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1
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Wang C, Lu M, Chen C, Chen J, Cai Y, Wang H, Tao L, Yin W, Chen J. Integrating scRNA-seq and Visium HD for the analysis of the tumor microenvironment in the progression of colorectal cancer. Int Immunopharmacol 2025; 145:113752. [PMID: 39642568 DOI: 10.1016/j.intimp.2024.113752] [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: 10/29/2024] [Revised: 11/26/2024] [Accepted: 11/27/2024] [Indexed: 12/09/2024]
Abstract
BACKGROUND Colorectal cancer (CRC) development is a complex, multi-stage process, transitioning from normal to adenomatous tissue, and then to invasive carcinoma. Despite research, there's a knowledge gap on using high-resolution spatial omics to understand CRC's tumor microenvironment dynamics. METHODS We used single-cell transcriptomics to study major biological changes and cell interactions in CRC progression. Additionally, high-resolution spatial transcriptomics helped us examine the spatial distribution of cells with significant pathway changes, offering insights into the tumor microenvironment's development throughout CRC stages. RESULTS In the progression of CRC, plasma cells, neutrophils, and fibroblasts exhibit the most significant changes in hallmark pathways, while epithelial cells show the most pronounced alterations in metabolic pathways. We also identified a population of NOTUM + epithelial cells and IGHG1/3 + plasma cells that are concentrated at the boundary between normal tissue and adenomas. Pathway analysis further suggests that these NOTUM + cells activate numerous cancer-related pathways, despite the absence of significant pathological morphological changes. Additionally, we conducted a targeted drug prediction analysis to identify potential therapeutic agents for NOTUM-expressing epithelial cells. CONCLUSIONS Analyzing scRNA-seq and Visium HD data, we found that IGHG1/3 + plasma cells and tumor-associated neutrophil (TANs) may significantly affect colorectal tissue transformation from normal to adenoma and carcinoma. These cells are concentrated at the transition between normal and adenomatous tissue. We also found NOTUM-expressing cells at the edge of normal and adenomatous areas, possibly indicating a morphological transition as normal cells evolve into adenoma cells.
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Affiliation(s)
- Chun Wang
- Department of Pathology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Mengying Lu
- Department of Pathology, Peking University Shenzhen Hospital, Shenzhen, China; School of Medicine,Southern University of Science and Technology, Shenzhen, China
| | - Cuimin Chen
- Department of Pathology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Jiajun Chen
- Department of Pathology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Yusi Cai
- Department of Pathology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Hao Wang
- Department of Pathology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Lili Tao
- Department of Pathology, Peking University Shenzhen Hospital, Shenzhen, China; School of Medicine,Southern University of Science and Technology, Shenzhen, China
| | - Weihua Yin
- Department of Pathology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Jiakang Chen
- Department of Pathology, Peking University Shenzhen Hospital, Shenzhen, China.
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Xu M, Liu J, Yu J, Wang J, Li H, Zhong T, Hao Y, Li Z, Wang J, Huang X, Wang H, Tian Y, Zhao H, Wei Q, Zhang X. Methyl-β-cyclodextrin Enhances Tumor Cellular Uptake and Accumulation of α-Linolenic Acid-Paclitaxel Conjugate Nanoparticles. Mol Pharm 2024. [PMID: 39495317 DOI: 10.1021/acs.molpharmaceut.4c00190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2024]
Abstract
Improving nanomedicine uptake by tumor cells is key to achieving intracellular drug delivery. In this study, we found that methyl-β-cyclodextrin (MβCD) can significantly promote the intracellular accumulation of nanoparticulated α-linolenic acid-paclitaxel conjugates (ALA-PTX NPs) via enhanced clathrin-mediated endocytosis and limited degradation in lysosomes. Our in vitro results indicated that MβCD not only reduced the plasma membrane cholesterol content and increased plasma membrane fluidity, leading to ALA-PTX NPs being more easily incorporated into the plasma membrane, further enhancing membrane fluidity and making the plasma membrane more susceptible to tensile deformation, forming intracellular vesicles to enhance ALA-PTX NP cellular uptake, but also destroyed lysosomes and then limited ALA-PTX NPs' degradation in lysosomes. In HepG2 tumor-bearing mice, MβCD was also able to enhance the antitumor activity of ALA-PTX NPs in vivo. Moreover, we found that MβCD specifically promoted PUFA-paclitaxel conjugate NP cellular uptake. The cellular uptake of PTX liposome which shares an endocytosis pathway with ALA-PTX NPs could be enhanced by MβCD combined with ALA or ALA-PTX NPs. Therefore, we suggested that MβCD combined with polyunsaturated fatty acid-conjugation would be an effective strategy for improving intracellular delivery of nanoparticulated chemotherapeutic drugs used for combination administration to enhance antitumor efficiency.
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Affiliation(s)
- Meiqi Xu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou 310015, China
| | - Junwei Liu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Jianming Yu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Jingwen Wang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Hui Li
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Ting Zhong
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Yanli Hao
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Zhuoyue Li
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Jingru Wang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Xu Huang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Hui Wang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Yubo Tian
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Heng Zhao
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Qingchao Wei
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Xuan Zhang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
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Liang X, Zhao Y, Yan J, Zhang Q, James TD, Lin W. Mechanosensitive fluorescence lifetime probes for investigating the dynamic mechanism of ferroptosis. Proc Natl Acad Sci U S A 2024; 121:e2316450121. [PMID: 39356672 PMCID: PMC11474025 DOI: 10.1073/pnas.2316450121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 08/27/2024] [Indexed: 10/04/2024] Open
Abstract
Deciphering the dynamic mechanism of ferroptosis can provide insights into pathogenesis, which is valuable for disease diagnosis and treatment. However, due to the lack of suitable time-resolved mechanosensitive tools, researchers have been unable to determine the membrane tension and morphology of the plasma membrane and the nuclear envelope during ferroptosis. With this research, we propose a rational strategy to develop robust mechanosensitive fluorescence lifetime probes which can facilitate simultaneous fluorescence lifetime imaging of the plasma membrane and nuclear envelope. Fluorescence lifetime imaging microscopy using the unique mechanosensitive probes reveal a dynamic mechanism for ferroptosis: The membrane tension of both the plasma membrane and the nuclear envelope decreases during ferroptosis, and the nuclear envelope exhibits budding during the advanced stage of ferroptosis. Significantly, the membrane tension of the plasma membrane is always larger than that of the nuclear envelope, and the membrane tension of the nuclear envelope is slightly larger than that of the nuclear membrane bubble. Meanwhile, the membrane lesions are repaired in the low-tension regions through exocytosis.
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Affiliation(s)
- Xing Liang
- School of Chemistry and Chemical Engineering, Institute of Optical Materials and Chemical Biology, Guangxi Key Laboratory of Electrochemical Energy Materials, School of Chemistry and Chemical Engineering, Guangxi University, Nanning, Guangxi530004, People’s Republic of China
| | - Yuping Zhao
- School of Chemistry and Chemical Engineering, Institute of Optical Materials and Chemical Biology, Guangxi Key Laboratory of Electrochemical Energy Materials, School of Chemistry and Chemical Engineering, Guangxi University, Nanning, Guangxi530004, People’s Republic of China
| | - Jun Yan
- School of Chemistry and Chemical Engineering, Institute of Optical Materials and Chemical Biology, Guangxi Key Laboratory of Electrochemical Energy Materials, School of Chemistry and Chemical Engineering, Guangxi University, Nanning, Guangxi530004, People’s Republic of China
| | - Qian Zhang
- School of Chemistry and Chemical Engineering, Institute of Optical Materials and Chemical Biology, Guangxi Key Laboratory of Electrochemical Energy Materials, School of Chemistry and Chemical Engineering, Guangxi University, Nanning, Guangxi530004, People’s Republic of China
| | - Tony D. James
- Department of Chemistry, University of Bath, BathBA2 7AY, United Kingdom
- School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang453007, People’s Republic of China
| | - Weiying Lin
- School of Chemistry and Chemical Engineering, Institute of Optical Materials and Chemical Biology, Guangxi Key Laboratory of Electrochemical Energy Materials, School of Chemistry and Chemical Engineering, Guangxi University, Nanning, Guangxi530004, People’s Republic of China
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Qin J, Ye L, Wen X, Zhang X, Di Y, Chen Z, Wang Z. Fatty acids in cancer chemoresistance. Cancer Lett 2023; 572:216352. [PMID: 37597652 DOI: 10.1016/j.canlet.2023.216352] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 08/14/2023] [Accepted: 08/16/2023] [Indexed: 08/21/2023]
Abstract
Despite the remarkable clinical success of immunotherapy and molecular targeted therapy in patients with advanced tumors, chemotherapy remains the most commonly used treatment for most tumor patients. Chemotherapy drugs effectively inhibit tumor cell proliferation and survival through their remarkable mechanisms. However, tumor cells often develop severe intrinsic and acquired chemoresistance under chemotherapy stress, limiting the effectiveness of chemotherapy and leading to treatment failure. Growing evidence suggests that alterations in lipid metabolism may be implicated in the development of chemoresistance in tumors. Therefore, in this review, we provide a comprehensive overview of fatty acid metabolism and its impact on chemoresistance mechanisms. Additionally, we discuss the potential of targeting fatty acid metabolism as a therapeutic strategy to overcome drug resistance.
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Affiliation(s)
- Jiale Qin
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China
| | - Lvlan Ye
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China
| | - Xiangqiong Wen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China
| | - Xiang Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China
| | - Yuqin Di
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China
| | - Zhihui Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Guangxi Hospital Division of The First Affiliated Hospital, Sun Yat-sen University, Guangxi, 530025, China.
| | - Ziyang Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
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Petrusca DN, Lee KP, Galson DL. Role of Sphingolipids in Multiple Myeloma Progression, Drug Resistance, and Their Potential as Therapeutic Targets. Front Oncol 2022; 12:925807. [PMID: 35756630 PMCID: PMC9213658 DOI: 10.3389/fonc.2022.925807] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 05/16/2022] [Indexed: 11/13/2022] Open
Abstract
Multiple myeloma (MM) is an incapacitating hematological malignancy characterized by accumulation of cancerous plasma cells in the bone marrow (BM) and production of an abnormal monoclonal protein (M-protein). The BM microenvironment has a key role in myeloma development by facilitating the growth of the aberrant plasma cells, which eventually interfere with the homeostasis of the bone cells, exacerbating osteolysis and inhibiting osteoblast differentiation. Recent recognition that metabolic reprograming has a major role in tumor growth and adaptation to specific changes in the microenvironmental niche have led to consideration of the role of sphingolipids and the enzymes that control their biosynthesis and degradation as critical mediators of cancer since these bioactive lipids have been directly linked to the control of cell growth, proliferation, and apoptosis, among other cellular functions. In this review, we present the recent progress of the research investigating the biological implications of sphingolipid metabolism alterations in the regulation of myeloma development and its progression from the pre-malignant stage and discuss the roles of sphingolipids in in MM migration and adhesion, survival and proliferation, as well as angiogenesis and invasion. We introduce the current knowledge regarding the role of sphingolipids as mediators of the immune response and drug-resistance in MM and tackle the new developments suggesting the manipulation of the sphingolipid network as a novel therapeutic direction for MM.
