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Alzahrani SM, Al Doghaither HA, Alkhatabi HA, Basabrain MA, Pushparaj PN. Propranolol and Capecitabine Synergy on Inducing Ferroptosis in Human Colorectal Cancer Cells: Potential Implications in Cancer Therapy. Cancers (Basel) 2025; 17:1470. [PMID: 40361395 PMCID: PMC12071015 DOI: 10.3390/cancers17091470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 04/17/2025] [Accepted: 04/19/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND/OBJECTIVES Colorectal cancer (CRC) is a significant global health issue with rising incidence and mortality rates. In oncology, drug repurposing has emerged as a promising therapeutic strategy in conjunction with conventional treatments. This study aimed to evaluate the potential of repurposing propranolol (PRO), a beta blocker, for the treatment of CRC cell lines (HCT-116 and HT-29), both as a monotherapy and in combination with capecitabine (CAP). METHODS Effects of mono- and combination therapies on viability, combination index, morphology, and cell death induction of CRC cells were assessed. Transcriptome analysis of HT-29 cells was performed using RNA sequencing. Metabolite profiling was conducted, and changes in biochemical parameters were evaluated using flow cytometry and biochemical analyses. RESULTS The combination index showed that HT-29 cells were the most responsive to the combined treatment, even with PIK3CA, B-RAF (V600E), and TP53 mutations. Moreover, ferroptosis was synergistically activated in the combined group of HT-29 in comparison to control. Furthermore, we observed an increase in OXPHOS metabolites, along with elevated intracellular and mitochondrial ROS, disruption of mitochondrial membrane potential, and greater levels of malondialdehyde (MDA) in the HT-29 combined group, which are the features of ferroptosis. Furthermore, ferroptosis induction was coupled with necroptosis, as indicated by RNA-sequencing data. Combination therapy inhibited cell migration and enhanced the immune response of HT-29 cells. CONCLUSIONS These findings suggest that PRO is promising as a potential adjuvant therapy in combination with CAP for the treatment of CRC. Only HT-29 cells with the B-RAF (V600E) mutation showed promising findings in this study.
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Affiliation(s)
- Shiekhah Mohammad Alzahrani
- Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah P.O. Box 21589, Saudi Arabia
- Institute of Genomic Medicine Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah P.O. Box 21589, Saudi Arabia
| | | | - Hind Ali Alkhatabi
- Department of Biological Science, College of Science, University of Jeddah, Jeddah P.O. Box 21589, Saudi Arabia
| | - Mohammad Abdullah Basabrain
- Institute of Genomic Medicine Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah P.O. Box 21589, Saudi Arabia
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah P.O. Box 21589, Saudi Arabia
| | - Peter Natesan Pushparaj
- Institute of Genomic Medicine Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah P.O. Box 21589, Saudi Arabia
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah P.O. Box 21589, Saudi Arabia
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2
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Huang X, Ali A, Yachioui DEI, Le Dévédec SE, Hankemeier T. Lipid dysregulation in triple negative breast cancer: Insights from mass spectrometry-based approaches. Prog Lipid Res 2025; 98:101330. [PMID: 39914749 DOI: 10.1016/j.plipres.2025.101330] [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: 09/05/2024] [Revised: 02/02/2025] [Accepted: 02/03/2025] [Indexed: 02/10/2025]
Abstract
Triple negative breast cancer (TNBC) has the worst prognosis among breast cancers due to its aggressive nature and the absence of targeted treatments. Development of novel anti-cancer drugs for TNBC faces challenges stemming from its heterogeneity and high potential for metastasis. Metabolomics can be a useful technology in finding novel therapeutic targets and probing the heterogeneity of TNBC. Metabolomics has been enabled by advancements in mass spectrometry (MS)-based platforms that facilitated comprehensive profiling of TNBC metabolism. This review provides an overview of metabolomic changes in TNBC with emphasis on lipid alterations, and describes the key MS analytical techniques, providing the necessary background for examining the role of lipids in TNBC development.
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Affiliation(s)
- Xiaoyue Huang
- Metabolomics and Analytics Center, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands
| | - Ahmed Ali
- Metabolomics and Analytics Center, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands.
| | - Dounia E I Yachioui
- Metabolomics and Analytics Center, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands
| | - Sylvia E Le Dévédec
- Division of Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands.
| | - Thomas Hankemeier
- Metabolomics and Analytics Center, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands
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3
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Rees SWP, Rees TA, Paulin EK, Arnerich OR, Leung E, Walker CS, Barker D, Pilkington LI. Structure-activity relationship expansion and microsomal stability assessment of the 2-morpholinobenzoic acid scaffold as antiproliferative phosphatidylcholine-specific phospholipase C inhibitors. RSC Med Chem 2025:d4md00831f. [PMID: 39823042 PMCID: PMC11734694 DOI: 10.1039/d4md00831f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 12/29/2024] [Indexed: 01/19/2025] Open
Abstract
Dysregulation of choline phospholipid metabolism and overexpression of phosphatidylcholine-specific phospholipase C (PC-PLC) is implicated in various cancers. Current known enzyme inhibitors include compounds based on a 2-morpholino-5-N-benzylamino benzoic acid, or hydroxamic acid, scaffold. In this work, 81 compounds were made by modifying this core structure to explore the pharmacophore. Specifically, these novel compounds result from changes to the central ring substitution pattern, alkyl heterocycle and methylation of the N-benzyl bridge. The anti-proliferative activity of the synthesised compounds was assessed against cancer cell lines MDA-MB-231 and HCT116. PC-PLCBC enzyme inhibition was also assessed, and the development of a pharmacokinetic profile was initiated using a microsomal stability assay. The findings confirmed the optimal pharmacophore as a 2-morpholino-5-N-benzylamino benzoic acid, or acid derivative, scaffold, and that this family of molecules demonstrate a high degree of stability following treatment with rat microsomes. Additionally, benzylic N-methylated compounds were the most biologically active compounds, encouraging further investigation into this region of the pharmacophore.
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Affiliation(s)
- Shaun W P Rees
- School of Chemical Sciences, University of Auckland Auckland 1010 New Zealand
| | - Tayla A Rees
- School of Biological Sciences, University of Auckland Auckland 1010 New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland Auckland 1010 New Zealand
| | - Emily K Paulin
- School of Chemical Sciences, University of Auckland Auckland 1010 New Zealand
| | - Olivia R Arnerich
- School of Chemical Sciences, University of Auckland Auckland 1010 New Zealand
- The MacDiarmid Institute for Advanced Materials and Nanotechnology Wellington New Zealand
| | - Euphemia Leung
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland Auckland 1010 New Zealand
- Auckland Cancer Society Research Centre, University of Auckland Grafton Auckland 1023 New Zealand
| | - Christopher S Walker
- School of Biological Sciences, University of Auckland Auckland 1010 New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland Auckland 1010 New Zealand
| | - David Barker
- School of Chemical Sciences, University of Auckland Auckland 1010 New Zealand
- The MacDiarmid Institute for Advanced Materials and Nanotechnology Wellington New Zealand
| | - Lisa I Pilkington
- School of Chemical Sciences, University of Auckland Auckland 1010 New Zealand
- Te Pūnaha Matatini Auckland 1142 New Zealand
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4
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Chen S, Tang Q, Hu M, Song S, Wu X, Zhou Y, Yang Z, Liao S, Zhou L, Wang Q, Liu H, Yang M, Chen Z, Zhao W, He S, Zhou Z. Loss of Carbamoyl Phosphate Synthetase 1 Potentiates Hepatocellular Carcinoma Metastasis by Reducing Aspartate Level. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2402703. [PMID: 39387452 PMCID: PMC11615744 DOI: 10.1002/advs.202402703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 09/01/2024] [Indexed: 10/15/2024]
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. Numerous studies have shown that metabolic reprogramming is crucial for the development of HCC. Carbamoyl phosphate synthase 1 (CPS1), a rate-limiting enzyme in urea cycle, is an abundant protein in normal hepatocytes, however, lacking systemic research in HCC. It is found that CPS1 is low-expressed in HCC tissues and circulating tumor cells, negatively correlated with HCC stage and prognosis. Further study reveals that CPS1 is a double-edged sword. On the one hand, it inhibits the activity of phosphatidylcholine-specific phospholipase C to block the biosynthesis of diacylglycerol (DAG), leading to the downregulation of the DAG/protein kinase C pathway to inhibit invasion and metastasis of cancer cells. On the other hand, CPS1 promotes cell proliferation by increasing intracellular S-adenosylmethionin to enhance the m6A modification of solute carrier family 1 member 3 mRNA, a key transporter for aspartate intake. Finally, CPS1 overexpressing adeno-associated virus can dampen HCC progression. Collectively, this results uncovered that CPS1 is a switch between HCC proliferation and metastasis by increasing intracellular aspartate level.
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Affiliation(s)
- Siyuan Chen
- Department of GastroenterologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqing400010China
| | - Qin Tang
- Department of GastroenterologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqing400010China
| | - Manqiu Hu
- Department of GastroenterologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqing400010China
| | - Sijie Song
- Department of GastroenterologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqing400010China
| | - Xiaohong Wu
- Department of GastroenterologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqing400010China
| | - You Zhou
- Department of GastroenterologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqing400010China
| | - Zihan Yang
- Department of Biomedical Sciencesand Tung Biomedical Sciences CenterCity University of Hong Kong83 Tat Chee AvenueKowloonHong Kong SAR999077P. R. China
| | - Siqi Liao
- Department of GastroenterologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqing400010China
| | - Li Zhou
- Department of GastroenterologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqing400010China
| | - Qingliang Wang
- Department of PathologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqing400010China
| | - Hongtao Liu
- Department of GastroenterologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqing400010China
| | - Mengsu Yang
- Department of Biomedical Sciencesand Tung Biomedical Sciences CenterCity University of Hong Kong83 Tat Chee AvenueKowloonHong Kong SAR999077P. R. China
| | - Zhe‐Sheng Chen
- Department of Pharmaceutical SciencesInstitute for BiotechnologyCollege of Pharmacy and Health SciencesSt. John's UniversityQueensNY11439USA
| | - Wei Zhao
- School of Clinical MedicineThe First Affiliated HospitalChengdu Medical CollegeSichuan610500P. R. China
- Department of Clinical BiochemistrySchool of Laboratory MedicineChengdu Medical CollegeSichuan610500P. R. China
| | - Song He
- Department of GastroenterologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqing400010China
| | - Zhihang Zhou
- Department of GastroenterologyThe Second Affiliated Hospital of Chongqing Medical UniversityChongqing400010China
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Zhen W, Germanas T, Weichselbaum RR, Lin W. Multifunctional Nanomaterials Mediate Cholesterol Depletion for Cancer Treatment. Angew Chem Int Ed Engl 2024; 63:e202412844. [PMID: 39146242 PMCID: PMC11534517 DOI: 10.1002/anie.202412844] [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: 07/08/2024] [Revised: 08/02/2024] [Accepted: 08/14/2024] [Indexed: 08/17/2024]
Abstract
Cholesterol is an essential membrane component, and the metabolites from cholesterol play important biological functions to intricately support cancer progression and dampen immune responses. Preclinical and clinical studies have demonstrated the role of cholesterol metabolism regulation on inhibiting tumor growth, remodeling the immunosuppressive tumor microenvironment (TME), and enhancing anti-tumor immunity. In this minireview, we discuss complex cholesterol metabolism in tumors, its important role in cancer progression, and its influences on immune cells in the TME. We provide an overview of recent advances in cancer treatment through regulating cholesterol metabolism. We discuss the design of cholesterol-altering multifunctional nanomaterials to regulate oxidative stress, modulate immune checkpoints, manipulate mechanical stress responses, and alter cholesterol metabolic pathways. Additionally, we examine the interactions between cholesterol metabolism regulation and established cancer treatments with the aim of identifying efficient strategies to disrupt cholesterol metabolism and synergistic combination therapies for effective cancer treatment.
