligands inorganic phosphate (Pi), inorganic pyrophosphate (PPi) and isopentenyl pyrophosphate (IPP) have recently been reported. Only the co-binding of the bisphosphonate with either PPi or IPP resulted in the full closure of the C-terminal tail of the enzyme, a conformational change that is required for catalysis and that is also responsible for the potent in vivo efficacy of N-BPs. In the present communication, a co-crystal structure of hFPPS in complex with YS0470 and two molecules of Pi is reported. The unusually close proximity between these ligands, which was confirmed by anomalous diffraction data, suggests that they interact with one another, with their anionic charges neutralized in their bound state. The structure also showed the tail of the enzyme to be fully disordered, indicating that simultaneous binding of two Pi molecules with a bisphosphonate cannot induce the tail-closing conformational change in hFPPS. Examination of homologous FPPSs suggested that this ligand-dependent tail closure is only conserved in the mammalian proteins. The prevalence of Pi-bound hFPPS structures in the PDB raises a question regarding the in vivo relevance of Pi binding to the function of the enzyme.
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Affiliation(s)
- Jaeok Park
- Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
| | - Yih-Shyan Lin
- Department of Chemistry, McGill University, 801 Rue Sherbrooke Ouest, Montreal, QC H3A 0B8, Canada
| | - Youla S. Tsantrizos
- Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
- Department of Chemistry, McGill University, 801 Rue Sherbrooke Ouest, Montreal, QC H3A 0B8, Canada
- Groupe de Recherche Axé sur la Structure des Protéines, McGill University, 3649 Promenade Sir William Osler, Montreal, QC H3G 0B1, Canada
| | - Albert M. Berghuis
- Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
- Groupe de Recherche Axé sur la Structure des Protéines, McGill University, 3649 Promenade Sir William Osler, Montreal, QC H3G 0B1, Canada
- Department of Microbiology and Immunology, McGill University, 3775 Rue University, Montreal, QC H3A 2B4, Canada
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Alexandrino EM, Ritz S, Marsico F, Baier G, Mailänder V, Landfester K, Wurm FR. Paclitaxel-loaded polyphosphate nanoparticles: a potential strategy for bone cancer treatment. J Mater Chem B 2014; 2:1298-1306. [DOI: 10.1039/c3tb21295e] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Kamba SA, Ismail M, Hussein-Al-Ali SH, Ibrahim TAT, Zakaria ZAB. In vitro delivery and controlled release of Doxorubicin for targeting osteosarcoma bone cancer. Molecules 2013; 18:10580-98. [PMID: 23999729 PMCID: PMC6270004 DOI: 10.3390/molecules180910580] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2013] [Revised: 07/30/2013] [Accepted: 08/01/2013] [Indexed: 12/14/2022] Open
Abstract
Drug delivery systems are designed to achieve drug therapeutic index and enhance the efficacy of controlled drug release targeting with specificity and selectivity by successful delivery of therapeutic agents at the desired sites without affecting the non-diseased neighbouring cells or tissues. In this research, we developed and demonstrated a bio-based calcium carbonate nanocrystals carrier that can be loaded with anticancer drug and selectively deliver it to cancer cells with high specificity by achieving the effective osteosarcoma cancer cell death without inducing specific toxicity. The results showed pH sensitivity of the controlled release characteristics of the drug at normal physiological pH 7.4 with approximately 80% released within 1,200 min but when exposed pH 4.8 the corresponding 80% was released in 50 min. This study showed that the DOX-loaded CaCO₃ nanocrystals have promising applications in delivery of anticancer drugs.
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Affiliation(s)
- Shafiu Abdullahi Kamba
- Laboratory of Molecular Biomedicine, Institute of Bioscience, University Putra Malaysia, UPM 43400, Serdang, Malaysia; E-Mails: (S.A.K.); (M.I.); (S.H.H.-A.-A.)
| | - Maznah Ismail
- Laboratory of Molecular Biomedicine, Institute of Bioscience, University Putra Malaysia, UPM 43400, Serdang, Malaysia; E-Mails: (S.A.K.); (M.I.); (S.H.H.-A.-A.)
| | - Samer Hasan Hussein-Al-Ali
- Laboratory of Molecular Biomedicine, Institute of Bioscience, University Putra Malaysia, UPM 43400, Serdang, Malaysia; E-Mails: (S.A.K.); (M.I.); (S.H.H.-A.-A.)
| | | | - Zuki Abu Bakar Zakaria
- Laboratory of Molecular Biomedicine, Institute of Bioscience, University Putra Malaysia, UPM 43400, Serdang, Malaysia; E-Mails: (S.A.K.); (M.I.); (S.H.H.-A.-A.)