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Affiliation(s)
- Daniela N Petrusca
- Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Kelvin P Lee
- Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, United States.,Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, United States
| | - Deborah L Galson
- Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, McGowan Institute for Regenerative Medicine, HCC Research Pavilion, University of Pittsburgh, Pittsburgh, PA, United States
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6
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Agarwala PK, Aneja R, Kapoor S. Lipidomic landscape in cancer: Actionable insights for membrane-based therapy and diagnoses. Med Res Rev 2021; 42:983-1018. [PMID: 34719798 DOI: 10.1002/med.21868] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 08/18/2021] [Accepted: 10/24/2021] [Indexed: 01/17/2023]
Abstract
Cancer cells display altered cellular lipid metabolism, including disruption in endogenous lipid synthesis, storage, and exogenous uptake for membrane biogenesis and functions. Altered lipid metabolism and, consequently, lipid composition impacts cellular function by affecting membrane structure and properties, such as fluidity, rigidity, membrane dynamics, and lateral organization. Herein, we provide an overview of lipid membranes and how their properties affect cellular functions. We also detail how the rewiring of lipid metabolism impacts the lipidomic landscape of cancer cell membranes and influences the characteristics of cancer cells. Furthermore, we discuss how the altered cancer lipidome provides cues for developing lipid-inspired innovative therapeutic and diagnostic strategies while improving our limited understanding of the role of lipids in cancer initiation and progression. We also present the arcade of membrane characterization techniques to cement their relevance in cancer diagnosis and monitoring of treatment response.
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Affiliation(s)
- Prema K Agarwala
- Department of Chemistry, Indian Institute of Technology Bombay, Mumbai, India
| | - Ritu Aneja
- Department of Biology, Georgia State University, Atlanta, Georgia, USA
| | - Shobhna Kapoor
- Department of Chemistry, Indian Institute of Technology Bombay, Mumbai, India.,Depertment of Biofunctional Science and Technology, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
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Mameri A, Bournine L, Mouni L, Bensalem S, Iguer-Ouada M. Oxidative stress as an underlying mechanism of anticancer drugs cytotoxicity on human red blood cells' membrane. Toxicol In Vitro 2021; 72:105106. [PMID: 33539984 DOI: 10.1016/j.tiv.2021.105106] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/17/2021] [Accepted: 01/30/2021] [Indexed: 11/29/2022]
Abstract
The aim of this study is to investigate the direct in vitro effects of anticancer drugs on red blood cells (RBCs) and to explore the underlying mechanism, mainly by measuring RBCs oxidative stress (OS) status. After RBCs direct contact with fourteen (14) anticancer drugs, several parameters were assessed including: cellular turbidity, methemoglobin (metHb) generation, released Hb and Hb stability. Moreover, intracellular Hb, considered as new molecular target of anticancer drugs, was quantified inside RBCs. MDA level, the main biomarker of OS, was simultaneously measured. The cellular turbidity reveled severe (docetaxel "TXT", 0.03 ± 0.002), moderate (methotrexate "MTX", 0.49 ± 0.009), or none (5-fluorouracil "5-FU", 0.76 ± 0.029) membrane cytotoxicity (MC). An inverse relationship between cell concentration, released Hb and metHb content was obtained. High metHb generation, revealing intense OS, was also mostly expressed in paclitaxel "TXL" and etoposide "VP16". Further, epirubicin "EPI" and "TXT" induced important oxidation of membrane lipids with 0.32 ± 0.014 and 0.26 ± 0.004, respectively. Also, MTX (0.17 ± 0.006) and doxorubicin "DOX" (0.32 ± 0.034) affected significantly Hb stability by a direct contact with molecule. These findings demonstrated that anticancer drugs have the ability to induce membrane damages by the exacerbation of OS through membrane lipid peroxidation and Hb oxidation even inside RBCs.
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Affiliation(s)
- Amal Mameri
- Laboratoire de Gestion et Valorisation des Ressources Naturelles et Assurances Qualités (LGVRNAQ), Faculté des Sciences de la Nature et de la Vie et des Sciences de la Terre, Université de Bouira, 10000 Bouira, Algeria
| | - Lamine Bournine
- Département des Sciences Biologiques, Faculté des Sciences de la Nature et de la Vie et des Sciences de la Terre, Université de Bouira, 10000 Bouira, Algeria; Laboratoire de Biotechnologie Végétales et Ethnobotanique (LBVEB), Faculté des Sciences de la Nature et de la Vie, Université de Bejaia, 06000 Bejaia, Algeria.
| | - Lotfi Mouni
- Laboratoire de Gestion et Valorisation des Ressources Naturelles et Assurances Qualités (LGVRNAQ), Faculté des Sciences de la Nature et de la Vie et des Sciences de la Terre, Université de Bouira, 10000 Bouira, Algeria; Département des Sciences Biologiques, Faculté des Sciences de la Nature et de la Vie et des Sciences de la Terre, Université de Bouira, 10000 Bouira, Algeria
| | - Sihem Bensalem
- Laboratoire de Biotechnologie Végétales et Ethnobotanique (LBVEB), Faculté des Sciences de la Nature et de la Vie, Université de Bejaia, 06000 Bejaia, Algeria
| | - Mokrane Iguer-Ouada
- Laboratoire Associé en Ecosystèmes Marins et Aquacoles (LAEMA), Faculté des Sciences de la Nature et de la Vie, Université de Bejaia, 06000 Bejaia, Algeria
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Effect of Cilastatin on Cisplatin-Induced Nephrotoxicity in Patients Undergoing Hyperthermic Intraperitoneal Chemotherapy. Int J Mol Sci 2021; 22:ijms22031239. [PMID: 33513824 PMCID: PMC7865672 DOI: 10.3390/ijms22031239] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/21/2021] [Accepted: 01/22/2021] [Indexed: 12/24/2022] Open
Abstract
Cisplatin is one of the most widely used chemotherapeutic agents in oncology, although its nephrotoxicity limits application and dosage. We present the results of a clinical study on prophylaxis of cisplatin-induced nephrotoxicity in patients with peritoneal carcinomatosis undergoing cytoreduction and hyperthermic intraperitoneal intraoperative chemotherapy (HIPEC-cisplatin). Prophylaxis was with imipenem/cilastatin. Cilastatin is a selective inhibitor of renal dehydropeptidase I in the proximal renal tubule cells that can reduce the nephrotoxicity of cisplatin. Unfortunately, cilastatin is not currently marketed alone, and can only be administered in combination with imipenem. The study has a retrospective part that serves as a control (n = 99 patients receiving standard surgical prophylaxis) and a prospective part with imipenem/cilastatin prophylaxis corresponding to the study group (n = 85 patients). In both groups, we collected specific data on preoperative risk factors of renal damage, fluid management, hemodynamic control, and urine volume during surgery (including the hyperthermic chemotherapy perfusion), as well as data on hemodynamic and renal function during the first seven days after surgery. The main finding of the study is that cilastatin may exert a nephroprotective effect in patients with peritoneal carcinomatosis undergoing cytoreduction and hyperthermic intraperitoneal cisplatin perfusion. Creatinine values remained lower than in the control group (ANOVA test, p = 0.037). This translates into easier management of these patients in the postoperative period, with significantly shorter intensive care unit (ICU) and hospital stay.
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Gurunathan S, Kang MH, Jeyaraj M, Kim JH. Platinum Nanoparticles Enhance Exosome Release in Human Lung Epithelial Adenocarcinoma Cancer Cells (A549): Oxidative Stress and the Ceramide Pathway are Key Players. Int J Nanomedicine 2021; 16:515-538. [PMID: 33519199 PMCID: PMC7837572 DOI: 10.2147/ijn.s291138] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 12/31/2020] [Indexed: 12/13/2022] Open
Abstract
Background Several studies have demonstrated various molecular mechanisms involved in the biogenesis and release of exosomes. However, how external stimuli, such as platinum nanoparticles (PtNPs), induces the biogenesis and release of exosomes remains unclear. To address this, PtNPs were synthesized using lutein to examine their effect on the biogenesis and release of exosomes in human lung epithelial adenocarcinoma cancer cells (A549). Methods The size and concentration of isolated exosomes were characterized by dynamic light scattering (DLS) and nanoparticle tracking analysis system (NTA). Morphology and structure of exosomes were examined using scanning electron microscopy and transmission electron microscopy (TEM), respectively. Quantification of exosomes were analyzed by EXOCETTM assay and fluorescence polarization (FP). The expression of typical markers of exosomes were analyzed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). Results A549 cells cultured with PtNPs enhance exosome secretion by altering various physiological processes. Interestingly, A549 cells treated with PtNPs increases total protein concentration, biogenesis and release of exosomes associated with PtNPs-induced oxidative stress. GW4869 inhibits PtNPs induced biogenesis and release of exosomes and also acetylcholinesterase (AChE), neutral sphingomyelinase activity (n-SMase), and exosome counts. A549 cells pre-treated with N-acetylcysteine (NAC) significantly inhibited PtNPs induced exosome biogenesis and release. These findings confirmed that PtNPs-induced exosome release was due to the induction of oxidative stress and the ceramide pathway. These factors enhanced exosome biogenesis and release and may be useful in understanding the mechanism of exosome formation, release, and function. Conclusion PtNPs provide a promising agent to increase exosome production in A549 cells. These findings offer novel strategies for enhancing exosome release, which can be applied in the treatment and prevention of cancer. Importantly, this is the first study, to our knowledge, showing that PtNPs stimulate exosome biogenesis by inducing oxidative stress and the ceramide pathway.