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Affiliation(s)
- Wenyao Zhen
- Department of Chemistry, The University of Chicago, Chicago, Illinois, 60637, United States
- Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois, 60637, United States
| | - Tomas Germanas
- Department of Chemistry, The University of Chicago, Chicago, Illinois, 60637, United States
| | - Ralph R Weichselbaum
- Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois, 60637, United States
| | - Wenbin Lin
- Department of Chemistry, The University of Chicago, Chicago, Illinois, 60637, United States
- Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois, 60637, United States
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Jin HR, Wang J, Wang ZJ, Xi MJ, Xia BH, Deng K, Yang JL. Lipid metabolic reprogramming in tumor microenvironment: from mechanisms to therapeutics. J Hematol Oncol 2023; 16:103. [PMID: 37700339 PMCID: PMC10498649 DOI: 10.1186/s13045-023-01498-2] [Citation(s) in RCA: 129] [Impact Index Per Article: 64.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 08/29/2023] [Indexed: 09/14/2023] Open
Abstract
Lipid metabolic reprogramming is an emerging hallmark of cancer. In order to sustain uncontrolled proliferation and survive in unfavorable environments that lack oxygen and nutrients, tumor cells undergo metabolic transformations to exploit various ways of acquiring lipid and increasing lipid oxidation. In addition, stromal cells and immune cells in the tumor microenvironment also undergo lipid metabolic reprogramming, which further affects tumor functional phenotypes and immune responses. Given that lipid metabolism plays a critical role in supporting cancer progression and remodeling the tumor microenvironment, targeting the lipid metabolism pathway could provide a novel approach to cancer treatment. This review seeks to: (1) clarify the overall landscape and mechanisms of lipid metabolic reprogramming in cancer, (2) summarize the lipid metabolic landscapes within stromal cells and immune cells in the tumor microenvironment, and clarify their roles in tumor progression, and (3) summarize potential therapeutic targets for lipid metabolism, and highlight the potential for combining such approaches with other anti-tumor therapies to provide new therapeutic opportunities for cancer patients.
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Affiliation(s)
- Hao-Ran Jin
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, No.37 Guoxue Road, Wuhou District, Chengdu, 610041, China
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Jin Wang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, No.37 Guoxue Road, Wuhou District, Chengdu, 610041, China
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Zi-Jing Wang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, No.37 Guoxue Road, Wuhou District, Chengdu, 610041, China
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Ming-Jia Xi
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, No.37 Guoxue Road, Wuhou District, Chengdu, 610041, China
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Bi-Han Xia
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, No.37 Guoxue Road, Wuhou District, Chengdu, 610041, China
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Kai Deng
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, No.37 Guoxue Road, Wuhou District, Chengdu, 610041, China.
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
| | - Jin-Lin Yang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, No.37 Guoxue Road, Wuhou District, Chengdu, 610041, China.
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
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Mondal S, Sthanikam Y, Kumar A, Nandy A, Chattopadhyay S, Koner D, Rukmangadha N, Narendra H, Banerjee S. Mass Spectrometry Imaging of Lumpectomy Specimens Deciphers Diacylglycerols as Potent Biomarkers for the Diagnosis of Breast Cancer. Anal Chem 2023; 95:8054-8062. [PMID: 37167069 DOI: 10.1021/acs.analchem.3c01019] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/13/2023]
Abstract
Detecting breast tumor markers with a fast turnaround time from frozen sections should foster intraoperative histopathology in breast-conserving surgery, reducing the need for a second operation. Hence, rapid label-free discrimination of the spatially resolved molecular makeup between cancer and adjacent normal breast tissue is of growing importance. We performed desorption electrospray ionization mass spectrometry imaging (DESI-MSI) of fresh-frozen excision specimens, including cancer and paired adjacent normal sections, obtained from the lumpectomy of 73 breast cancer patients. The results demonstrate that breast cancer tissue posits sharp metabolic upregulation of diacylglycerol, a lipid second messenger that activates protein kinase C for promoting tumor growth. We identified four specific sn-1,2-diacylglycerols that outperformed all other lipids simultaneously mapped by the positive ion mode DESI-MSI for distinguishing cancers from adjacent normal specimens. This result contrasts with several previous DESI-MSI studies that probed metabolic dysregulation of glycerophospholipids, sphingolipids, and free fatty acids for cancer diagnoses. A random forest-based supervised machine learning considering all detected ion signals also deciphered the highest diagnostic potential of these four diacylglycerols with the top four importance scores. This led us to construct a classifier with 100% overall prediction accuracy of breast cancer by using the parsimonious set of four diacylglycerol biomarkers only. The metabolic pathway analysis suggested that increased catabolism of phosphatidylcholine in breast cancer contributes to diacylglycerol overexpression. These results open up opportunities for mapping diacylglycerol signaling in breast cancer in the context of novel therapeutic and diagnostic developments, including the intraoperative assessment of breast cancer margin status.
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Affiliation(s)
- Supratim Mondal
- Department of Chemistry, Indian Institute of Science Education and Research Tirupati, Tirupati 517507, India
| | - Yeswanth Sthanikam
- Department of Chemistry, Indian Institute of Science Education and Research Tirupati, Tirupati 517507, India
| | - Anubhav Kumar
- Department of Chemistry, Indian Institute of Science Education and Research Tirupati, Tirupati 517507, India
| | - Abhijit Nandy
- Department of Chemistry, Indian Institute of Science Education and Research Tirupati, Tirupati 517507, India
| | - Sutirtha Chattopadhyay
- Department of Chemistry, Indian Institute of Science Education and Research Tirupati, Tirupati 517507, India
| | - Debasish Koner
- Department of Chemistry, Indian Institute of Science Education and Research Tirupati, Tirupati 517507, India
| | - Nandyala Rukmangadha
- Department of Pathology, Sri Venkateswara Institute of Medical Sciences, Tirupati 517507, India
| | - Hulikal Narendra
- Department of Surgical Oncology, Sri Venkateswara Institute of Medical Sciences, Tirupati 517507, India
| | - Shibdas Banerjee
- Department of Chemistry, Indian Institute of Science Education and Research Tirupati, Tirupati 517507, India
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Nasrollahpour H, Khalilzadeh B, Hasanzadeh M, Rahbarghazi R, Estrela P, Naseri A, Tasoglu S, Sillanpää M. Nanotechnology‐based electrochemical biosensors for monitoring breast cancer biomarkers. Med Res Rev 2022; 43:464-569. [PMID: 36464910 DOI: 10.1002/med.21931] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 10/01/2022] [Accepted: 11/04/2022] [Indexed: 12/07/2022]
Abstract
Breast cancer is categorized as the most widespread cancer type among women globally. On-time diagnosis can decrease the mortality rate by making the right decision in the therapy procedure. These features lead to a reduction in medication time and socioeconomic burden. The current review article provides a comprehensive assessment for breast cancer diagnosis using nanomaterials and related technologies. Growing use of the nano/biotechnology domain in terms of electrochemical nanobiosensor designing was discussed in detail. In this regard, recent advances in nanomaterial applied for amplified biosensing methodologies were assessed for breast cancer diagnosis by focusing on the advantages and disadvantages of these approaches. We also monitored designing methods, advantages, and the necessity of suitable (nano) materials from a statistical standpoint. The main objective of this review is to classify the applicable biosensors based on breast cancer biomarkers. With numerous nano-sized platforms published for breast cancer diagnosis, this review tried to collect the most suitable methodologies for detecting biomarkers and certain breast cancer cell types.
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Affiliation(s)
- Hassan Nasrollahpour
- Department of Analytical Chemistry, Faculty of Chemistry University of Tabriz Tabriz Iran
| | - Balal Khalilzadeh
- Stem Cell Research Center Tabriz University of Medical Sciences Tabriz Iran
| | - Mohammad Hasanzadeh
- Pharmaceutical Analysis Research Center Tabriz University of Medical Sciences Tabriz Iran
| | - Reza Rahbarghazi
- Stem Cell Research Center Tabriz University of Medical Sciences Tabriz Iran
- Department of Applied Cellular Sciences, Faculty of Advanced Medical Sciences Tabriz University of Medical Sciences Tabriz Iran
| | - Pedro Estrela
- Centre for Biosensors, Bioelectronics and Biodevices (C3Bio) and Department of Electronic and Electrical Engineering University of Bath Bath UK
| | - Abdolhossein Naseri
- Department of Analytical Chemistry, Faculty of Chemistry University of Tabriz Tabriz Iran
| | - Savas Tasoglu
- Koç University Translational Medicine Research Center (KUTTAM) Rumeli Feneri, Sarıyer Istanbul Turkey
| | - Mika Sillanpää
- Environmental Engineering and Management Research Group Ton Duc Thang University Ho Chi Minh City Vietnam
- Faculty of Environment and Labour Safety Ton Duc Thang University Ho Chi Minh City Vietnam
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9
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Dadhich R, Kapoor S. Lipidomic and Membrane Mechanical Signatures in Triple-Negative Breast Cancer: Scope for Membrane-Based Theranostics. Mol Cell Biochem 2022; 477:2507-2528. [PMID: 35595957 DOI: 10.1007/s11010-022-04459-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 04/28/2022] [Indexed: 10/18/2022]
Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer associated with poor prognosis, higher grade, and a high rate of metastatic occurrence. Limited therapeutic interventions and the compounding issue of drug resistance in triple-negative breast cancer warrants the discovery of novel therapeutic targets and diagnostic modules. To this view, in addition to proteins, lipids also regulate cellular functions via the formation of membranes that modulate membrane protein function, diffusion, and their localization; thus, orchestrating signaling hot spots enriched in specific lipids/proteins on cell membranes. Lipid deregulation in cancer leads to reprogramming of the membrane dynamics and functions impacting cell proliferation, metabolism, and metastasis, providing exciting starting points for developing lipid-based approaches for treating TNBC. In this review, we provide a detailed account of specific lipidic changes in breast cancer, link the altered lipidome with membrane structure and mechanical properties, and describe how these are linked to subsequent downstream functions implicit in cancer progression, metastasis, and chemoresistance. At the fundamental level, we discuss how the lipid-centric findings in TNBC are providing cues for developing lipid-inspired theranostic strategies while bridging existing gaps in our understanding of the functional involvement of lipid membranes in cancer.