- Faculty of Veterinary Medicine, University Putra Malaysia, UPM 43400, Serdang, Malaysia; E-Mail:
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Anderson JJB. Potential health concerns of dietary phosphorus: cancer, obesity, and hypertension. Ann N Y Acad Sci 2013; 1301:1-8. [PMID: 23848306 DOI: 10.1111/nyas.12208] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Adult Americans typically consume on average 1400 mg, or more, of phosphorus (P) daily in meals, which almost doubles the recommended dietary allowance. After a meal phosphorus is rapidly absorbed at a high efficiency and hormonal mechanisms act swiftly to maintain the serum inorganic phosphate (Pi) concentration within fairly narrow limits. Both parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23) reduce serum phosphate during postprandial periods through homeostatic actions on the kidney. However, it is speculated that exposure of cells to a brief high-serum Pi concentration may signal alterations in cell functions that lead to deleterious effects. Elevation of serum FGF-23 or PTH may also be harmful to specific cell types. Examples of possible adverse health effects include cancer, obesity, and hypertension. Here I review potential mechanisms through which high-P intake may contribute to cell metabolic abnormalities and the development of chronic disease; high-dietary phosphorus, especially from foods processed with phosphate salts, may be associated with these chronic diseases. Further investigation is needed to establish the significance of high-phosphate diets within a large segment of the U.S. population with normal renal function.
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Affiliation(s)
- John J B Anderson
- Department of Nutrition, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina
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36
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Ocotillol Enhanced the Antitumor Activity of Doxorubicin via p53-Dependent Apoptosis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:468537. [PMID: 23956772 PMCID: PMC3727205 DOI: 10.1155/2013/468537] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Revised: 05/23/2013] [Accepted: 05/28/2013] [Indexed: 11/21/2022]
Abstract
The use of doxorubicin (Dox) was severely constrained by dose-dependent side effects, which might be attenuated by combining a “sensitizer” to decrease its cumulative dosage. In this study, it was investigated whether ocotillol could enhance the antiproliferation activity of Dox. MTT assays and xenograft tumor model were firstly conducted to evaluate the effect of ocotillol on the antitumor activity of Dox. Flow cytometry and Hoechst staining assays were then performed to assess cell apoptosis. Western blot and real-time PCR were finally used to detect the expression of p53 and its target genes. Our results showed ocotillol to enhance Dox-induced cell death in p53 wild-type cancer cells. Compared with Dox alone, Dox with ocotillol (Dox-O) could induce much more cell apoptosis and activate p53 to a much greater degree, which in turn markedly increased expression of proapoptosis genes. The enhanced cytotoxic activity was partially blocked by pifithrin-α, which might be through attenuating the increased apoptosis. Furthermore, ocotillol significantly increased the antitumor activity of Dox in A549 xenograft tumor in nude mice. These findings indicated that ocotillol could potentiate the cytotoxic effect of Dox through p53-dependent apoptosis and suggested that coadministration of ocotillol with Dox might be a potential therapeutic strategy.