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Affiliation(s)
- Sangiliyandi Gurunathan
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea
| | - Min-Hee Kang
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea
| | - Muniyandi Jeyaraj
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea
| | - Jin-Hoi Kim
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea
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Guo J, Shen S, Xing S, Huan T. DaDIA: Hybridizing Data-Dependent and Data-Independent Acquisition Modes for Generating High-Quality Metabolomic Data. Anal Chem 2021; 93:2669-2677. [DOI: 10.1021/acs.analchem.0c05022] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Jian Guo
- Department of Chemistry, Faculty of Science, University of British Columbia, Vancouver Campus, 2036 Main Mall, Vancouver V6T 1Z1, British Columbia, Canada
| | - Sam Shen
- Department of Chemistry, Faculty of Science, University of British Columbia, Vancouver Campus, 2036 Main Mall, Vancouver V6T 1Z1, British Columbia, Canada
| | - Shipei Xing
- Department of Chemistry, Faculty of Science, University of British Columbia, Vancouver Campus, 2036 Main Mall, Vancouver V6T 1Z1, British Columbia, Canada
| | - Tao Huan
- Department of Chemistry, Faculty of Science, University of British Columbia, Vancouver Campus, 2036 Main Mall, Vancouver V6T 1Z1, British Columbia, Canada
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Petit K, Suwalsky M, Colina JR, Contreras D, Aguilar LF, Jemiola-Rzeminska M, Strzalka K. Toxic effects of the anticancer drug epirubicin in vitro assayed in human erythrocytes. Toxicol In Vitro 2020; 68:104964. [PMID: 32800948 DOI: 10.1016/j.tiv.2020.104964] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 07/13/2020] [Accepted: 08/06/2020] [Indexed: 12/16/2022]
Abstract
Epirubicin is a cytotoxic drug used in the treatment of different types of cancer and increasing evidence suggests that its target is cell membranes. In order to gain insight on its toxic effects, intact red blood cells (RBC), human erythrocyte membranes and molecular models were used. The latter consisted in bilayers of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), phospholipid classes found mainly in the outer and inner monolayers of the human erythrocyte membrane, respectively. The results obtained by X-ray diffraction displayed that epirubicin induced structural perturbations in multilayers of DMPC. Differential scanning calorimetry (DSC) showed that epirubicin disturbed the thermotropic behavior of both DMPC and DMPE vesicles, whereas fluorescence spectroscopy demonstrated alterations in the fluidity of DMPC vesicles and the erythrocyte membrane. Scanning electron microscopy (SEM) revealed that epirubicin changed the normal discoid form of RBC to echinocytes and stomatocytes. Electron paramagnetic resonance (EPR) disclosed that this drug induced conformational changes in the erythrocyte membrane proteins. These findings demonstrate that epirubicin interacts with lipids and proteins of the human erythrocyte membrane, effects that might compromise the integrity and function of cell membranes. This is the first time that its toxic effects on the human erythrocyte membrane have been described.
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Affiliation(s)
- Karla Petit
- Faculty of Chemical Sciences, University of Concepción, Concepción, Chile
| | - Mario Suwalsky
- Faculty of Chemical Sciences, University of Concepción, Concepción, Chile.
| | - José R Colina
- Faculty of Chemical Sciences, University of Concepción, Concepción, Chile
| | - David Contreras
- Faculty of Chemical Sciences, University of Concepción, Concepción, Chile; Center of Biotecnology, University of Concepción, Concepción, Chile
| | - Luis F Aguilar
- Instituto de Química, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | - Malgorzata Jemiola-Rzeminska
- Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Kazimierz Strzalka
- Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
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Ceramide Domains in Health and Disease: A Biophysical Perspective. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1159:79-108. [DOI: 10.1007/978-3-030-21162-2_6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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de Souza A, Campos DJ, Schieferdecker MEM, Funke VAM, Vilela RM. Phase angle as a screening tool for mortality risk among hematopoietic stem cell transplanted adult patients. Clin Nutr ESPEN 2019; 29:65-71. [DOI: 10.1016/j.clnesp.2018.12.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 12/07/2018] [Indexed: 10/27/2022]
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14
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Mohammadi AS, Li X, Ewing AG. Mass Spectrometry Imaging Suggests That Cisplatin Affects Exocytotic Release by Alteration of Cell Membrane Lipids. Anal Chem 2018; 90:8509-8516. [PMID: 29912552 DOI: 10.1021/acs.analchem.8b01395] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
We used time-of-flight secondary ion mass spectrometry (TOF-SIMS) imaging to investigate the effect of cisplatin, the first member of the platinum-based anticancer drugs, on the membrane lipid composition of model cells to see if lipid changes might be involved in the changes in exocytosis observed. Platinum-based anticancer drugs have been reported to affect neurotransmitter release resulting in what is called the "chemobrain"; however, the mechanism for the influence is not yet understood. TOF-SIMS imaging was carried out using a high energy 40 keV (CO2)6000+ gas cluster ion beam with improved sensitivity for intact lipids in biological samples. Principal components analysis showed that cisplatin treatment of PC12 cells significantly affects the abundance of different lipids and their derivatives, particularly phosphatidylcholine and cholesterol, which are diminished. Treatment of cells with 2 μM and 100 μM cisplatin showed similar effects on induced lipid changes. Lipid content alterations caused by cisplatin treatment at the cell surface are associated with the molecular and bimolecular signaling pathways of cisplatin-induced apoptosis of cells. We suggest that lipid alterations measured by TOF-SIMS are involved, at least in part, in the regulation of exocytosis by cisplatin.
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Affiliation(s)
- Amir Saeid Mohammadi
- Department of Chemistry and Molecular Biology , University of Gothenburg , 40530 Gothenburg , Sweden.,National Center for Imaging Mass Spectrometry , 41296 Gothenburg , Sweden
| | - Xianchan Li
- Department of Chemistry and Molecular Biology , University of Gothenburg , 40530 Gothenburg , Sweden
| | - Andrew G Ewing
- Department of Chemistry and Molecular Biology , University of Gothenburg , 40530 Gothenburg , Sweden.,National Center for Imaging Mass Spectrometry , 41296 Gothenburg , Sweden.,Department of Chemistry and Chemical Engineering , Chalmers University of Technology , 41296 Gothenburg , Sweden
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15
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Alves AC, Ribeiro D, Horta M, Lima JLFC, Nunes C, Reis S. A biophysical approach to daunorubicin interaction with model membranes: relevance for the drug's biological activity. J R Soc Interface 2018; 14:rsif.2017.0408. [PMID: 28855387 DOI: 10.1098/rsif.2017.0408] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 08/04/2017] [Indexed: 01/10/2023] Open
Abstract
Daunorubicin is extensively used in chemotherapy for diverse types of cancer. Over the years, evidence has suggested that the mechanisms by which daunorubicin causes cytotoxic effects are also associated with interactions at the membrane level. The aim of the present work was to study the interplay between daunorubicin and mimetic membrane models composed of different ratios of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), sphingomyelin (SM) and cholesterol (Chol). Several biophysical parameters were assessed using liposomes as mimetic model membranes. Thereby, the ability of daunorubicin to partition into lipid bilayers, its apparent location within the membrane and its effect on membrane fluidity were investigated. The results showed that daunorubicin has higher affinity for lipid bilayers composed of DMPC, followed by DMPC : SM, DMPC : Chol and lastly by DMPC : SM : Chol. The addition of SM or Chol into DMPC membranes not only increases the complexity of the model membrane but also decreases its fluidity, which, in turn, reduces the amount of anticancer drug that can partition into these mimetic models. Fluorescence quenching studies suggest a broad distribution of the drug across the bilayer thickness, with a preferential location in the phospholipid tails. The gathered data support that daunorubicin permeates all types of membranes to different degrees, interacts with phospholipids through electrostatic and hydrophobic bonds and causes alterations in the biophysical properties of the bilayers, namely in membrane fluidity. In fact, a decrease in membrane fluidity can be observed in the acyl region of the phospholipids. Ultimately, such outcomes can be correlated with daunorubicin's biological action, where membrane structure and lipid composition have an important role. In fact, the results indicate that the intercalation of daunorubicin between the phospholipids can also take place in rigid domains, such as rafts that are known to be involved in different receptor processes, which are important for cellular function.
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Affiliation(s)
- Ana Catarina Alves
- UCIBIO, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira no. 228, 4050-313 Porto, Portugal
| | - Daniela Ribeiro
- UCIBIO, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira no. 228, 4050-313 Porto, Portugal
| | - Miguel Horta
- UCIBIO, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira no. 228, 4050-313 Porto, Portugal
| | - José L F C Lima
- UCIBIO, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira no. 228, 4050-313 Porto, Portugal
| | - Cláudia Nunes
- UCIBIO, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira no. 228, 4050-313 Porto, Portugal
| | - Salette Reis
- UCIBIO, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira no. 228, 4050-313 Porto, Portugal
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16
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Cell membrane modulation as adjuvant in cancer therapy. Cancer Treat Rev 2016; 52:48-57. [PMID: 27889637 DOI: 10.1016/j.ctrv.2016.10.008] [Citation(s) in RCA: 257] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 10/24/2016] [Accepted: 10/27/2016] [Indexed: 12/25/2022]
Abstract
Cancer is a complex disease involving numerous biological processes, which can exist in parallel, can be complementary, or are engaged when needed and as such can replace each other. This redundancy in possibilities cancer cells have, are fundamental to failure of therapy. However, intrinsic features of tumor cells and tumors as a whole provide also opportunities for therapy. Here we discuss the unique and specific makeup and arrangement of cell membranes of tumor cells and how these may help treatment. Interestingly, knowledge on cell membranes and associated structures is present already for decades, while application of membrane modification and manipulation as part of cancer therapy is lagging. Recent developments of scientific tools concerning lipids and lipid metabolism, opened new and previously unknown aspects of tumor cells and indicate possible differences in lipid composition and membrane function of tumor cells compared to healthy cells. This field, coined Lipidomics, demonstrates the importance of lipid components in cell membrane in several illnesses. Important alterations in cancer, and specially in resistant cancer cells compared to normal cells, opened the door to new therapeutic strategies. Moreover, the ability to modulate membrane components and/or properties has become a reality. Here, developments in cancer-related Lipidomics and strategies to interfere specifically with cancer cell membranes and how these affect cancer treatment are discussed. We hypothesize that combination of lipid or membrane targeted strategies with available care to improve chemotherapy, radiotherapy and immunotherapy will bring the much needed change in treatment in the years to come.