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Affiliation(s)
- Ruchika Dadhich
- Department of Chemistry, Indian Institute of Technology Bombay, Mumbai, 400076, India
| | - Shobhna Kapoor
- Department of Chemistry, Indian Institute of Technology Bombay, Mumbai, 400076, India. .,Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, 739-8528, Japan.
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10
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Saito RDF, Andrade LNDS, Bustos SO, Chammas R. Phosphatidylcholine-Derived Lipid Mediators: The Crosstalk Between Cancer Cells and Immune Cells. Front Immunol 2022; 13:768606. [PMID: 35250970 PMCID: PMC8889569 DOI: 10.3389/fimmu.2022.768606] [Citation(s) in RCA: 94] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 01/13/2022] [Indexed: 01/16/2023] Open
Abstract
To become resistant, cancer cells need to activate and maintain molecular defense mechanisms that depend on an energy trade-off between resistance and essential functions. Metabolic reprogramming has been shown to fuel cell growth and contribute to cancer drug resistance. Recently, changes in lipid metabolism have emerged as an important driver of resistance to anticancer agents. In this review, we highlight the role of choline metabolism with a focus on the phosphatidylcholine cycle in the regulation of resistance to therapy. We analyze the contribution of phosphatidylcholine and its metabolites to intracellular processes of cancer cells, both as the major cell membrane constituents and source of energy. We further extended our discussion about the role of phosphatidylcholine-derived lipid mediators in cellular communication between cancer and immune cells within the tumor microenvironment, as well as their pivotal role in the immune regulation of therapeutic failure. Changes in phosphatidylcholine metabolism are part of an adaptive program activated in response to stress conditions that contribute to cancer therapy resistance and open therapeutic opportunities for treating drug-resistant cancers.
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Affiliation(s)
- Renata de Freitas Saito
- Centro de Investigação Translacional em Oncologia (LIM24), Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo and Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil
| | - Luciana Nogueira de Sousa Andrade
- Centro de Investigação Translacional em Oncologia (LIM24), Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo and Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil
| | - Silvina Odete Bustos
- Centro de Investigação Translacional em Oncologia (LIM24), Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo and Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil
| | - Roger Chammas
- Centro de Investigação Translacional em Oncologia (LIM24), Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo and Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil
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11
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Calvillo-Rodríguez KM, Mendoza-Reveles R, Gómez-Morales L, Uscanga-Palomeque AC, Karoyan P, Martínez-Torres AC, Rodríguez-Padilla C. PKHB1, a thrombospondin-1 peptide mimic, induces anti-tumor effect through immunogenic cell death induction in breast cancer cells. Oncoimmunology 2022; 11:2054305. [PMID: 35402082 PMCID: PMC8986196 DOI: 10.1080/2162402x.2022.2054305] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death in women worldwide. Recent advances in the field of immuno-oncology demonstrate the beneficial immunostimulatory effects of the induction of immunogenic cell death (ICD). ICD increases tumor infiltration by T cells and is associated with improved prognosis in patients affected by triple negative breast cancer (TNBC) with residual disease. The aim of this study was to evaluate the antitumoral effect of PKHB1, a thrombospondin-1 peptide mimic, against breast cancer cells, and the immunogenicity of the cell death induced by PKHB1 in vitro, ex vivo, and in vivo. Our results showed that PKHB1 induces mitochondrial alterations, ROS production, intracellular Ca2+ accumulation, as well calcium-dependent cell death in breast cancer cells, including triple negative subtypes. PKHB1 has antitumor effect in vivo leading to a reduction of tumor volume and weight and promotes intratumoral CD8 + T cell infiltration. Furthermore, in vitro, PKHB1 induces calreticulin (CALR), HSP70, and HSP90 exposure and release of ATP and HMGB1. Additionally, the killed cells obtained after treatment with PKHB1 (PKHB1-KC) induced dendritic cell maturation, and T cell antitumor responses, ex vivo. Moreover, PKHB1-KC in vivo were able to induce an antitumor response against breast cancer cells in a prophylactic application, whereas in a therapeutic setting, PKHB1-KC induced tumor regression; both applications induced a long-term antitumor response. Altogether our data shows that PKHB1, a thrombospondin-1 peptide mimic, has in vivo antitumor effect and induce immune system activation through immunogenic cell death induction in breast cancer cells.
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Affiliation(s)
- Kenny Misael Calvillo-Rodríguez
- Facultad de Ciencias Biologicas, Laboratorio de Inmunología y Virología, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, Mexico
- Sorbonne Université, Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM, 75005 Paris, France
- Sorbonne Université, Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, DRUG Lab, Site OncoDesign, 25-27 Avenue du Québec, 91140 Les Ulis, France
| | - Rodolfo Mendoza-Reveles
- Facultad de Ciencias Biologicas, Laboratorio de Inmunología y Virología, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, Mexico
| | - Luis Gómez-Morales
- Facultad de Ciencias Biologicas, Laboratorio de Inmunología y Virología, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, Mexico
- Sorbonne Université, Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM, 75005 Paris, France
- Sorbonne Université, Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, DRUG Lab, Site OncoDesign, 25-27 Avenue du Québec, 91140 Les Ulis, France
- Kaybiotix, GmbH, Zugerstrasse 32, 6340 Baar, Switzerland
| | | | - Philippe Karoyan
- Sorbonne Université, Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM, 75005 Paris, France
- Sorbonne Université, Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, DRUG Lab, Site OncoDesign, 25-27 Avenue du Québec, 91140 Les Ulis, France
- Kaybiotix, GmbH, Zugerstrasse 32, 6340 Baar, Switzerland
- Kayvisa, AG, Industriestrasse, 44, 6300 Zug, Switzerland
- χ-Pharma, 25 Avenue du Québec, 91140 Les Ulis, France
| | - Ana Carolina Martínez-Torres
- Facultad de Ciencias Biologicas, Laboratorio de Inmunología y Virología, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, Mexico
| | - Cristina Rodríguez-Padilla
- Facultad de Ciencias Biologicas, Laboratorio de Inmunología y Virología, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, Mexico
- LONGEVEDEN SA de CV, Monterrey, Mexico
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12
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Bhat AH, Dar KB, Khan A, Alshahrani S, Alshehri SM, Ghoneim MM, Alam P, Shakeel F. Tricyclodecan-9-yl-Xanthogenate (D609): Mechanism of Action and Pharmacological Applications. Int J Mol Sci 2022; 23:3305. [PMID: 35328726 PMCID: PMC8954530 DOI: 10.3390/ijms23063305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/14/2022] [Accepted: 03/16/2022] [Indexed: 12/04/2022] Open
Abstract
Tricyclodecan-9-yl xanthogenate (D609) is a synthetic tricyclic compound possessing a xanthate group. This xanthogenate compound is known for its diverse pharmacological properties. Over the last three decades, many studies have reported the biological activities of D609, including antioxidant, antiapoptotic, anticholinergic, anti-tumor, anti-inflammatory, anti-viral, anti-proliferative, and neuroprotective activities. Its mechanism of action is extensively attributed to its ability to cause the competitive inhibition of phosphatidylcholine (PC)-specific phospholipase C (PC-PLC) and sphingomyelin synthase (SMS). The inhibition of PCPLC or SMS affects secondary messengers with a lipidic nature, i.e., 1,2-diacylglycerol (DAG) and ceramide. Various in vitro/in vivo studies suggest that PCPLC and SMS inhibition regulate the cell cycle, block cellular proliferation, and induce differentiation. D609 acts as a pro-inflammatory cytokine antagonist and diminishes Aβ-stimulated toxicity. PCPLC enzymatic activity essentially requires Zn2+, and D609 might act as a potential chelator of Zn2+, thereby blocking PCPLC enzymatic activity. D609 also demonstrates promising results in reducing atherosclerotic plaque formation, post-stroke cerebral infarction, and cancer progression. The present compilation provides a comprehensive mechanistic insight into D609, including its chemistry, mechanism of action, and regulation of various pharmacological activities.
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Affiliation(s)
- Aashiq Hussain Bhat
- Department of Clinical Biochemistry, University of Kashmir, Srinagar 190006, India; (A.H.B.); (K.B.D.)
| | - Khalid Bashir Dar
- Department of Clinical Biochemistry, University of Kashmir, Srinagar 190006, India; (A.H.B.); (K.B.D.)
| | - Andleeb Khan
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia;
| | - Saeed Alshahrani
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia;
| | - Sultan M. Alshehri
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (S.M.A.); (F.S.)
| | - Mohammed M. Ghoneim
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah 13713, Saudi Arabia;
| | - Prawez Alam
- Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia;
| | - Faiyaz Shakeel
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (S.M.A.); (F.S.)
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13
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Li H, Kim Y, Jung H, Hyun JY, Shin I. Near-infrared (NIR) fluorescence-emitting small organic molecules for cancer imaging and therapy. Chem Soc Rev 2022; 51:8957-9008. [DOI: 10.1039/d2cs00722c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
We discuss recent advances made in the development of NIR fluorescence-emitting small organic molecules for tumor imaging and therapy.
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Affiliation(s)
- Hui Li
- Department of Chemistry, Yonsei University, 03722 Seoul, Republic of Korea
| | - Yujun Kim
- Department of Chemistry, Yonsei University, 03722 Seoul, Republic of Korea
| | - Hyoje Jung
- Department of Chemistry, Yonsei University, 03722 Seoul, Republic of Korea
| | - Ji Young Hyun
- Department of Drug Discovery, Data Convergence Drug Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, Republic of Korea
| | - Injae Shin
- Department of Chemistry, Yonsei University, 03722 Seoul, Republic of Korea
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14
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Rees SWP, Rees TA, Leung E, Walker CS, Barker D, Pilkington LI. Incorporation of a Nitric Oxide Donating Motif into Novel PC-PLC Inhibitors Provides Enhanced Anti-Proliferative Activity. Int J Mol Sci 2021; 22:ijms222111518. [PMID: 34768947 PMCID: PMC8583960 DOI: 10.3390/ijms222111518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/18/2021] [Accepted: 10/22/2021] [Indexed: 11/16/2022] Open
Abstract
Inhibition of phosphatidylcholine-specific phospholipase C (PC-PLC) has previously been shown to be a potential target for novel cancer therapeutics. One downstream consequence of PC-PLC activity is the activation of NF-κB, a nuclear transcription factor responsible for transcribing genes related to oncogenic traits, such as proliferation, angiogenesis, metastasis, and cancer cell survival. Another biological pathway linked to NF-κB is the exogenous delivery of nitric oxide (NO), which decreases NF-κB activity through an apparent negative-feedback loop. In this study, we designed and synthesised 13 novel NO-releasing derivatives of our previously reported class of PC-PLC inhibitors, 2-morpholinobenzoic acids. These molecules contained a secondary benzylamine group, which was readily nitrosylated and subsequently confirmed to release NO in vitro using a DAF-FM fluorescence-based assay. It was then discovered that these NO-releasing derivatives possessed significantly improved anti-proliferative activity in both MDA-MB-231 and HCT116 cancer cell lines compared to their non-nitrosylated parent compounds. These results confirmed that the inclusion of an exogenous NO-releasing functional group onto a known PC-PLC inhibitor enhances anti-proliferative activity and that this relationship can be exploited in order to further improve the anti-proliferative activity of current/future PC-PLC inhibitors.