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Naviglio S. The possible use of inorganic phosphate in osteosarcoma therapy. Future Oncol 2013; 9:1249-51. [PMID: 23654203 DOI: 10.2217/fon.13.95] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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SPINA ANNAMARIA, SORVILLO LUCA, CHIOSI EMILIO, ESPOSITO ANTONIETTA, DI MAIOLO FRANCESCA, SAPIO LUIGI, CARAGLIA MICHELE, NAVIGLIO SILVIO. Synergistic cytotoxic effects of inorganic phosphate and chemotherapeutic drugs on human osteosarcoma cells. Oncol Rep 2013; 29:1689-1696. [PMID: 23446517 PMCID: PMC3658848 DOI: 10.3892/or.2013.2306] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2012] [Accepted: 12/11/2012] [Indexed: 02/07/2023] Open
Abstract
Novel therapeutic approaches are required for the treatment of osteosarcoma. Combination chemotherapy is receiving increased attention in order to identify compounds that may increase the therapeutic index of clinical anticancer drugs. In this regard, naturally occurring molecules with antitumor activity and with limited toxicity to normal tissues have been suggested as possible candidates for investigation of their synergistic efficacy in combination with antineoplastic drugs. Inorganic phosphate (Pi) is an essential nutrient for living organisms. Relevantly, Pi has emerged as an important signaling molecule capable of modulating multiple cellular functions by altering signal transduction pathways, gene expression and protein abundance in many cell types. Previously, we showed that Pi inhibits proliferation and aggressiveness of U2OS human osteosarcoma cells and that Pi is capable of inducing sensitization of osteosarcoma cells to doxorubicin in a p53-dependent manner. In this study, we extended the role of Pi in the chemosensitivity of osteosarcoma cells to other anticancer drugs. Specifically, we report and compare the antiproliferative effects of a combination between Pi and doxorubicin, Taxol and 5-fluorouracil (5-FU) treatments. We found that Pi increases the antiproliferative response to both Taxol and doxorubicin to a similar extent. On the other hand, Pi did not potentiate the anticancer effects induced by 5-FU. These effects were paralleled by apoptosis induction and were cell cycle-dependent. The clinical significance of our data and their potential therapeutic applications for improving osteosarcoma treatment are discussed.
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Affiliation(s)
- ANNAMARIA SPINA
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Medical School, I-80138 Naples, Italy
| | - LUCA SORVILLO
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Medical School, I-80138 Naples, Italy
| | - EMILIO CHIOSI
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Medical School, I-80138 Naples, Italy
| | - ANTONIETTA ESPOSITO
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Medical School, I-80138 Naples, Italy
| | - FRANCESCA DI MAIOLO
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Medical School, I-80138 Naples, Italy
| | - LUIGI SAPIO
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Medical School, I-80138 Naples, Italy
| | - MICHELE CARAGLIA
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Medical School, I-80138 Naples, Italy
| | - SILVIO NAVIGLIO
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Medical School, I-80138 Naples, Italy
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Spina A, Sapio L, Esposito A, Di Maiolo F, Sorvillo L, Naviglio S. Inorganic Phosphate as a Novel Signaling Molecule with Antiproliferative Action in MDA-MB-231 Breast Cancer Cells. Biores Open Access 2013; 2:47-54. [PMID: 23515235 PMCID: PMC3569927 DOI: 10.1089/biores.2012.0266] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Inorganic phosphate (Pi) is an essential nutrient for living organisms. It plays a key role in diverse physiological functions, including osteoblast differentiation and skeletal mineralization. Relevantly, Pi is emerging as an important signaling molecule capable of modulating multiple cellular functions by altering signal transduction pathways, gene expression, and protein abundance in many cell types. To our knowledge, the consequences of elevated Pi on behavior of breast cancer cells have been poorly addressed. In this study we investigate the effects of Pi on proliferation of MDA-MB-231 breast cancer cells. We report that Pi inhibits proliferation of MDA-MB-231 cells by slowing cell cycle progression, without apoptosis occurrence. We found that Pi causes cells to accumulate in G1 phase in a time-dependent manner. Accordingly, G1 accumulation was associated with a decrease of cyclin A and cyclin E and an increase of cell cycle inhibitors p21 and p27 protein levels, respectively. Moreover, the Pi-induced antiproliferative effect was dynamically accompanied by profound changes in ERK1/2 and STAT3 protein and phosphorylation levels in response to Pi. Altogether, our data represent the first evidence of Pi acting as a novel signaling molecule in MDA-MB-231 breast cancer cells, capable of eliciting a strong antiproliferative action and suggest that targeting Pi levels at local sites might represent the rationale for developing novel strategies for therapeutic intervention in triple-negative breast cancer.
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Affiliation(s)
- Annamaria Spina
- Department of Biochemistry and Biophysics, Medical School, Second University of Naples , Naples, Italy
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