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Biophysics in cancer: The relevance of drug-membrane interaction studies. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2016; 1858:2231-2244. [DOI: 10.1016/j.bbamem.2016.06.025] [Citation(s) in RCA: 116] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Revised: 05/31/2016] [Accepted: 06/26/2016] [Indexed: 12/26/2022]
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Lim SC, Parajuli KR, Han SI. The alkyllysophospholipid edelfosine enhances TRAIL-mediated apoptosis in gastric cancer cells through death receptor 5 and the mitochondrial pathway. Tumour Biol 2016; 37:6205-6216. [PMID: 26615420 DOI: 10.1007/s13277-015-4485-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 11/23/2015] [Indexed: 02/07/2023] Open
Abstract
The ether phospholipid edelfosine is the prototype of a group of synthetic antitumor alkyllysophospholipid (ALP) compounds that exert pro-apoptotic effects in various types of cancer cells through cell type-dependent mechanisms. In this study, we examined the antitumor effect of edelfosine in human gastric cancer cells. Edelfosine decreased cell viability and induced autophagic death at a moderate concentration (~30 μM), whereas it induced apoptotic cell death at concentrations over 30 μM. Interestingly, low concentrations of edelfosine (5-10 μM) effectively enhanced recombinant human tumor necrosis factor (TNF)-related apoptosis-inducing ligand (rhTRAIL/TNFSF10)-induced apoptosis and clonogenicity in gastric cancer cells, including TRAIL-resistant AGS cells. Edelfosine upregulated the protein level of death receptor 5 (DR5/TNFRSF10B) and/or increased DR5 upregulation in lipid rafts. In addition, edelfosine-mediated rhTRAIL sensitization was regulated by the DR5 pathway. Edelfosine also activated p38MAPK (MAPK14), and edelfosine-mediated rhTRAIL sensitization was partially regulated by a p38-mediated decrease in mitochondrial membrane potential. This study suggests a novel therapeutic strategy targeting gastric cancer cells by using the combination of edelfosine and TRAIL.
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Affiliation(s)
- Sung-Chul Lim
- Department of Pathology, College of Medicine, Chosun University, Gwangju, 61501, Korea
- Research Center for Resistant Cells, Chosun University, Gwangju, 61501, Korea
| | - Keshab Raj Parajuli
- Research Center for Resistant Cells, Chosun University, Gwangju, 61501, Korea
| | - Song Iy Han
- Research Center for Resistant Cells, Chosun University, Gwangju, 61501, Korea.
- Division of Premedical Science, College of Medicine, Chosun University, Gwangju, 61501, Korea.
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Li YL, Lin ML, He SQ, Jin JF. Sphingolipid metabolism affects the anticancer effect of cisplatin. World J Transl Med 2016; 5:37-45. [DOI: 10.5528/wjtm.v5.i1.37] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Revised: 12/09/2015] [Accepted: 01/11/2016] [Indexed: 02/06/2023] Open
Abstract
Cisplatin, a DNA crosslinking agent, is widely used for the treatment of a variety of solid tumors. Numerous studies have demonstrated that sphingolipid metabolism, which acts as a target for cisplatin treatment, is a highly complex network that consists of sphingolipid signaling molecules and related catalytic enzymes. Ceramide (Cer), which is the central molecule of this network, has been established to induce apoptosis. However, another molecule, sphingosine-1-phosphate (S1P), exerts the opposite function, i.e., serves as a regulator of pro-survival. Other sphingolipid molecules, including dihydroceramide, ceramide-1-phosphate, glucosylceramide (GluCer), and sphingosine (Sph), or sphingolipid catalytic enzymes such as Sph kinase (SphK), Cer synthase (CerS), and S1P lyase, have also attracted considerable attention, particularly Cer, GluCer, SphK, CerS, and S1P lyase, which have been implicated in cisplatin resistance. This review summarizes specific molecules involved in sphingolipid metabolism and related catalytic enzymes affecting the anticancer effect of cisplatin, particularly in relation to induction of apoptosis and drug resistance.
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20
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Zhu H, Deng K, Zhao YQ, Wang X, Shen YL, Liu TG, Cui DD, Xu F. The Effects of ASMase Mediated Endothelial Cell Apoptosis in Multiple Hypofractionated Irradiations in CT26 Tumor Bearing Mice. Asian Pac J Cancer Prev 2016; 16:4543-8. [PMID: 26107201 DOI: 10.7314/apjcp.2015.16.11.4543] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND To investigate the effects of ASMase mediated endothelial cell apoptosis in multiple hypofractionated irradiations in CT26 tumor bearing mice. MATERIALS AND METHODS Thirty-five CT26 tumor bearing mice were subjected to single ionizing radiation (IR) of 0, 3, 6, 9, 12, 15, 18 Gy. Eight hours after IR, the mice were sacrificed and tumor tissues were used for CD31 immunohistochemistry staining, TUNEL and CD31 double staining, ASMase activity assay. Then 6 and 12 Gy were chosen for multiple hypofractionated IR experiments according to the above results. Each time after IR, 5 mice were sacrificed and assayed as above. RESULTS The ASMase activities were increased significantly after a single IR of 12 Gy or higher which was accompanied with remarkable increased endothelial cell apoptosis and decreased MVD. For 6 Gy which was not high enough to trigger ASMase activation, after 2 or more times of IR, the ASMase activities were significantly increased accompanied with remarkable increased endothelial cell apoptosis and decreased MVD. While for 12 Gy, after 2 or more times of IR, the ASMase activities and endothelial cell apoptosis rates were maintained without remarkable increase; however, the MVD was significantly decreased. What's more, the cancer cell apoptosis rates were significantly increased after multiple IR for both 6 Gy and 12 Gy. CONCLUSIONS ASMase mediated endothelial cell apoptosis may play an important role in the process of multiple hypofractionated IR for CT26 colorectal carcinoma.
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Affiliation(s)
- Hong Zhu
- Department of Medical Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China E-mail :
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21
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Matsumoto Y, Kuwabara K, Ichihara H, Kuwano M. Therapeutic effects of trehalose liposomes against lymphoblastic leukemia leading to apoptosis in vitro and in vivo. Bioorg Med Chem Lett 2016; 26:301-305. [DOI: 10.1016/j.bmcl.2015.12.025] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 11/20/2015] [Accepted: 12/10/2015] [Indexed: 11/26/2022]
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Raghunathan K, Ahsan A, Ray D, Nyati MK, Veatch SL. Membrane Transition Temperature Determines Cisplatin Response. PLoS One 2015; 10:e0140925. [PMID: 26484687 PMCID: PMC4618528 DOI: 10.1371/journal.pone.0140925] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Accepted: 10/01/2015] [Indexed: 11/19/2022] Open
Abstract
Cisplatin is a classical chemotherapeutic agent used in treating several forms of cancer including head and neck. However, cells develop resistance to the drug in some patients through a range of mechanisms, some of which are poorly understood. Using isolated plasma membrane vesicles as a model system, we present evidence suggesting that cisplatin induced resistance may be due to certain changes in the bio-physical properties of plasma membranes. Giant plasma membrane vesicles (GPMVs) isolated from cortical cytoskeleton exhibit a miscibility transition between a single liquid phase at high temperature and two distinct coexisting liquid phases at low temperature. The temperature at which this transition occurs is hypothesized to reflect the magnitude of membrane heterogeneity at physiological temperature. We find that addition of cisplatin to vesicles isolated from cisplatin-sensitive cells result in a lowering of this miscibility transition temperature, whereas in cisplatin-resistant cells such treatment does not affect the transition temperature. To explore if this is a cause or consequence of cisplatin resistance, we tested if addition of cisplatin in combination with agents that modulate GPMV transition temperatures can affect cisplatin sensitivity. We found that cells become more sensitive to cisplatin when isopropanol, an agent that lowers GPMV transition temperature, was combined with cisplatin. Conversely, cells became resistant to cisplatin when added in combination with menthol that raises GPMV transition temperatures. These data suggest that changes in plasma membrane heterogeneity augments or suppresses signaling events initiated in the plasma membranes that can determine response to cisplatin. We postulate that desired perturbations of membrane heterogeneity could provide an effective therapeutic strategy to overcome cisplatin resistance for certain patients.
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Affiliation(s)
- Krishnan Raghunathan
- Department of Biophysics, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Aarif Ahsan
- Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Dipankar Ray
- Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Mukesh K. Nyati
- Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Sarah L. Veatch
- Department of Biophysics, University of Michigan, Ann Arbor, Michigan, United States of America
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23
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Membrane Interactions of Phytochemicals as Their Molecular Mechanism Applicable to the Discovery of Drug Leads from Plants. Molecules 2015; 20:18923-66. [PMID: 26501254 PMCID: PMC6332185 DOI: 10.3390/molecules201018923] [Citation(s) in RCA: 123] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Revised: 10/11/2015] [Accepted: 10/14/2015] [Indexed: 02/02/2023] Open
Abstract
In addition to interacting with functional proteins such as receptors, ion channels, and enzymes, a variety of drugs mechanistically act on membrane lipids to change the physicochemical properties of biomembranes as reported for anesthetic, adrenergic, cholinergic, non-steroidal anti-inflammatory, analgesic, antitumor, antiplatelet, antimicrobial, and antioxidant drugs. As well as these membrane-acting drugs, bioactive plant components, phytochemicals, with amphiphilic or hydrophobic structures, are presumed to interact with biological membranes and biomimetic membranes prepared with phospholipids and cholesterol, resulting in the modification of membrane fluidity, microviscosity, order, elasticity, and permeability with the potencies being consistent with their pharmacological effects. A novel mechanistic point of view of phytochemicals would lead to a better understanding of their bioactivities, an insight into their medicinal benefits, and a strategic implication for discovering drug leads from plants. This article reviews the membrane interactions of different classes of phytochemicals by highlighting their induced changes in membrane property. The phytochemicals to be reviewed include membrane-interactive flavonoids, terpenoids, stilbenoids, capsaicinoids, phloroglucinols, naphthodianthrones, organosulfur compounds, alkaloids, anthraquinonoids, ginsenosides, pentacyclic triterpene acids, and curcuminoids. The membrane interaction’s applicability to the discovery of phytochemical drug leads is also discussed while referring to previous screening and isolating studies.