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Affiliation(s)
- Shaun W. P. Rees
- School of Chemical Sciences, University of Auckland, Auckland 1010, New Zealand;
| | - Tayla A. Rees
- School of Biological Science, University of Auckland, Auckland 1010, New Zealand; (T.A.R.); (C.S.W.)
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland 1010, New Zealand;
| | - Euphemia Leung
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland 1010, New Zealand;
- Auckland Cancer Society Research Centre, University of Auckland, Grafton, Auckland 1023, New Zealand
| | - Christopher S. Walker
- School of Biological Science, University of Auckland, Auckland 1010, New Zealand; (T.A.R.); (C.S.W.)
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland 1010, New Zealand;
| | - David Barker
- School of Chemical Sciences, University of Auckland, Auckland 1010, New Zealand;
- MacDiarmid Institute for Advanced Materials and Nanotechnology, Wellington 6012, New Zealand
- Correspondence: (D.B.); (L.I.P.)
| | - Lisa I. Pilkington
- School of Chemical Sciences, University of Auckland, Auckland 1010, New Zealand;
- Correspondence: (D.B.); (L.I.P.)
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15
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Targeting Metabolic Reprogramming to Improve Breast Cancer Treatment: An In Vitro Evaluation of Selected Metabolic Inhibitors Using a Metabolomic Approach. Metabolites 2021; 11:metabo11080556. [PMID: 34436498 PMCID: PMC8399175 DOI: 10.3390/metabo11080556] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/18/2021] [Accepted: 08/20/2021] [Indexed: 11/21/2022] Open
Abstract
Characteristic metabolic adaptations are recognized as a cancer hallmark. Breast cancer, like other cancer types, displays cellular respiratory switches—in particular, the Warburg effect—and important fluctuations in the glutamine and choline metabolisms. This cancer remains a world health issue mainly due to the side effects associated with chemotherapy, which force a reduction in the administered dose or even a complete discontinuation of the treatment. For example, Doxorubicin is efficient to treat breast cancer but unfortunately induces severe cardiotoxicity. In the present in vitro study, selected metabolic inhibitors were evaluated alone or in combination as potential treatments against breast cancer. In addition, the same inhibitors were used to possibly potentiate the effects of Doxorubicin. As a result, the combination of CB-839 (glutaminase inhibitor) and Oxamate (lactate dehydrogenase inhibitor) and the combination of CB-839/Oxamate/D609 (a phosphatidylcholine-specific phospholipase C inhibitor) caused significant cell mortality in both MDA-MB-231 and MCF-7, two breast cancer cell lines. Furthermore, all inhibitors were able to improve the efficacy of Doxorubicin on the same cell lines. Those findings are quite encouraging with respect to the clinical goal of reducing the exposure of patients to Doxorubicin and, subsequently, the severity of the associated cardiotoxicity, while keeping the same treatment efficacy.
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16
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Rubtsova NI, Hart MC, Arroyo AD, Osharovich SA, Liebov BK, Miller J, Yuan M, Cochran JM, Chong S, Yodh AG, Busch TM, Delikatny EJ, Anikeeva N, Popov AV. NIR Fluorescent Imaging and Photodynamic Therapy with a Novel Theranostic Phospholipid Probe for Triple-Negative Breast Cancer Cells. Bioconjug Chem 2021; 32:1852-1863. [PMID: 34139845 DOI: 10.1021/acs.bioconjchem.1c00295] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
New exogenous probes are needed for both imaging diagnostics and therapeutics. Here, we introduce a novel nanocomposite near-infrared (NIR) fluorescent imaging probe and test its potency as a photosensitizing agent for photodynamic therapy (PDT) against triple-negative breast cancer cells. The active component in the nanocomposite is a small molecule, pyropheophorbide a-phosphatidylethanolamine-QSY21 (Pyro-PtdEtn-QSY), which is imbedded into lipid nanoparticles for transport in the body. The probe targets abnormal choline metabolism in cancer cells; specifically, the overexpression of phosphatidylcholine-specific phospholipase C (PC-PLC) in breast, prostate, and ovarian cancers. Pyro-PtdEtn-QSY consists of a NIR fluorophore and a quencher, attached to a PtdEtn moiety. It is selectively activated by PC-PLC resulting in enhanced fluorescence in cancer cells compared to normal cells. In our in vitro investigation, four breast cancer cell lines showed higher probe activation levels than noncancerous control cells, immortalized human mammary gland cells, and normal human T cells. Moreover, the ability of this nanocomposite to function as a sensitizer in PDT experiments on MDA-MB-231 cells suggests that the probe is promising as a theranostic agent.
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Affiliation(s)
- Natalia I Rubtsova
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, Pennsylvania 19104, United States
| | - Michael C Hart
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, Pennsylvania 19104, United States
| | - Alejandro D Arroyo
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, Pennsylvania 19104, United States
| | - Sofya A Osharovich
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, Pennsylvania 19104, United States
| | - Benjamin K Liebov
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, Pennsylvania 19104, United States
| | - Joann Miller
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Bldg 421, Philadelphia, Pennsylvania 19104, United States
| | - Min Yuan
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Bldg 421, Philadelphia, Pennsylvania 19104, United States
| | - Jeffrey M Cochran
- Department of Physics and Astronomy, University of Pennsylvania, 3231 Walnut Street, Philadelphia, Pennsylvania 19104, United States
| | - Sanghoon Chong
- Department of Physics and Astronomy, University of Pennsylvania, 3231 Walnut Street, Philadelphia, Pennsylvania 19104, United States
| | - Arjun G Yodh
- Department of Physics and Astronomy, University of Pennsylvania, 3231 Walnut Street, Philadelphia, Pennsylvania 19104, United States
| | - Theresa M Busch
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Bldg 421, Philadelphia, Pennsylvania 19104, United States
| | - E James Delikatny
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, Pennsylvania 19104, United States
| | - Nadia Anikeeva
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, United States
| | - Anatoliy V Popov
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, Pennsylvania 19104, United States
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17
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Rees SWP, Leung E, Reynisson J, Barker D, Pilkington LI. Development of 2-Morpholino-N-hydroxybenzamides as anti-proliferative PC-PLC inhibitors. Bioorg Chem 2021; 114:105152. [PMID: 34328856 DOI: 10.1016/j.bioorg.2021.105152] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/29/2021] [Accepted: 07/02/2021] [Indexed: 11/15/2022]
Abstract
Phosphatidylcholine-specific phospholipase C (PC-PLC) is a key enzyme involved in the metabolism of the mammalian phospholipid phosphatidylcholine into secondary messengers diacylglycerol (DAG) and phosphocholine. DAG and phosphocholine have been identified to amplify various cellular processes involved in oncogenesis such as proliferation, cell-cycle activation, differentiation and motility, therefore making PC-PLC a potential target for novel anti-cancer treatments. The current literature standard for PC-PLC inhibition, tricyclodecan-9-yl-potassium xanthate (D609), has been shown to arrest proliferation in multiple cancer cell lines, however, it is not drug-like resulting in low aqueous stability, making it a poor drug candidate. 2-Morpholinobenzoic acids have been shown to have improved PC-PLC inhibitory activity compared to D609, with molecular modelling identifying chelation of the carboxylic acid to catalytic Zn2+ ions in the PC-PLC active site being a key interaction. In this study, the carboxylic acid motif was replaced with a hydroxamic acid to strengthen the Zn2+ interaction. It was found that the hydroxamic acid derivatives displayed PC-PLC inhibitory activity similar, or better, than D609. Furthermore, these novel inhibitors had potent anti-proliferative activity in MDA-MB-231 and HCT-116 cancer cell lines, far greater than D609 and previous 2-morpholinobenzoic acids.
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Affiliation(s)
- Shaun W P Rees
- School of Chemical Sciences, University of Auckland, Auckland 1010, New Zealand
| | - Euphemia Leung
- Auckland Cancer Society Research Centre, University of Auckland, Grafton, Auckland 1023, New Zealand
| | - Jóhannes Reynisson
- School of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Staffordshire ST5 5BG, United Kingdom
| | - David Barker
- School of Chemical Sciences, University of Auckland, Auckland 1010, New Zealand; MacDiarmid Institute for Advanced Materials and Nanotechnology, Wellington, New Zealand.
| | - Lisa I Pilkington
- School of Chemical Sciences, University of Auckland, Auckland 1010, New Zealand.
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18
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Iorio E, Podo F, Leach MO, Koutcher J, Blankenberg FG, Norfray JF. A novel roadmap connecting the 1H-MRS total choline resonance to all hallmarks of cancer following targeted therapy. Eur Radiol Exp 2021; 5:5. [PMID: 33447887 PMCID: PMC7809082 DOI: 10.1186/s41747-020-00192-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 10/29/2020] [Indexed: 11/15/2022] Open
Abstract
This review describes a cellular adaptive stress signalling roadmap connecting the 1H magnetic resonance spectroscopy (MRS) total choline peak at 3.2 ppm (tCho) to cancer response after targeted therapy (TT). Recent research on cell signalling, tCho metabolism, and TT of cancer has been retrospectively re-examined. Signalling research describes how the unfolded protein response (UPR), a major stress signalling network, transduces, regulates, and rewires the total membrane turnover in different cancer hallmarks after a TT stress. In particular, the UPR signalling maintains or increases total membrane turnover in all pro-survival hallmarks, whilst dramatically decreases turnover during apoptosis, a pro-death hallmark. Recent research depicts the TT-induced stress as a crucial event responsible for interrupting UPR pro-survival pathways, leading to an UPR-mediated cell death. The 1H-MRS tCho resonance represents the total mobile precursors and products during the enzymatic modification of phosphatidylcholine membrane abundance. The tCho profile represents a biomarker that noninvasively monitors TT-induced enzymatic changes in total membrane turnover in a wide variety of existing and new anticancer treatments targeting specific layers of the UPR signalling network. Our overview strongly suggests further evaluating and validating the 1H-MRS tCho peak as a powerful noninvasive imaging biomarker of cancer response in TT clinical trials.
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Affiliation(s)
- Egidio Iorio
- High Resolution NMR Unit-Core Facilities, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Roma, Italy.
| | - Franca Podo
- High Resolution NMR Unit-Core Facilities, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Roma, Italy
| | - Martin O Leach
- MRI Unit, Royal Marsden Hospital, Downs Road, Sutton, Surrey, SM2 5PT, UK
| | - Jason Koutcher
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | | | - Joseph F Norfray
- Emeritus, Chicago Northside MRI Center, 2818 N. Sheridan Rd, Chicago, IL, 60657, USA
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Phosphoinositide-specific phospholipase C isoforms are conveyed by osteosarcoma-derived extracellular vesicles. J Cell Commun Signal 2020; 14:417-426. [PMID: 32583269 DOI: 10.1007/s12079-020-00571-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 06/14/2020] [Indexed: 10/24/2022] Open
Abstract
Cancer cells are able to release high amounts of extracellular vesicles, thereby conditioning the normal cells in the surrounding tissue and/or in distant target organs. In the context of bone cancers, previous studies suggested that osteosarcoma cancer cells produce transforming extracellular vesicles able to induce a tumour-like phenotype in normal recipient cells. Indeed, phosphoinositide-specific phospholipase C (PI-PLC) enzymes are differentially expressed in osteosarcoma cell lines with increasing aggressiveness, thus providing helpful insights to better define their role and functions in this bone tumour. By confocal microscopy analysis, we demonstrated that osteosarcoma-derived extracellular vesicles convey all the assessed PI-PLC isoforms, and that they localize into cell membrane bubble-like structures, resembling extracellular vesicles about to be released, as conveyed and/or membrane protein. Cytofluorimetric analysis confirmed the presence of PI-PLC isoforms in the extracellular vesicles collected from conditioned media of osteosarcoma cells. These findings suggest the feasibility to use circulating extracellular vesicles as biomarkers of osteosarcoma progression and/or the monitoring of this distressing disease.
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20
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Development, synthesis and biological investigation of a novel class of potent PC-PLC inhibitors. Eur J Med Chem 2020; 191:112162. [DOI: 10.1016/j.ejmech.2020.112162] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 02/18/2020] [Accepted: 02/18/2020] [Indexed: 11/24/2022]
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21
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Yang C, Wang C, Rong Z, Xu Z, Deng K, Zhao W, Cao L, Lu Y, Adnan H, Li K, Hou Y. Mediation Analysis Reveals Potential Biological Mechanism of Ascites Influencing Recurrence in Patients with Epithelial Ovarian Cancer. Cancer Manag Res 2020; 12:793-799. [PMID: 32099475 PMCID: PMC7007789 DOI: 10.2147/cmar.s232357] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 12/28/2019] [Indexed: 12/21/2022] Open
Abstract
Objective Ascites, an accumulation of peritoneal fluid, is associated with poor prognosis of certain cancers. The potential mechanism that ascites worsens prognosis has not been well understood. Lipids have been reported to correlate with the prognosis of patients with epithelial ovarian cancer (EOC). Therefore, we aimed here to investigate whether lipids mediate the effect of ascites on the recurrence of EOC. Methods We collected the demographic and pathological data of 437 previously untreated patients with EOC to investigate the influence of ascites on recurrence. To identify the mechanism that mediates the potential influence of ascites on recurrence, we used ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS) to determine the plasma lipid profiles of 53 patients with EOC. We used mediation analysis to evaluate if lipids mediated the effects of ascites on the recurrence of EOC. Results Patients with ascites had a poorer prognosis, which was associated with higher levels of carbohydrate antigen-CA125 (CA125) and FIGO stage. We identified six different lipid metabolites that were associated with ascites and recurrence. Mediation analysis revealed that the lipids LysoPC(P-15:0), PC(P-34:4), and PC(38:6) may mediate the effects of ascites on recurrence. Conclusion Our findings suggest that LysoPC(P-15:0), PC(P-34:4), and PC(38:6) mediate the effect of ascites on the prognosis of patients with EOC. We believe therefore that it is reasonable to consider metabolic interventions targeting the metabolism of LysoPC(P-15:0), PC(P-34:4), and PC(38:6) as a palliative treatment for patients with EOC with ascites. Further studies of more patients will be required to validate our findings.
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Affiliation(s)
- Chunyan Yang
- Department of Epidemiology and Biostatistics, Public Health School, Harbin Medical University, Harbin, People's Republic of China
| | - Ce Wang
- Department of Epidemiology and Biostatistics, Public Health School, Harbin Medical University, Harbin, People's Republic of China
| | - Zhiwei Rong
- Department of Epidemiology and Biostatistics, Public Health School, Harbin Medical University, Harbin, People's Republic of China
| | - Zhenyi Xu
- Department of Epidemiology and Biostatistics, Public Health School, Harbin Medical University, Harbin, People's Republic of China
| | - Kui Deng
- Department of Epidemiology and Biostatistics, Public Health School, Harbin Medical University, Harbin, People's Republic of China
| | - Weiwei Zhao
- Department of Epidemiology and Biostatistics, Public Health School, Harbin Medical University, Harbin, People's Republic of China
| | - Lei Cao
- Department of Epidemiology and Biostatistics, Public Health School, Harbin Medical University, Harbin, People's Republic of China
| | - Yaxin Lu
- Department of Epidemiology and Biostatistics, Public Health School, Harbin Medical University, Harbin, People's Republic of China
| | - Humara Adnan
- Department of Epidemiology and Biostatistics, Public Health School, Harbin Medical University, Harbin, People's Republic of China
| | - Kang Li
- Department of Epidemiology and Biostatistics, Public Health School, Harbin Medical University, Harbin, People's Republic of China
| | - Yan Hou
- Department of Epidemiology and Biostatistics, Public Health School, Harbin Medical University, Harbin, People's Republic of China
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22
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Eurtivong C, Pilkington LI, van Rensburg M, White RM, Brar HK, Rees S, Paulin EK, Xu CS, Sharma N, Leung IK, Leung E, Barker D, Reynisson J. Discovery of novel phosphatidylcholine-specific phospholipase C drug-like inhibitors as potential anticancer agents. Eur J Med Chem 2020; 187:111919. [DOI: 10.1016/j.ejmech.2019.111919] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 11/11/2019] [Accepted: 11/26/2019] [Indexed: 01/09/2023]
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23
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Zhao Y, Su L, Li K, Zhao B. Discovery of novel PC‐PLC activity inhibitors. Chem Biol Drug Des 2019; 95:380-387. [DOI: 10.1111/cbdd.13606] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 06/13/2019] [Accepted: 08/03/2019] [Indexed: 12/31/2022]
Affiliation(s)
- YanChun Zhao
- Jinan Hangchen Biotechnology Co., Ltd. Jinan China
| | - Le Su
- State Key Laboratory of Biobased Material and Green Papermaking School of Bioengineering Shandong Academy of Sciences Qilu University of Technology Jinan China
| | - Kunlun Li
- Jinan Hangchen Biotechnology Co., Ltd. Jinan China
| | - BaoXiang Zhao
- Institute of Organic Chemistry School of Chemistry and Chemical Engineering Shandong University Jinan China
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24
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Liebov B, Arroyo AD, Rubtsova NI, Osharovich SA, Delikatny EJ, Popov AV. Nonprotecting Group Synthesis of a Phospholipase C Activatable Probe with an Azo-Free Quencher. ACS OMEGA 2018; 3:6867-6873. [PMID: 29978148 PMCID: PMC6026834 DOI: 10.1021/acsomega.8b00635] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 06/18/2018] [Indexed: 06/08/2023]
Abstract
The near-infrared fluorescent activatable smart probe Pyro-phosphatidylethanolamine (PtdEtn)-QSY was synthesized and observed to selectively fluoresce in the presence of phosphatidylcholine-specific phospholipase C (PC-PLC). PC-PLC is an important biological target as it is known to be upregulated in a variety of cancers, including triple negative breast cancer. Pyro-PtdEtn-QSY features a QSY21 quenching moiety instead of the Black Hole Quencher-3 (BHQ-3) used previously because the latter contains an azo bond, which could lead to biological instability.
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25
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Cala MP, Aldana J, Medina J, Sánchez J, Guio J, Wist J, Meesters RJW. Multiplatform plasma metabolic and lipid fingerprinting of breast cancer: A pilot control-case study in Colombian Hispanic women. PLoS One 2018; 13:e0190958. [PMID: 29438405 PMCID: PMC5810980 DOI: 10.1371/journal.pone.0190958] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2017] [Accepted: 12/22/2017] [Indexed: 01/22/2023] Open
Abstract
Breast cancer (BC) is a highly heterogeneous disease associated with metabolic reprogramming. The shifts in the metabolome caused by BC still lack data from Latin populations of Hispanic origin. In this pilot study, metabolomic and lipidomic approaches were performed to establish a plasma metabolic fingerprint of Colombian Hispanic women with BC. Data from 1H-NMR, GC-MS and LC-MS were combined and compared. Statistics showed discrimination between breast cancer and healthy subjects on all analytical platforms. The differentiating metabolites were involved in glycerolipid, glycerophospholipid, amino acid and fatty acid metabolism. This study demonstrates the usefulness of multiplatform approaches in metabolic/lipid fingerprinting studies to broaden the outlook of possible shifts in metabolism. Our findings propose relevant plasma metabolites that could contribute to a better understanding of underlying metabolic shifts driven by BC in women of Colombian Hispanic origin. Particularly, the understanding of the up-regulation of long chain fatty acyl carnitines and the down-regulation of cyclic phosphatidic acid (cPA). In addition, the mapped metabolic signatures in breast cancer were similar but not identical to those reported for non-Hispanic women, despite racial differences.
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Affiliation(s)
- Mónica P. Cala
- Department of Chemistry, Grupo de Investigación en Química Analítica y Bioanalítica (GABIO), Universidad de los Andes, Bogotá D.C., Colombia
| | - Julian Aldana
- Department of Chemistry, Grupo de Investigación en Química Analítica y Bioanalítica (GABIO), Universidad de los Andes, Bogotá D.C., Colombia
| | - Jessica Medina
- Department of Chemistry, Universidad del Valle, Cali, Colombia
| | - Julián Sánchez
- Liga contra el Cáncer Seccional Bogotá, Bogotá, Colombia
| | - José Guio
- Liga contra el Cáncer Seccional Bogotá, Bogotá, Colombia
| | - Julien Wist
- Department of Chemistry, Universidad del Valle, Cali, Colombia
| | - Roland J. W. Meesters
- Department of Chemistry, Grupo de Investigación en Química Analítica y Bioanalítica (GABIO), Universidad de los Andes, Bogotá D.C., Colombia
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26
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Abstract
Phospholipases are lipolytic enzymes that hydrolyze phospholipid substrates at specific ester bonds. Phospholipases are widespread in nature and play very diverse roles from aggression in snake venom to signal transduction, lipid mediator production, and metabolite digestion in humans. Phospholipases vary considerably in structure, function, regulation, and mode of action. Tremendous advances in understanding the structure and function of phospholipases have occurred in the last decades. This introductory chapter is aimed at providing a general framework of the current understanding of phospholipases and a discussion of their mechanisms of action and emerging biological functions.