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24
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Tsukamoto S, Huang Y, Kumazoe M, Lesnick C, Yamada S, Ueda N, Suzuki T, Yamashita S, Kim YH, Fujimura Y, Miura D, Kay NE, Shanafelt TD, Tachibana H. Sphingosine Kinase-1 Protects Multiple Myeloma from Apoptosis Driven by Cancer-Specific Inhibition of RTKs. Mol Cancer Ther 2015; 14:2303-12. [PMID: 26264277 DOI: 10.1158/1535-7163.mct-15-0185] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Accepted: 08/06/2015] [Indexed: 11/16/2022]
Abstract
Activation of acid sphingomyelinase (ASM) leads to ceramide accumulation and induces apoptotic cell death in cancer cells. In the present study, we demonstrate that the activation of ASM by targeting cancer-overexpressed 67-kDa laminin receptors (67LR) induces lipid raft disruption and inhibits receptor tyrosine kinase (RTK) activation in multiple myeloma cells. Sphingosine kinase 1 (SphK1), a negative regulator of ceramide accumulation with antiapoptotic effects, was markedly elevated in multiple myeloma cells. The silencing of SphK1 potentiated the apoptotic effects of the green tea polyphenol epigallocatechin-3-O-gallate (EGCG), an activator of ASM through 67LR. Furthermore, the SphK1 inhibitor safingol synergistically sensitized EGCG-induced proapoptotic cell death and tumor suppression in multiple myeloma cells by promoting the prevention of RTK phosphorylation and activation of death-associated protein kinase 1 (DAPK1). We propose that targeting 67LR/ASM and SphK1 may represent a novel therapeutic strategy against multiple myeloma.
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Affiliation(s)
- Shuntaro Tsukamoto
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan
| | - Yuhui Huang
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan
| | - Motofumi Kumazoe
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan
| | - Connie Lesnick
- Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Shuhei Yamada
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan
| | - Naoki Ueda
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan
| | - Takashi Suzuki
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan
| | - Shuya Yamashita
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan
| | - Yoon Hee Kim
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan
| | - Yoshinori Fujimura
- Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan
| | - Daisuke Miura
- Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan
| | - Neil E Kay
- Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | | | - Hirofumi Tachibana
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan. Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan. Food Functional Design Research Center, Kyushu University, Fukuoka, Japan.
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25
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Gatti L, Cassinelli G, Zaffaroni N, Lanzi C, Perego P. New mechanisms for old drugs: Insights into DNA-unrelated effects of platinum compounds and drug resistance determinants. Drug Resist Updat 2015; 20:1-11. [PMID: 26003720 DOI: 10.1016/j.drup.2015.04.001] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Revised: 04/27/2015] [Accepted: 04/29/2015] [Indexed: 01/11/2023]
Abstract
Platinum drugs have been widely used for the treatment of several solid tumors. Although DNA has been recognized as the primary cellular target for these agents, there are unresolved issues concerning their effects and the molecular mechanisms underlying the antitumor efficacy. These cytotoxic agents interact with sub-cellular compartments other than the nucleus. Here, we review how such emerging phenomena contribute to the pharmacologic activity as well as to drug resistance phenotypes. DNA-unrelated effects of platinum drugs involve alterations at the plasma membrane and in endo-lysosomal compartments. A direct interaction with the mitochondria also appears to be implicated in drug-induced cell death. Moreover, the pioneering work of a few groups has shown that platinum drugs can act on the tumor microenvironment as well, and potentiate antitumor activity of the immune system. These poorly understood aspects of platinum drug activity sites may be harnessed to enhance their antitumor efficacy. A complete understanding of DNA-unrelated effects of platinum compounds might reveal new aspects of drug resistance allowing the implementation of the antitumor therapeutic efficacy of platinum compound-based regimens and minimization of their toxic side effects.
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Affiliation(s)
- Laura Gatti
- Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42/via Venezian 1, 20133 Milan, Italy
| | - Giuliana Cassinelli
- Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42/via Venezian 1, 20133 Milan, Italy
| | - Nadia Zaffaroni
- Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42/via Venezian 1, 20133 Milan, Italy
| | - Cinzia Lanzi
- Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42/via Venezian 1, 20133 Milan, Italy
| | - Paola Perego
- Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42/via Venezian 1, 20133 Milan, Italy.
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26
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Saritemur M, Un H, Cadirci E, Karakus E, Akpinar E, Halici Z, Ugan RA, Karaman A, Atmaca HT. Tnf-α inhibition by infliximab as a new target for the prevention of glycerol-contrast-induced nephropathy. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2015; 39:577-588. [PMID: 25682004 DOI: 10.1016/j.etap.2015.01.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Revised: 12/31/2014] [Accepted: 01/10/2015] [Indexed: 06/04/2023]
Abstract
Contrast medium-induced nephropathy (CIN) remains as a problem with high incidence and mortality rates. The aim of this study is to examine the roles of infliximab (INF) in the glycerol (GLY) and CIN model in rats. The rats were separated into five groups (n=8): Healthy, GLY, GLY+CM, GLY+CM+INF 5mg/kg intraperitoneally (i.p.), and GLY+CM+INF 7 mg/kg (i.p.). Antioxidant levels in the therapy groups were observed to be quite similar to those in the healthy group. In this study, while the kidney TNF-α, IL-1β, TGF-1β and Caspase 3 gene expressions' levels increased in the nephrotoxic groups, these levels were found to have decreased in the treatment groups. Moreover, histopathologic examination showed that hyaline, haemorrhagic casts and necrosis were increased in nephrotoxicity group, whereas they decreased in the therapy group. Furthermore, TNF-α and NF-κB expression were decreased with infliximab administrated groups similar to control group. In conclusion, we suggest that infliximab have protective roles on CIN.
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Affiliation(s)
- Murat Saritemur
- Department of Emergency Medicine; Ataturk University Faculty of Medicine, 25240 Erzurum Turkey
| | - Harun Un
- Department of Biochemistry; Agri Ibrahim Cecen University Faculty of Pharmacy, 04100 Agri Turkey
| | - Elif Cadirci
- Department of Pharmacology; Ataturk University Faculty of Pharmacy, 25240 Erzurum Turkey.
| | - Emre Karakus
- Department of Pharmacology; Ataturk University Faculty of Veterinary Medicine, 25240 Erzurum Turkey
| | - Erol Akpinar
- Department of Pharmacology; Ataturk University Faculty of Medicine, 25240 Erzurum Turkey
| | - Zekai Halici
- Department of Pharmacology; Ataturk University Faculty of Medicine, 25240 Erzurum Turkey
| | - Rustem Anil Ugan
- Department of Pharmacology; Ataturk University Faculty of Medicine, 25240 Erzurum Turkey
| | - Adem Karaman
- Department of Radiology; Ataturk University Faculty of Medicine, 25240 Erzurum Turkey
| | - Hasan Tarik Atmaca
- Department of Pathology; Kırıkkale University Faculty of Veterinary, 71450 Kirikkale Turkey
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Resveratrol and its oligomers: modulation of sphingolipid metabolism and signaling in disease. Arch Toxicol 2014; 88:2213-32. [PMID: 25344023 DOI: 10.1007/s00204-014-1386-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Accepted: 10/08/2014] [Indexed: 01/10/2023]
Abstract
Resveratrol, a natural compound endowed with multiple health-promoting effects, has received much attention given its potential for the treatment of cardiovascular, inflammatory, neurodegenerative, metabolic and age-related diseases. However, the translational potential of resveratrol has been limited by its specificity, poor bioavailability and uncertain toxicity. In recent years, there has been an accumulation of evidence demonstrating that resveratrol modulates sphingolipid metabolism. Moreover, resveratrol forms higher order oligomers that exhibit better selectivity and potency in modulating sphingolipid metabolism. This review evaluates the evidence supporting the modulation of sphingolipid metabolism and signaling as a mechanism of action underlying the therapeutic efficacy of resveratrol and oligomers in diseases, such as cancer.
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Sigurðsson HH, Olesen CW, Dybboe R, Lauritzen G, Pedersen SF. Constitutively active ErbB2 regulates cisplatin-induced cell death in breast cancer cells via pro- and antiapoptotic mechanisms. Mol Cancer Res 2014; 13:63-77. [PMID: 25143433 DOI: 10.1158/1541-7786.mcr-14-0011] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
UNLABELLED Despite the frequent expression of N-terminally truncated ErbB2 (ΔNErbB2/p95HER2) in breast cancer and its association with Herceptin resistance and poor prognosis, it remains poorly understood how ΔNErbB2 affects chemotherapy-induced cell death. Previously it was shown that ΔNErbB2 upregulates acid extrusion from MCF-7 breast cancer cells and that inhibition of the Na(+)/H(+) exchanger (SLC9A1/NHE1) strongly sensitizes ΔNErbB2-expressing MCF-7 cells to cisplatin chemotherapy. The aim of this study was to identify the mechanism through which ΔNErbB2 regulates cisplatin-induced breast cancer cell death, and determine how NHE1 regulates this process. Cisplatin treatment elicited apoptosis, ATM phosphorylation, upregulation of p53, Noxa (PMAIP1), and PUMA (BBC3), and cleavage of caspase-9, -7, fodrin, and PARP-1 in MCF-7 cells. Inducible ΔNErbB2 expression strongly reduced cisplatin-induced ATM- and p53-phosphorylation, augmented Noxa upregulation and caspase-9 and -7 cleavage, doubled p21(WAF1/Cip1) (CDKN1A) expression, and nearly abolished Bcl-2 expression. LC3-GFP analysis demonstrated that autophagic flux was reduced by cisplatin in a manner augmented by ΔNErbB2, yet did not contribute to cisplatin-induced death. Using knockdown approaches, it was shown that cisplatin-induced caspase-7 cleavage in ΔNErbB2-MCF-7 cells was Noxa- and caspase-9 dependent. This pathway was augmented by NHE1 inhibition, while the Na(+)/HCO3 (-) cotransporter (SLC4A7/NBCn1) was internalized following cisplatin exposure. IMPLICATIONS This work reveals that ΔNErbB2 strongly affects several major pro- and antiapoptotic pathways and provides mechanistic insight into the role of NHE1 in chemotherapy resistance. These findings have relevance for defining therapy regimens in breast cancers with ΔNErbB2 and/or NHE1 overexpression.
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Affiliation(s)
- Haraldur H Sigurðsson
- Department of Biology, Section for Cell and Developmental Biology, University of Copenhagen, Copenhagen, Denmark
| | - Christina W Olesen
- Department of Biology, Section for Cell and Developmental Biology, University of Copenhagen, Copenhagen, Denmark
| | - Rie Dybboe
- Department of Biology, Section for Cell and Developmental Biology, University of Copenhagen, Copenhagen, Denmark
| | - Gitte Lauritzen
- Department of Biology, Section for Cell and Developmental Biology, University of Copenhagen, Copenhagen, Denmark
| | - Stine F Pedersen
- Department of Biology, Section for Cell and Developmental Biology, University of Copenhagen, Copenhagen, Denmark.
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Bourgaux C, Couvreur P. Interactions of anticancer drugs with biomembranes: what can we learn from model membranes? J Control Release 2014; 190:127-38. [PMID: 24859379 DOI: 10.1016/j.jconrel.2014.05.012] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Revised: 05/05/2014] [Accepted: 05/07/2014] [Indexed: 10/25/2022]
Abstract
The interactions of anticancer drugs with cell membranes are of primary importance for drug transport, accumulation and activity. However, these interactions are very difficult to investigate because of the complexity of biological membranes. Lipid model membranes have therefore been built to gain insight into the collective role of lipids in drug-membrane interactions. Membranes can act as a barrier for drug molecules, sequester them or conversely may allow them to freely diffuse, thereby modulating the accumulation of drugs into cells. Lipid membranes also affect the ability of the efflux pump Pgp to bind and efflux anticancer drugs from cells. On the other hand, anticancer drugs can alter the structure and properties of lipid membranes, which are expected to influence the functioning of embedded proteins. The relevance of lipid model membranes to assess interactions between anticancer drugs and biomembranes is evidenced.
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Affiliation(s)
- Claudie Bourgaux
- Institut Galien-Paris Sud, UMR CNRS 8612, Faculté de Pharmacie, Université Paris-Sud, 5 rue J.B. Clément, 92 296 Châtenay-Malabry Cedex, France
| | - Patrick Couvreur
- Institut Galien-Paris Sud, UMR CNRS 8612, Faculté de Pharmacie, Université Paris-Sud, 5 rue J.B. Clément, 92 296 Châtenay-Malabry Cedex, France
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Bahreman A, Rabe M, Kros A, Bruylants G, Bonnet S. Binding of a ruthenium complex to a thioether ligand embedded in a negatively charged lipid bilayer: a two-step mechanism. Chemistry 2014; 20:7429-38. [PMID: 24782232 DOI: 10.1002/chem.201400377] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Indexed: 01/14/2023]
Abstract
The interaction between the ruthenium polypyridyl complex [Ru(terpy)(dcbpy)(H2O)](2+) (terpy = 2,2';6',2"-terpyridine, dcbpy = 6,6'-dichloro-2,2'-bipyridine) and phospholipid membranes containing either thioether ligands or cholesterol were investigated using UV-visible spectroscopy, Langmuir-Blodgett monolayer surface pressure measurements, and isothermal titration calorimety (ITC). When embedded in a membrane, the thioether ligand coordinated to the dicationic metal complex only when the phospholipids of the membrane were negatively charged, that is, in the presence of attractive electrostatic interaction. In such a case coordination is much faster than in homogeneous conditions. A two-step model for the coordination of the metal complex to the membrane-embedded sulfur ligand is proposed, in which adsorption of the complex to the negative surface of the monolayers or bilayers occurs within minutes, whereas formation of the coordination bond between the surface-bound metal complex and ligand takes hours. Finally, adsorption of the aqua complex to the membrane is driven by entropy. It does not involve insertion of the metal complex into the hydrophobic lipid layer, but rather simple electrostatic adsorption at the water-bilayer interface.
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Affiliation(s)
- Azadeh Bahreman
- Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, Leiden, 2300 RA (The Netherlands)
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Lin HY, Delmas D, Vang O, Hsieh TC, Lin S, Cheng GY, Chiang HL, Chen CE, Tang HY, Crawford DR, Whang-Peng J, Hwang J, Liu LF, Wu JM. Mechanisms of ceramide-induced COX-2-dependent apoptosis in human ovarian cancer OVCAR-3 cells partially overlapped with resveratrol. J Cell Biochem 2013; 114:1940-54. [PMID: 23495037 DOI: 10.1002/jcb.24539] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Accepted: 02/28/2013] [Indexed: 01/15/2023]
Abstract
Ceramide is a member of the sphingolipid family of bioactive molecules demonstrated to have profound, diverse biological activities. Ceramide is a potential chemotherapeutic agent via the induction of apoptosis. Exposure to ceramide activates extracellular-signal-regulated kinases (ERK)1/2- and p38 kinase-dependent apoptosis in human ovarian cancer OVCAR-3 cells, concomitant with an increase in the expression of COX-2 and p53 phosphorylation. Blockade of cyclooxygenase-2 (COX-2) activity by siRNA or NS398 correspondingly inhibited ceramide-induced p53 Ser-15 phosphorylation and apoptosis; thus COX-2 appears at the apex of the p38 kinase-mediated signaling cascade induced by ceramide. Induction of apoptosis by ceramide or resveratrol was inhibited by the endocytosis inhibitor, cytochalasin D (CytD); however, cells exposed to resveratrol showed greater sensitivity than ceramide-treated cells. Ceramide-treated cells underwent a dose-dependent reduction in trans-membrane potential. Although both ceramide and resveratrol induced the expressions of caspase-3 and -7, the effect of inducible COX-2 was different in caspase-7 expression induced by ceramide compared to resveratrol. In summary, resveratrol and ceramide converge on an endocytosis-requiring, ERK1/2-dependent signal transduction pathway and induction of COX-expression as an essential molecular antecedent for subsequent p53-dependent apoptosis. In addition, expressions of caspase-3 and -7 are observed. However, a p38 kinase-dependent signal transduction pathway and change in mitochondrial potential are also involved in ceramide-induced apoptosis.
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Affiliation(s)
- Hung-Yun Lin
- Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
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Signalling mechanisms involved in renal pathological changes during cisplatin-induced nephropathy. Eur J Clin Pharmacol 2013; 69:1863-74. [PMID: 23929259 DOI: 10.1007/s00228-013-1568-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2013] [Accepted: 07/24/2013] [Indexed: 12/20/2022]
Abstract
CONTEXT Cisplatin, a coordination platinum complex, is used as a potential anti-neoplastic agent, having well recognized DNA-damaging property that triggers cell-cycle arrest and cell death in cancer therapy. Beneficial chemotherapeutic actions of cisplatin can be detrimental for kidneys. BACKGROUND Unbound cisplatin gets accumulated in renal tubular cells, leading to cell injury and death. This liable action of cisplatin on kidneys is mediated by altered intracellular signalling pathways such as mitogen-activated protein kinase (MAPK), extracellular regulated kinase (ERK), or C- Jun N terminal kinase/stress-activated protein kinase (JNK/SAPK). Further, these signalling alterations are responsible for release and activation of tumour necrosis factor (TNF-α), mitochondrial dysfunction, and apoptosis, which ultimately cause the renal pathogenic process. Cisplatin itself enhances the generation of reactive oxygen species (ROS) and activation of nuclear factor-κB (NF-κB), inflammation, and mitochondrial dysfunction, which further leads to renal apoptosis. Cisplatin-induced nephropathy is also mediated through the p53 and protein kinase-Cδ (PKCδ) signalling pathways. OBJECTIVE This review explores these signalling alterations and their possible role in the pathogenesis of cisplatin-induced renal injury.
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Daniel C, Bell C, Burton C, Harguindey S, Reshkin SJ, Rauch C. The role of proton dynamics in the development and maintenance of multidrug resistance in cancer. Biochim Biophys Acta Mol Basis Dis 2013; 1832:606-17. [DOI: 10.1016/j.bbadis.2013.01.020] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2012] [Revised: 01/15/2013] [Accepted: 01/24/2013] [Indexed: 12/27/2022]
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Tekpli X, Holme JA, Sergent O, Lagadic-Gossmann D. Role for membrane remodeling in cell death: Implication for health and disease. Toxicology 2013; 304:141-57. [DOI: 10.1016/j.tox.2012.12.014] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Revised: 11/29/2012] [Accepted: 12/20/2012] [Indexed: 12/31/2022]
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Abstract
Chemotherapy is frequently used to treat primary or metastatic cancers, but intrinsic or acquired drug resistance limits its efficiency. Sphingolipids are important regulators of various cellular processes including proliferation, apoptosis, differentiation, angiogenesis, stress, and inflammatory responses which are linked to various aspects of cancer, like tumor growth, neoangiogenesis, and response to chemotherapy. Ceramide, the central molecule of sphingolipid metabolism, generally mediates antiproliferative and proapoptotic functions, whereas sphingosine-1-phosphate and other derivatives have opposing effects. Among the variety of enzymes that control ceramide generation, acid or neutral sphingomyelinases and ceramide synthases are important targets to allow killing of cancer cells by chemotherapeutic drugs. On the contrary, glucosylceramide synthase, ceramidase, and sphingosine kinase are other targets driving cancer cell resistance to chemotherapy. This chapter focuses on ceramide-based mechanisms leading to cancer therapy sensitization or resistance which could have some impacts on the development of novel cancer therapeutic strategies.