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27
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Kalluri HS, Kuo JS, Dempsey RJ. Chronic D609 treatment interferes with cell cycle and targets the expression of Olig2 in Glioma Stem like Cells. Eur J Pharmacol 2017; 814:81-86. [DOI: 10.1016/j.ejphar.2017.08.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 07/08/2017] [Accepted: 08/03/2017] [Indexed: 01/16/2023]
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Recurrent triple-negative breast cancer (TNBC) tissues contain a higher amount of phosphatidylcholine (32:1) than non-recurrent TNBC tissues. PLoS One 2017; 12:e0183724. [PMID: 28832678 PMCID: PMC5568295 DOI: 10.1371/journal.pone.0183724] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 08/09/2017] [Indexed: 11/19/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is one of the breast cancer subtype that displays a high risk of early recurrence and short overall survival. Improvement of the prognosis of patients with TNBC requires identifying a predictive factor of recurrence, which would make it possible to provide beneficial personalized treatment. However, no clinically reliable predictive factor is currently known. In this study, we investigated the predictive factor of recurrence in TNBC using matrix-assisted laser desorption/ionization-imaging mass spectrometry for lipid profiling of breast cancer specimens obtained from three and six patients with recurrent and non-recurrent TNBC, respectively. The signal for phosphatidylcholine (PC) (32:1) at m/z 732.5 was significantly higher in the recurrence group compared to the non-recurrence group (P = 0.024). PC (32:1) was more abundant in the cancer epithelial area than it was in the surrounding stroma, suggesting that abnormal lipid metabolism was associated with malignant transformation. Our results indicate PC (32:1) as a candidate predictive factor of TNBC recurrence. A future prospective study investigating whether personalized therapy based on PC (32:1) intensity improves the prognosis of patients with TNBC is recommended.
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29
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Paris L, Podo F, Spadaro F, Abalsamo L, Pisanu ME, Ricci A, Cecchetti S, Altabella L, Buoncervello M, Lozneanu L, Bagnoli M, Ramoni C, Canevari S, Mezzanzanica D, Iorio E, Canese R. Phosphatidylcholine-specific phospholipase C inhibition reduces HER2-overexpression, cell proliferation and in vivo tumor growth in a highly tumorigenic ovarian cancer model. Oncotarget 2017; 8:55022-55038. [PMID: 28903399 PMCID: PMC5589638 DOI: 10.18632/oncotarget.18992] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Accepted: 06/19/2017] [Indexed: 01/02/2023] Open
Abstract
Antagonizing the oncogenic effects of human epidermal growth factor receptor 2 (HER2) with current anti-HER2 agents has not yet yielded major progress in the treatment of advanced HER2-positive epithelial ovarian cancer (EOC). Using preclinical models to explore alternative molecular mechanisms affecting HER2 overexpression and oncogenicity may lead to new strategies for EOC patient treatment. We previously reported that phosphatidylcholine-specific phospholipase C (PC-PLC) exerts a pivotal role in regulating HER2 overexpression in breast cancer cells. The present study, conducted on two human HER2-overexpressing EOC cell lines - SKOV3 and its in vivo-passaged SKOV3.ip cell variant characterized by enhanced in vivo tumorigenicity - and on SKOV3.ip xenografts implanted in SCID mice, showed: a) about 2-fold higher PC-PLC and HER2 protein expression levels in SKOV3.ip compared to SKOV3 cells; b) physical association of PC-PLC with HER2 in non-raft domains; c) HER2 internalization and ca. 50% reduction of HER2 mRNA and protein expression levels in SKOV3.ip cells exposed to the PC-PLC inhibitor tricyclodecan-9-yl-potassium xanthate (D609); d) differential effects of D609 and trastuzumab on HER2 protein expression and cell proliferation; e) decreased in vivo tumor growth in SKOV3.ip xenografts during in vivo treatment with D609; f) potential use of in vivo magnetic resonance spectroscopy (MRS) and imaging (MRI) parameters as biomarkers of EOC response to PC-PLC inhibition. Overall, these findings support the view that PC-PLC inhibition may represent an effective means to target the tumorigenic effects of HER2 overexpression in EOC and that in vivo MR approaches can efficiently monitor its effects.
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Affiliation(s)
- Luisa Paris
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161, Roma, Italy
| | - Franca Podo
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161, Roma, Italy
| | - Francesca Spadaro
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161, Roma, Italy
| | - Laura Abalsamo
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161, Roma, Italy
| | - Maria Elena Pisanu
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161, Roma, Italy
| | - Alessandro Ricci
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161, Roma, Italy
| | - Serena Cecchetti
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161, Roma, Italy
| | - Luisa Altabella
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161, Roma, Italy
| | - Maria Buoncervello
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161, Roma, Italy
| | - Ludmila Lozneanu
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milano, Italy.,Department of Histology, University of Medicine and Pharmacy "Grigore T. Popa", 700115, Iasi, Romania
| | - Marina Bagnoli
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milano, Italy
| | - Carlo Ramoni
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161, Roma, Italy
| | - Silvana Canevari
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milano, Italy
| | - Delia Mezzanzanica
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milano, Italy
| | - Egidio Iorio
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161, Roma, Italy
| | - Rossella Canese
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161, Roma, Italy
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30
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Podo F, Bhujwalla ZM, Iorio E. Editorial: Exploring Cancer Metabolic Reprogramming through Molecular Imaging. Front Oncol 2017; 7:79. [PMID: 28491821 PMCID: PMC5405072 DOI: 10.3389/fonc.2017.00079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Accepted: 04/11/2017] [Indexed: 11/13/2022] Open
Affiliation(s)
- Franca Podo
- Istituto Superiore di Sanità, Rome, Italy
- *Correspondence: Franca Podo, ,
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31
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Phosphatidylcholine-specific phospholipase C inhibition down- regulates CXCR4 expression and interferes with proliferation, invasion and glycolysis in glioma cells. PLoS One 2017; 12:e0176108. [PMID: 28423060 PMCID: PMC5397108 DOI: 10.1371/journal.pone.0176108] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 04/05/2017] [Indexed: 02/07/2023] Open
Abstract
Background The chemokine receptor CXCR4 plays a crucial role in tumors, including glioblastoma multiforme (GBM), the most aggressive glioma. Phosphatidylcholine-specific phospholipase C (PC-PLC), a catabolic enzyme of PC metabolism, is involved in several aspects of cancer biology and its inhibition down-modulates the expression of growth factor membrane receptors interfering with their signaling pathways. In the present work we investigated the possible interplay between CXCR4 and PC-PLC in GBM cells. Methods Confocal microscopy, immunoprecipitation, western blot analyses, and the evaluation of migration and invasion potential were performed on U87MG cells after PC-PLC inhibition with the xanthate D609. The intracellular metabolome was investigated by magnetic resonance spectroscopy; lactate levels and lactate dehydrogenase (LDH) activity were analyzed by colorimetric assay. Results Our studies demonstrated that CXCR4 and PC-PLC co-localize and are associated on U87MG cell membrane. D609 reduced CXCR4 expression, cell proliferation and invasion, interfering with AKT and EGFR activation and expression. Metabolic analyses showed a decrease in intracellular lactate concentration together with a decrement in LDH activity. Conclusions Our data suggest that inhibition of PC-PLC could represent a new molecular approach in glioma biology not only for its ability in modulating cell metabolism, glioma growth and motility, but also for its inhibitory effect on crucial molecules involved in cancer progression.
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32
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Shang M, Xie Z, Tang Z, He L, Wang X, Wang C, Wu Y, Li Y, Zhao L, Lv Z, Wu Z, Huang Y, Yu X, Li X. Expression of Clonorchis sinensis GIIIsPLA 2 protein in baculovirus-infected insect cells and its overexpression facilitating epithelial-mesenchymal transition in Huh7 cells via AKT pathway. Parasitol Res 2017; 116:1307-1316. [PMID: 28220242 DOI: 10.1007/s00436-017-5409-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 02/12/2017] [Indexed: 12/29/2022]
Abstract
Although prior studies confirmed that group III secretory phospholipase A2 of Clonorchis sinensis (CsGIIIsPLA2) had stimulating effect on liver fibrosis by binding to LX-2 cells, large-scale expression of recombinant protein and its function in the progression of hepatoma are worth exploring. Because of high productivity and low lipopolysaccharides (LPS) in the Sf9-baculovirus expression system, we firstly used this system to express the coding region of CsGIIIsPLA2. The molecular weight of recombinant CsGIIIsPLA2 protein was about 34 kDa. Further investigation showed that most of the recombinant protein presented intracellular expression in Sf9 insect cell nucleus and could be detected only into cell debris, which made the protein purification and further functional study difficult. Therefore, to study the role of CsGIIIsPLA2 in hepatocellular carcinoma (HCC) progression, CsGIIIsPLA2 overexpression Huh7 cell model was applied. Cell proliferation, migration, and the expression level of epithelial-mesenchymal transition (EMT)-related molecules (E-cadherin, N-cadherin, α-catenin, Vimentin, p300, Snail, and Slug) along with possible mechanism were measured. The results indicated that CsGIIIsPLA2 overexpression not only inhibited cell proliferation and promoted migration and EMT but also enhanced the phosphorylation of AKT in HCC cells. In conclusion, this study supported that CsGIIIsPLA2 overexpression suppressed cell proliferation and induced EMT through the AKT pathway.
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Affiliation(s)
- Mei Shang
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.,Key Laboratory for Tropical Diseases Control, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Zhizhi Xie
- Department of Clinical Laboratory, Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Zeli Tang
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.,Key Laboratory for Tropical Diseases Control, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Lei He
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.,Key Laboratory for Tropical Diseases Control, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.,Department of Clinical Laboratory, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou, 510060, People's Republic of China
| | - Xiaoyun Wang
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.,Key Laboratory for Tropical Diseases Control, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Caiqin Wang
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.,Key Laboratory for Tropical Diseases Control, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Yinjuan Wu
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.,Key Laboratory for Tropical Diseases Control, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Ye Li
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.,Key Laboratory for Tropical Diseases Control, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Lu Zhao
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.,Key Laboratory for Tropical Diseases Control, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Zhiyue Lv
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.,Key Laboratory for Tropical Diseases Control, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Zhongdao Wu
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.,Key Laboratory for Tropical Diseases Control, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Yan Huang
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.,Key Laboratory for Tropical Diseases Control, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Xinbing Yu
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.,Key Laboratory for Tropical Diseases Control, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Xuerong Li
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China. .,Key Laboratory for Tropical Diseases Control, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.