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OUYANG WEN, YANG CHUNXU, ZHANG SIMIN, LIU YU, YANG BO, ZHANG JUNHONG, ZHOU FUXIANG, ZHOU YUNFENG, XIE CONGHUA. Absence of death receptor translocation into lipid rafts in acquired TRAIL-resistant NSCLC cells. Int J Oncol 2012; 42:699-711. [DOI: 10.3892/ijo.2012.1748] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2012] [Accepted: 11/30/2012] [Indexed: 11/05/2022] Open
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Boini KM, Xia M, Abais JM, Xu M, Li CX, Li PL. Acid sphingomyelinase gene knockout ameliorates hyperhomocysteinemic glomerular injury in mice lacking cystathionine-β-synthase. PLoS One 2012; 7:e45020. [PMID: 23024785 PMCID: PMC3443210 DOI: 10.1371/journal.pone.0045020] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Accepted: 08/16/2012] [Indexed: 02/07/2023] Open
Abstract
Acid sphingomyelinase (ASM) has been implicated in the development of hyperhomocysteinemia (hHcys)-induced glomerular oxidative stress and injury. However, it remains unknown whether genetically engineering of ASM gene produces beneficial or detrimental action on hHcys-induced glomerular injury. The present study generated and characterized the mice lacking cystathionine β-synthase (Cbs) and Asm mouse gene by cross breeding Cbs(+/-) and Asm(+/-) mice. Given that the homozygotes of Cbs(-/-/)Asm(-/-) mice could not survive for 3 weeks. Cbs(+/-/)Asm(+/+), Cbs(+/-/)Asm(+/-) and Cbs(+/-/)Asm(-/-) as well as their Cbs wild type littermates were used to study the role of Asm(-/-) under a background of Cbs(+/-) with hHcys. HPLC analysis revealed that plasma Hcys level was significantly elevated in Cbs heterozygous (Cbs(+/-)) mice with different copies of Asm gene compared to Cbs(+/+) mice with different Asm gene copies. Cbs(+/-/)Asm(+/+) mice had significantly increased renal Asm activity, ceramide production and O(2.)(-) level compared to Cbs(+/+)/Asm(+/+), while Cbs(+/-/)Asm(-/-) mice showed significantly reduced renal Asm activity, ceramide production and O(2.)(-) level due to increased plasma Hcys levels. Confocal microscopy demonstrated that colocalization of podocin with ceramide was much lower in Cbs(+/-/)Asm(-/-) mice compared to Cbs(+/-/)Asm(+/+) mice, which was accompanied by a reduced glomerular damage index, albuminuria and proteinuria in Cbs(+/-/)Asm(-/-) mice. Immunofluorescent analyses of the podocin, nephrin and desmin expression also illustrated less podocyte damages in the glomeruli from Cbs(+/-/)Asm(-/-) mice compared to Cbs(+/-/)Asm(+/+) mice. In in vitro studies of podocytes, hHcys-enhanced O(2.)(-) production, desmin expression, and ceramide production as well as decreases in VEGF level and podocin expression in podocytes were substantially attenuated by prior treatment with amitriptyline, an Asm inhibitor. In conclusion, Asm gene knockout or corresponding enzyme inhibition protects the podocytes and glomeruli from hHcys-induced oxidative stress and injury.
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Affiliation(s)
- Krishna M. Boini
- Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Min Xia
- Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Justine M. Abais
- Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Ming Xu
- Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Cai-xia Li
- Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Pin-Lan Li
- Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia, United States of America
- * E-mail:
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38
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Lim BJ, Jeong JY, Chang YK, Na KR, Lee KW, Shin YT, Choi DE. C-phycocyanin attenuates cisplatin-induced nephrotoxicity in mice. Ren Fail 2012; 34:892-900. [PMID: 22681485 DOI: 10.3109/0886022x.2012.690925] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Although cisplatin is a highly effective antineoplastic agent, nephrotoxicity is its major clinical problem. Recently, it was reported that Spirulina, a blue-green algae, has potent antioxidant properties. The aim of this study was to establish the possible protective role of C-phycocyanin (PC), one of the active ingredients of Spirulina, against cisplatin-induced nephrotoxicity. This study was carried out using human kidney-2 (HK-2) cells and male C57BL6 mice. Cells and mice were divided into four groups; untreated control group, PC-treated control group, cisplatin-treated group, and PC plus cisplatin-treated group. The molecular, functional, and structural parameters were measured. PC significantly attenuated blood urea nitrogen, serum creatinine, renal histological damages, and apoptotic cell death in cisplatin-treated mice. The cisplatin-induced cell death was significantly attenuated in cells pretreated with PC. PC also significantly attenuated the elevation of p-ERK, p-JNK, and p-p38 induced by cisplatin treatment. The expression of Bax, caspase-9, and caspase-3 in cisplatin-treated cells were also decreased by PC treatment. In conclusion, PC ameliorates cisplatin-induced nephrotoxicity and, at least in part, suppression of p-ERK, p-JNK, p-p38, Bax, caspase-9, and caspase-3 may be involved in this mechanism.
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Affiliation(s)
- Beom Jin Lim
- Department of Pathology, Chungnam National University Hospital, Daejeon, Korea
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39
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Green tea polyphenol EGCG induces lipid-raft clustering and apoptotic cell death by activating protein kinase Cδ and acid sphingomyelinase through a 67 kDa laminin receptor in multiple myeloma cells. Biochem J 2012; 443:525-34. [DOI: 10.1042/bj20111837] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
EGCG [(−)-epigallocatechin-3-O-gallate], the major polyphenol of green tea, has cancer chemopreventive and chemotherapeutic activities. EGCG selectively inhibits cell growth and induces apoptosis in cancer cells without adversely affecting normal cells; however, the underlying molecular mechanism in vivo is unclear. In the present study, we show that EGCG-induced apoptotic activity is attributed to a lipid-raft clustering mediated through 67LR (67 kDa laminin receptor) that is significantly elevated in MM (multiple myeloma) cells relative to normal peripheral blood mononuclear cells, and that aSMase (acid sphingomyelinase) is critical for the lipid-raft clustering and the apoptotic cell death induced by EGCG. We also found that EGCG induces aSMase translocation to the plasma membrane and PKCδ (protein kinase Cδ) phosphorylation at Ser664, which was necessary for aSMase/ceramide signalling via 67LR. Additionally, orally administered EGCG activated PKCδ and aSMase in a murine MM xenograft model. These results elucidate a novel cell-death pathway triggered by EGCG for the specific killing of MM cells.
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40
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Sakr SA, El-shenawy SM, Al-Shabka AM. Aqueous Fenugreek Seed Extract Ameliorates Adriamycin-Induced Cytotoxicity and Testicular Alterations in Albino Rats. Reprod Sci 2011; 19:70-80. [DOI: 10.1177/1933719111413301] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Saber A. Sakr
- Department of Zoology, Faculty of Science, Menoufia University, Shibin el-Kom, Egypt
| | - Salama M. El-shenawy
- Laboratory Department, Teaching Hospital, Menoufia University, Shebin el-Kom, Egypt
| | - Ahmed M. Al-Shabka
- Department of Zoology, Faculty of Science, Menoufia University, Shibin el-Kom, Egypt
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Li X, Yuan YJ. Lipidomic Analysis of Apoptotic Hela Cells Induced by Paclitaxel. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2011; 15:655-64. [DOI: 10.1089/omi.2011.0027] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- Xia Li
- Key Laboratory of Systems Bioengineering, Ministry of Education and Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, People's Republic of China
| | - Ying-Jin Yuan
- Key Laboratory of Systems Bioengineering, Ministry of Education and Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, People's Republic of China
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42
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Boini KM, Xia M, Li C, Zhang C, Payne LP, Abais JM, Poklis JL, Hylemon PB, Li PL. Acid sphingomyelinase gene deficiency ameliorates the hyperhomocysteinemia-induced glomerular injury in mice. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 179:2210-9. [PMID: 21893018 DOI: 10.1016/j.ajpath.2011.07.019] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2011] [Revised: 07/05/2011] [Accepted: 07/29/2011] [Indexed: 02/06/2023]
Abstract
Hyperhomocysteinemia (hHcys) enhances ceramide production, leading to the activation of NADPH oxidase and consequent glomerular oxidative stress and sclerosis. The present study was performed to determine whether acid sphingomyelinase (Asm), a ceramide-producing enzyme, is implicated in the development of hHcys-induced glomerular oxidative stress and injury. Uninephrectomized Asm-knockout (Asm(-/-)) and wild-type (Asm(+/+)) mice, with or without Asm short hairpin RNA (shRNA) transfection, were fed a folate-free (FF) diet for 8 weeks, which significantly elevated the plasma Hcys level compared with mice fed normal chow. By using in vivo molecular imaging, we found that transfected shRNAs were expressed in the renal cortex starting on day 3 and continued for 24 days. The FF diet significantly increased renal ceramide production, Asm mRNA and activity, urinary total protein and albumin excretion, glomerular damage index, and NADPH-dependent superoxide production in the renal cortex from Asm(+/+) mice compared with that from Asm(-/-) or Asm shRNA-transfected wild-type mice. Immunofluorescence analysis showed that the FF diet decreased the expression of podocin but increased desmin and ceramide levels in glomeruli from Asm(+/+) mice but not in those from Asm(-/-) and Asm shRNA-transfected wild-type mice. In conclusion, our observations reveal that Asm plays a pivotal role in mediating podocyte injury and glomerular sclerosis associated with NADPH oxidase-associated local oxidative stress during hHcys.
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Affiliation(s)
- Krishna M Boini
- Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia, USA
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Truman JP, Al Gadban MM, Smith KJ, Hammad SM. Acid sphingomyelinase in macrophage biology. Cell Mol Life Sci 2011; 68:3293-305. [PMID: 21533981 DOI: 10.1007/s00018-011-0686-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2011] [Revised: 03/28/2011] [Accepted: 04/05/2011] [Indexed: 12/21/2022]
Abstract
Macrophages play a central role in innate immune responses, in disposal of cholesterol, and in tissue homeostasis and remodeling. To perform these vital functions macrophages display high endosomal/lysosomal activities. Recent studies have highlighted that acid sphingomyelinase (ASMase), which generates ceramide from sphingomyelin, is involved in modulation of membrane structures and signal transduction in addition to its metabolic role in the lysosome. In this review, we bring together studies on ASMase, its different forms and locations that are necessary for the macrophage to accomplish its diverse functions. We also address the importance of ASMase to several disease processes that are mediated by activated macrophages.
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Affiliation(s)
- Jean-Philip Truman
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
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44
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Lee JS, Hong EK. Hericium erinaceus enhances doxorubicin-induced apoptosis in human hepatocellular carcinoma cells. Cancer Lett 2010; 297:144-54. [PMID: 20554107 DOI: 10.1016/j.canlet.2010.05.006] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2010] [Revised: 05/04/2010] [Accepted: 05/05/2010] [Indexed: 11/26/2022]
Abstract
It has been demonstrated that the Hericium erinaceus (HE) mushroom, which primarily consists of polysaccharides, possesses anti-tumor activities. However, the mechanisms by which HE inhibits human hepatocellular carcinoma growth remain unknown. Our study demonstrates that HE acts as an enhancer to sensitize doxorubicin (Dox)-mediated apoptotic signaling, and this sensitization can be achieved by reducing c-FLIP expression via JNK activation and enhancing intracellular Dox accumulation via the inhibition of NF-κB activity. These findings suggest that HE in combination with Dox serves as an effective tool for treating drug-resistant human hepatocellular carcinoma.