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Akekawatchai C, Roytrakul S, Kittisenachai S, Isarankura-Na-Ayudhya P, Jitrapakdee S. Protein Profiles Associated with Anoikis Resistance of Metastatic MDA-MB-231 Breast Cancer Cells. Asian Pac J Cancer Prev 2017; 17:581-90. [PMID: 26925647 DOI: 10.7314/apjcp.2016.17.2.581] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Resistance to anoikis, a cell-detachment induced apoptosis, is one of the malignant phenotypes which support tumor metastasis. Molecular mechanisms underlying the establishment of this phenotype require further investigation. This study aimed at exploring protein expression profiles associated with anoikis resistance of a metastatic breast cancer cell. Cell survival of suspension cultures of non-metastatic MCF-7 and metastatic MDA-MB-231 cells were compared with their adherent cultures. Trypan blue exclusion assays demonstrated a significantly higher percentage of viable cells in MDA-MB-231 than MCF-7 cell cultures, consistent with analysis of annexin V-7-AAD stained cells indicating that MDA-MB-231 possess anti-apoptotic ability 1.7 fold higher than MCF-7 cells. GeLC-MS/MS analysis of protein lysates of MDA-MB-231 and MCF-7 cells grown under both culture conditions identified 925 proteins which are differentially expressed, 54 of which were expressed only in suspended and adherent MDA-MB-231 but not in MCF-7 cells. These proteins have been implicated in various cellular processes, including DNA replication and repair, transcription, translation, protein modification, cytoskeleton, transport and cell signaling. Analysis based on the STITCH database predicted the interaction of phospholipases, PLC and PLD, and 14-3-3 beta/alpha, YWHAB, with the intrinsic and extrinsic apoptotic signaling network, suggesting putative roles in controlling anti-anoikis ability. MDA-MB-231 cells grown in the presence of inhibitors of phospholipase C, U73122, and phospholipase D, FIPI, demonstrated reduced ability to survive in suspension culture, indicating functional roles of PLC and PLD in the process of anti-anoikis. Our study identified intracellular mediators potentially associated with establishment of anoikis resistance of metastatic cells. These proteins require further clarification as prognostic and therapeutic targets for advanced breast cancer.
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Affiliation(s)
- Chareeporn Akekawatchai
- Department of Medical Technology, Faculty of Allied Health Sciences, Thammasat University, Bangkok, Thailand E-mail : ,
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34
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Cheng M, Bhujwalla ZM, Glunde K. Targeting Phospholipid Metabolism in Cancer. Front Oncol 2016; 6:266. [PMID: 28083512 PMCID: PMC5187387 DOI: 10.3389/fonc.2016.00266] [Citation(s) in RCA: 142] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Accepted: 12/14/2016] [Indexed: 12/14/2022] Open
Abstract
All cancers tested so far display abnormal choline and ethanolamine phospholipid metabolism, which has been detected with numerous magnetic resonance spectroscopy (MRS) approaches in cells, animal models of cancer, as well as the tumors of cancer patients. Since the discovery of this metabolic hallmark of cancer, many studies have been performed to elucidate the molecular origins of deregulated choline metabolism, to identify targets for cancer treatment, and to develop MRS approaches that detect choline and ethanolamine compounds for clinical use in diagnosis and treatment monitoring. Several enzymes in choline, and recently also ethanolamine, phospholipid metabolism have been identified, and their evaluation has shown that they are involved in carcinogenesis and tumor progression. Several already established enzymes as well as a number of emerging enzymes in phospholipid metabolism can be used as treatment targets for anticancer therapy, either alone or in combination with other chemotherapeutic approaches. This review summarizes the current knowledge of established and relatively novel targets in phospholipid metabolism of cancer, covering choline kinase α, phosphatidylcholine-specific phospholipase D1, phosphatidylcholine-specific phospholipase C, sphingomyelinases, choline transporters, glycerophosphodiesterases, phosphatidylethanolamine N-methyltransferase, and ethanolamine kinase. These enzymes are discussed in terms of their roles in oncogenic transformation, tumor progression, and crucial cancer cell properties such as fast proliferation, migration, and invasion. Their potential as treatment targets are evaluated based on the current literature.
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Affiliation(s)
- Menglin Cheng
- Division of Cancer Imaging Research, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine , Baltimore, MD , USA
| | - Zaver M Bhujwalla
- Division of Cancer Imaging Research, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kristine Glunde
- Division of Cancer Imaging Research, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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35
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Adamiak M, Suszynska M, Abdel-Latif A, Abdelbaset-Ismail A, Ratajczak J, Ratajczak MZ. The Involvment of Hematopoietic-Specific PLC -β2 in Homing and Engraftment of Hematopoietic Stem/Progenitor Cells. Stem Cell Rev Rep 2016; 12:613-620. [PMID: 27704316 PMCID: PMC5106505 DOI: 10.1007/s12015-016-9689-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Migration and bone marrow (BM) homing of hematopoietic stem progenitor cells (HSPCs) is regulated by several signaling pathways, and here we provide evidence for the involvement in this process of hematopoietic-specific phospholipase C-β2 (PLC-β2). This enzyme is involved in release of intracellular calcium and activation of protein kinase C (PKC). Recently we reported that PLC-β2 promotes mobilization of HSPCs from BM into peripheral blood (PB), and this effect is mediated by the involvement of PLC-β2 in the release of proteolytic enzymes from granulocytes and its role in disintegration of membrane lipid rafts. Here we report that, besides the role of PLC-β2 in the release of HSPCs from BM niches, PLC-β2 regulates the migration of HSPCs in response to chemotactic gradients of BM homing factors, including SDF-1, S1P, C1P, and ATP. Specifically, HSPCs from PLC-β2-KO mice show impaired homing and engraftment in vivo after transplantation into lethally irradiated mice. This decrease in migration of HSPCs can be explained by impaired calcium release in PLC-β2-KO mice and a high baseline level of heme oxygenase 1 (HO-1), an enzyme that negatively regulates cell migration.
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Affiliation(s)
- Mateusz Adamiak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 South Floyd Street, Louisville, KY, 40202, USA
| | - Malwina Suszynska
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 South Floyd Street, Louisville, KY, 40202, USA
| | - Ahmed Abdel-Latif
- Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, KY, USA
| | - Ahmed Abdelbaset-Ismail
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 South Floyd Street, Louisville, KY, 40202, USA
| | - Janina Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 South Floyd Street, Louisville, KY, 40202, USA
| | - Mariusz Z Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 South Floyd Street, Louisville, KY, 40202, USA.
- Department of Regenerative Medicine, Warsaw Medical University, Warsaw, Poland.
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36
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Iorio E, Caramujo MJ, Cecchetti S, Spadaro F, Carpinelli G, Canese R, Podo F. Key Players in Choline Metabolic Reprograming in Triple-Negative Breast Cancer. Front Oncol 2016; 6:205. [PMID: 27747192 PMCID: PMC5043614 DOI: 10.3389/fonc.2016.00205] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Accepted: 09/12/2016] [Indexed: 01/08/2023] Open
Abstract
Triple-negative breast cancer (TNBC), defined as lack of estrogen and progesterone receptors in the absence of protein overexpression/gene amplification of human epidermal growth factor receptor 2, is still a clinical challenge despite progress in breast cancer care. 1H magnetic resonance spectroscopy allows identification and non-invasive monitoring of TNBC metabolic aberrations and elucidation of some key mechanisms underlying tumor progression. Thus, it has the potential to improve in vivo diagnosis and follow-up and also to identify new targets for treatment. Several studies have shown an altered phosphatidylcholine (PtdCho) metabolism in TNBCs, both in patients and in experimental models. Upregulation of choline kinase-alpha, an enzyme of the Kennedy pathway that phosphorylates free choline (Cho) to phosphocholine (PCho), is a major contributor to the increased PCho content detected in TNBCs. Phospholipase-mediated PtdCho headgroup hydrolysis also contributes to the build-up of a PCho pool in TNBC cells. The oncogene-driven PtdCho cycle appears to be fine tuned in TNBC cells in at least three ways: by modulating the choline import, by regulating the activity or expression of specific metabolic enzymes, and by contributing to the rewiring of the entire metabolic network. Thus, only by thoroughly dissecting these mechanisms, it will be possible to effectively translate this basic knowledge into further development and implementation of Cho-based imaging techniques and novel classes of therapeutics.
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Affiliation(s)
- Egidio Iorio
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità , Rome , Italy
| | - Maria José Caramujo
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità , Rome , Italy
| | - Serena Cecchetti
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità , Rome , Italy
| | - Francesca Spadaro
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità , Rome , Italy
| | - Giulia Carpinelli
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità , Rome , Italy
| | - Rossella Canese
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità , Rome , Italy
| | - Franca Podo
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità , Rome , Italy
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Hu S, Ding Y, Gong J, Yan N. Sphingomyelin synthase 2 affects CD14‑associated induction of NF‑κB by lipopolysaccharides in acute lung injury in mice. Mol Med Rep 2016; 14:3301-6. [PMID: 27510408 DOI: 10.3892/mmr.2016.5611] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Accepted: 07/22/2016] [Indexed: 11/05/2022] Open
Abstract
Lipopolysaccharide (LPS) is the predominant component of the outer membrane of Gram-negative bacteria, which can cause severe inflammation in the body. The acute lung injury (ALI) induced by LPS can cause extensive damage to the lung tissue, the severe stage of which is termed acute respiratory distress syndrome, when multiple organ dysfunction syndrome may appear. There are no effective clinical treatment measures at present. The involvement of cluster of differentiation (CD)14 assists LPS in causing inflammatory reactions, and CD14 and sphingomyelin (SM), located in lipid rafts areas, are closely associated. SM synthase (SMS) is a key enzyme in the synthesis of SM, however, the effect of SMS on the inflammatory pathway involving nuclear factor (NF)‑κB induced by LPS remains to be elucidated. Under the premise of the establishment of an ALI mouse model induced by LPS, the present study established a control group, LPS group and pyrrolidine dithiocarbamate (PDTC; an NF‑κB pathway inhibitor) group. Hematoxylin‑eosin staining, reverse transcription‑quantitative polymerase chain reaction analysis, western blot analysis and thin layer chromatography were used to investigate the mechanism of SMS in ALI. Compared with the control group, the mRNA and protein levels of CD14 were significantly increased (P<0.001; n=5 and P<0.05, n=5), and the activity of SMS and expression of SMS2 were significantly upregulated (P<0.001; n=5 and P<0.05, n=5) in the model group. The increases of SMS2 and CD14 in the PDTC group were less marked, compared with those in the model group (P<0.05; n=5). These findings suggested that the degree of lung injury was reduced during the acute inflammatory reaction when NF‑κB was inhibited, and that the expression of SMS2 may affect the induction of the NF‑κB pathway by LPS through CD14.