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Affiliation(s)
- Jong Seok Lee
- Department of Bioengineering and Technology, Kangwon National University, Chuncheon 200-701, Republic of Korea
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Effects of resveratrol on membrane biophysical properties: relevance for its pharmacological effects. Chem Phys Lipids 2010; 163:747-54. [PMID: 20691168 DOI: 10.1016/j.chemphyslip.2010.07.004] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2010] [Revised: 07/05/2010] [Accepted: 07/22/2010] [Indexed: 01/05/2023]
Abstract
The current study gathers a range of spectrophotometric and spectrofluorimetric techniques to systematically monitor the effects of resveratrol (trans-3,5,4'-trihydrostilbene) on the biophysical properties of membrane model systems consisting of unilamellar liposomes of phosphatidylcholine (DPPC) with the ultimate goal of relating these effects with some of the well documented pharmacological properties of this compound, and clarifying some controversial results reported on the literature. Physiological conditions have been pursued, such as a buffered pH control with adjusted ionic strength similar to the blood plasma conditions (pH 7.4, I=0.1M) and the study at different membrane physical states (gel phase and fluid phase) for the assessment of resveratrol-membrane: aqueous partition coefficient by derivative spectroscopy. Results obtained by fluorescence quenching and anisotropy studies indicate that resveratrol has a membrane fluidizing effect and is able to permeate the membrane even in the gel phase. These results mirror the well described antioxidant effect of resveratrol, since antioxidants have to reach peroxidised rigid membranes and increase membrane fluidity in order to interact more efficiently with lipid radicals in the disordered lipid bilayer. Location of resveratrol pointed also to a membrane distribution that is favourable for scavenging the lipid radicals and was elucidated using probes positioned at different membrane depths suggesting that this compound penetrates into the acyl membrane region but also positions its polar hydroxyl group near the headgroup region of the membrane.
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46
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Camano S, Lazaro A, Moreno-Gordaliza E, Torres AM, de Lucas C, Humanes B, Lazaro JA, Milagros Gomez-Gomez M, Bosca L, Tejedor A. Cilastatin attenuates cisplatin-induced proximal tubular cell damage. J Pharmacol Exp Ther 2010; 334:419-429. [PMID: 20435919 DOI: 10.1124/jpet.110.165779] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
A major area in cancer therapy is the search for protective strategies against cisplatin-induced nephrotoxicity. We investigated the protective effect of cilastatin on cisplatin-induced injury to renal proximal tubular cells. Cilastatin is a specific inhibitor of renal dehydrodipeptidase I (DHP-I), which prevents hydrolysis of imipenem and its accumulation in the proximal tubule. Primary cultures of proximal cells were treated with cisplatin (1-30 microM) in the presence or absence of cilastatin (200 microg/ml). Apoptosis and mitochondrial injury were assessed by different techniques. Cisplatin uptake and DNA binding were measured by inductively coupled plasma spectrometry. HeLa cells were used to control the effect of cilastatin on the tumoricidal activity of cisplatin. Cisplatin increased cell death, apoptotic-like morphology, caspase activation, and mitochondrial injury in proximal tubular cells in a dose- and time-dependent way. Concomitant treatment with cilastatin reduced cisplatin-induced changes. Cilastatin also reduced the DNA-bound platinum but did not modify cisplatin-dependent up-regulation of death receptors (Fas) or ligands (tumor necrosis factor alpha, Fas ligand). In contrast, cilastatin did not show any effects on cisplatin-treated HeLa cells. Renal DHP-I was virtually absent in HeLa cells. Cilastatin attenuates cisplatin-induced cell death in proximal tubular cells without reducing the cytotoxic activity of cisplatin in tumor cells. Our findings suggest that the affinity of cilastatin for renal dipeptidase makes this effect specific for proximal tubular cells and may be related to a reduction in intracellular drug accumulation. Therefore, cilastatin administration might represent a novel strategy in the prevention of cisplatin-induced acute renal injury.
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Affiliation(s)
- Sonia Camano
- Renal Physiopathology Laboratory, Department of Nephrology, Hospital General Universitario Gregorio Maranon, 28007 Madrid, Spain
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Pozuelo-Rubio M. Proteomic and biochemical analysis of 14-3-3-binding proteins during C2-ceramide-induced apoptosis. FEBS J 2010; 277:3321-42. [DOI: 10.1111/j.1742-4658.2010.07730.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Brozovic A, Ambriović-Ristov A, Osmak M. The relationship between cisplatin-induced reactive oxygen species, glutathione, and BCL-2 and resistance to cisplatin. Crit Rev Toxicol 2010; 40:347-59. [PMID: 20163198 DOI: 10.3109/10408441003601836] [Citation(s) in RCA: 190] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Cisplatin (cDDP) is an anticancer agent that is widely used in the treatment of many solid tumors. A major obstacle to successful cDDP-based chemotherapy, however, is the intrinsic and acquired resistance of tumor cells to this drug. Greater insight into the molecular mechanisms underlying the modulation of cellular responses to cDDP will aid in the development and optimization of new therapeutic strategies. Apart from induction of DNA damage, recent data have suggested that cDDP also induces the formation of reactive oxygen species that can trigger cell death. Cell death occurs as the result of several simultaneously activated signaling pathways. The specific pathway responsible for cell death depends on the cell type and the treatment conditions. This review focuses on the relationship between glutathione and BCL-2 and their protective role in cDDP-induced reactive oxygen species formation and cDDP resistance.
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Affiliation(s)
- Anamaria Brozovic
- Laboratory for Genotoxic Agents, Division of Molecular Biology, Rudjer Boskovic Institute, Zagreb, Croatia.
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Abdel-Hamid NM, Morsy MA. Novel biochemical pathways for 5-Fluorouracil in managing experimental hepatocellular carcinoma in rats. J Membr Biol 2010; 234:29-34. [PMID: 20177669 DOI: 10.1007/s00232-010-9236-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2009] [Accepted: 01/26/2010] [Indexed: 11/28/2022]
Abstract
Five fluorouracil (5-FU) is extensively used in the treatment of hepatocellular carcinoma (HCC). It is well documented that 5-FU and its metabolites inhibit DNA synthesis through inhibition of thymidylate synthetase. Little is known about additional pathways for 5-FU in managing HCC. The present experiment was mainly designed to study possible biochemical pathways that can be added to 5-FU's mechanisms of action. Four groups of rats constituted a control group (given saline only), a trichloroacetic acid group (TCA, 0.5 g/kg/day for 5 days, orally), a 5-FU-positive group (75 mg/kg body weight, intraperitoneally, once weekly for 3 weeks) and a TCA-treated with 5-FU group (24 h from last TCA dose). We executed both biochemical-serum alpha-fetoprotein (AFP), liver tissue contents of total glycosaminoglycan (TGAGs), collagen (represented as hydroxyproline), total sialic acid (TSA), free glucosamine (FGA) and proteolytic enzyme activity (as pepsin and free cathepsin-D-and histological examinations of the liver tissue. The results revealed histological changes such as central vein congestion and irregularly shaped, substantially enlarged, vesiculated and binucleated hepatocytes. The nuclei were mostly polymorphic and hyperchromatic, and several vacuolation was noticed in the cytoplasm encircling the nucleus with masses of acidophilic material. 5-FU greatly corrected these changes, except that some necrotic and cytotoxic effects of 5-FU were still shown. AFP was significantly elevated in TCA-intoxicated, but reversed in 5-FU-treated, groups. Increased proteolytic activity by TCA was reversed by 5-FU, which also restored TGAG contents to normal; but both TCA and 5-FU depleted collagen content. TCA significantly elevated FGA but depressed TSA; this action was reversed by 5-FU treatment. In conclusion, it is possible that proteolytic activity, expressed as upregulated pepsin and free cathepsin-D activities, is increased in HCC. This is accompanied by extracellular matrix macromolecular disturbance, manifested as decreased TGAGs, collagen and TSA, with marked increase in FGA liver tissue content. The elevated FGA with depressed TSA content of liver tissue may be attributed to a cancer-hampered N-acetylation of FGA into SA. 5-FU administration markedly depressed hepatic tissue proteolysis, possibly reactivated N-acetylation of FGA into SA and elevated TGAGs without stopping tissue fibrosis as collagen was not affected. This study explores additional pathways for the mechanism of action of 5-FU, through conservation of extracellular matrix composition in situ, inhibiting invasion and metastasis in addition to its DNA-disturbing pathway.
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Affiliation(s)
- Nabil M Abdel-Hamid
- Department of Biochemistry, College of Pharmacy, Minia University, Minia, Egypt.
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Sebai H, Hovsépian S, Ristorcelli E, Aouani E, Lombardo D, Fayet G. Resveratrol increases iodide trapping in the rat thyroid cell line FRTL-5. Thyroid 2010; 20:195-203. [PMID: 20151827 DOI: 10.1089/thy.2009.0171] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Resveratrol, a polyphenol found in grapes, exhibits several beneficial health effects by its antioxidant, antiinflammatory, and chemopreventive properties. The aim of the present study was to determine the effect of resveratrol on iodide trapping and efflux as well as its mode of action using FRTL-5 cells, having in mind the pivotal role of the natrium iodide symporter (NIS) in the treatment of differentiated thyroid cancers. METHODS Cells were treated with resveratrol for various times and doses, in the presence or absence of thyrotropin (TSH). Iodide trapping, iodide efflux, rat NIS (rNIS) protein expression, and cyclic AMP (cAMP) production were evaluated. RESULTS Resveratrol increased iodide trapping in a time-dependent (optimal 6 hours) and dose-dependent (100 microM) way in the presence of TSH. It showed an additive effect when concomitantly added with an optimal dose of TSH. Resveratrol (50 microM) increased (threefold) rNIS protein expression. In TSH-deprived cells, resveratrol also provoked an increase in rNIS protein (>3-fold in 6 hours) with an optimum at 40 microM. Resveratrol did not inhibit iodide efflux from FRTL-5 cells. It neither increased intracellular cAMP nor induced the arborization of living cells, two TSH-induced effects. A non-cAMP mode of action is highly suspected. CONCLUSIONS Resveratrol increases iodide trapping in FRTL-5 cells, increasing iodide influx and rNIS protein level even in the absence of TSH. It has an additive effect with TSH. Consequently, resveratrol could be a promising molecule for radioiodide therapy in follicular and papillary differentiated thyroid carcinoma in association with recombinant human TSH.
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Affiliation(s)
- Hichem Sebai
- INSERM UMR-911 and Research Center in Biological and Oncopharmacological Oncology (CrO2), School of Medicine-Timone, Aix-Marseille University, France
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