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Affiliation(s)
- Shidong Hu
- Department of General Surgery, The General Hospital of Chinese People's Liberation Army, Beijing 100853, P.R. China
| | - Yi Ding
- Department of Graduate School, Nanchang University Health Science Center, Nanchang, Jiangxi 330006, P.R. China
| | - Jie Gong
- Department of Anesthesiology, The General Hospital of Chinese People's Liberation Army, Beijing 100853, P.R. China
| | - Nianlong Yan
- Department of Biochemistry, College of Basic Medical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Podo F, Paris L, Cecchetti S, Spadaro F, Abalsamo L, Ramoni C, Ricci A, Pisanu ME, Sardanelli F, Canese R, Iorio E. Activation of Phosphatidylcholine-Specific Phospholipase C in Breast and Ovarian Cancer: Impact on MRS-Detected Choline Metabolic Profile and Perspectives for Targeted Therapy. Front Oncol 2016; 6:171. [PMID: 27532027 PMCID: PMC4969288 DOI: 10.3389/fonc.2016.00171] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 07/05/2016] [Indexed: 12/12/2022] Open
Abstract
Elucidation of molecular mechanisms underlying the aberrant phosphatidylcholine cycle in cancer cells plays in favor of the use of metabolic imaging in oncology and opens the way for designing new targeted therapies. The anomalous choline metabolic profile detected in cancer by magnetic resonance spectroscopy and spectroscopic imaging provides molecular signatures of tumor progression and response to therapy. The increased level of intracellular phosphocholine (PCho) typically detected in cancer cells is mainly attributed to upregulation of choline kinase, responsible for choline phosphorylation in the biosynthetic Kennedy pathway, but can also be partly produced by activation of phosphatidylcholine-specific phospholipase C (PC-PLC). This hydrolytic enzyme, known for implications in bacterial infection and in plant survival to hostile environmental conditions, is reported to be activated in mitogen- and oncogene-induced phosphatidylcholine cycles in mammalian cells, with effects on cell signaling, cell cycle regulation, and cell proliferation. Recent investigations showed that PC-PLC activation could account for 20–50% of the intracellular PCho production in ovarian and breast cancer cells of different subtypes. Enzyme activation was associated with PC-PLC protein overexpression and subcellular redistribution in these cancer cells compared with non-tumoral counterparts. Moreover, PC-PLC coimmunoprecipitated with the human epidermal growth factor receptor-2 (HER2) and EGFR in HER2-overexpressing breast and ovarian cancer cells, while pharmacological PC-PLC inhibition resulted into long-lasting HER2 downregulation, retarded receptor re-expression on plasma membrane and antiproliferative effects. This body of evidence points to PC-PLC as a potential target for newly designed therapies, whose effects can be preclinically and clinically monitored by metabolic imaging methods.
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Affiliation(s)
- Franca Podo
- Molecular and Cellular Imaging Unit, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità , Rome , Italy
| | - Luisa Paris
- Molecular and Cellular Imaging Unit, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità , Rome , Italy
| | - Serena Cecchetti
- Molecular and Cellular Imaging Unit, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità , Rome , Italy
| | - Francesca Spadaro
- Molecular and Cellular Imaging Unit, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità , Rome , Italy
| | - Laura Abalsamo
- Molecular and Cellular Imaging Unit, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità , Rome , Italy
| | - Carlo Ramoni
- Molecular and Cellular Imaging Unit, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità , Rome , Italy
| | - Alessandro Ricci
- Molecular and Cellular Imaging Unit, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità , Rome , Italy
| | - Maria Elena Pisanu
- Molecular and Cellular Imaging Unit, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità , Rome , Italy
| | - Francesco Sardanelli
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, Research Hospital Policlinico San Donato , Milan , Italy
| | - Rossella Canese
- Molecular and Cellular Imaging Unit, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità , Rome , Italy
| | - Egidio Iorio
- Molecular and Cellular Imaging Unit, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità , Rome , Italy
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Moreno-Sanz G. Can You Pass the Acid Test? Critical Review and Novel Therapeutic Perspectives of Δ 9-Tetrahydrocannabinolic Acid A. Cannabis Cannabinoid Res 2016; 1:124-130. [PMID: 28861488 PMCID: PMC5549534 DOI: 10.1089/can.2016.0008] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Δ9-tetrahydrocannabinolic acid A (THCA-A) is the acidic precursor of Δ9-tetrahydrocannabinol (THC), the main psychoactive compound found in Cannabis sativa. THCA-A is biosynthesized and accumulated in glandular trichomes present on flowers and leaves, where it serves protective functions and can represent up to 90% of the total THC contained in the plant. THCA-A slowly decarboxylates to form THC during storage and fermentation and can further degrade to cannabinol. Decarboxylation also occurs rapidly during baking of edibles, smoking, or vaporizing, the most common ways in which the general population consumes Cannabis. Contrary to THC, THCA-A does not elicit psychoactive effects in humans and, perhaps for this reason, its pharmacological value is often neglected. In fact, many studies use the term “THCA” to refer indistinctly to several acid derivatives of THC. Despite this perception, many in vitro studies seem to indicate that THCA-A interacts with a number of molecular targets and displays a robust pharmacological profile that includes potential anti-inflammatory, immunomodulatory, neuroprotective, and antineoplastic properties. Moreover, the few in vivo studies performed with THCA-A indicate that this compound exerts pharmacological actions in rodents, likely by engaging type-1 cannabinoid (CB1) receptors. Although these findings may seem counterintuitive due to the lack of cannabinoid-related psychoactivity, a careful perusal of the available literature yields a plausible explanation to this conundrum and points toward novel therapeutic perspectives for raw, unheated Cannabis preparations in humans.
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Affiliation(s)
- Guillermo Moreno-Sanz
- Department of Anatomy & Neurobiology, School of Medicine, University of California Irvine, Irvine, California
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Mercurio L, Ajmone-Cat MA, Cecchetti S, Ricci A, Bozzuto G, Molinari A, Manni I, Pollo B, Scala S, Carpinelli G, Minghetti L. Targeting CXCR4 by a selective peptide antagonist modulates tumor microenvironment and microglia reactivity in a human glioblastoma model. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2016; 35:55. [PMID: 27015814 PMCID: PMC4807593 DOI: 10.1186/s13046-016-0326-y] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Accepted: 03/17/2016] [Indexed: 01/01/2023]
Abstract
BACKGROUND The CXCL12/CXCR4 pathway regulates tumor cell proliferation, metastasis, angiogenesis and the tumor-microenvironment cross-talk in several solid tumors, including glioblastoma (GBM), the most common and fatal brain cancer. In the present study, we evaluated the effects of peptide R, a new specific CXCR4 antagonist that we recently developed by a ligand-based approach, in an in vitro and in vivo model of GBM. The well-characterized CXCR4 antagonist Plerixafor was also included in the study. METHODS The effects of peptide R on CXCR4 expression, cell survival and migration were assessed on the human glioblastoma cell line U87MG exposed to CXCL12, by immunofluorescence and western blotting, MTT assay, flow cytometry and transwell chamber migration assay. Peptide R was then tested in vivo, by using U87MG intracranial xenografts in CD1 nude mice. Peptide R was administered for 23 days since cell implantation and tumor volume was assessed by magnetic resonance imaging (MRI) at 4.7 T. Glioma associated microglia/macrophage (GAMs) polarization (anti-tumor M1 versus pro-tumor M2 phenotypes) and expressions of vascular endothelial growth factor (VEGF) and CD31 were assessed by immunohistochemistry and immunofluorescence. RESULTS We found that peptide R impairs the metabolic activity and cell proliferation of human U87MG cells and stably reduces CXCR4 expression and cell migration in response to CXCL12 in vitro. In the orthotopic U87MG model, peptide R reduced tumor cellularity, promoted M1 features of GAMs and astrogliosis, and hindered intra-tumor vasculature. CONCLUSIONS Our findings suggest that targeting CXCR4 by peptide R might represent a novel therapeutic approach against GBM, and contribute to the rationale to further explore in more complex pre-clinical settings the therapeutic potential of peptide R, alone or in combination with standard therapies of GBM.
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Affiliation(s)
- Laura Mercurio
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
| | | | - Serena Cecchetti
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
| | - Alessandro Ricci
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
| | - Giuseppina Bozzuto
- Department of Technology and Health, Istituto Superiore di Sanità, Rome, Italy
| | - Agnese Molinari
- Department of Technology and Health, Istituto Superiore di Sanità, Rome, Italy
| | - Isabella Manni
- Department of Research, Diagnosis and Innovative Technologies, Regina Elena National Cancer Institute, Rome, Italy
| | - Bianca Pollo
- Division of Neuropathology, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy
| | - Stefania Scala
- Molecular Immunology, Functional Genomics, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale" IRCCS, Napoli, Italy
| | - Giulia Carpinelli
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
| | - Luisa Minghetti
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
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Smith TAD, Phyu SM. Metformin Decouples Phospholipid Metabolism in Breast Cancer Cells. PLoS One 2016; 11:e0151179. [PMID: 26959405 PMCID: PMC4784930 DOI: 10.1371/journal.pone.0151179] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 02/24/2016] [Indexed: 12/25/2022] Open
Abstract
INTRODUCTION The antidiabetic drug metformin, currently undergoing trials for cancer treatment, modulates lipid and glucose metabolism both crucial in phospholipid synthesis. Here the effect of treatment of breast tumour cells with metformin on phosphatidylcholine (PtdCho) metabolism which plays a key role in membrane synthesis and intracellular signalling has been examined. METHODS MDA-MB-468, BT474 and SKBr3 breast cancer cell lines were treated with metformin and [3H-methyl]choline and [14C(U)]glucose incorporation and lipid accumulation determined in the presence and absence of lipase inhibitors. Activities of choline kinase (CK), CTP:phosphocholine cytidylyl transferase (CCT) and PtdCho-phospholipase C (PLC) were also measured. [3H] Radiolabelled metabolites were determined using thin layer chromatography. RESULTS Metformin-treated cells exhibited decreased formation of [3H]phosphocholine but increased accumulation of [3H]choline by PtdCho. CK and PLC activities were decreased and CCT activity increased by metformin-treatment. [14C] incorporation into fatty acids was decreased and into glycerol was increased in breast cancer cells treated with metformin incubated with [14C(U)]glucose. CONCLUSION This is the first study to show that treatment of breast cancer cells with metformin induces profound changes in phospholipid metabolism.
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Affiliation(s)
- Tim A. D. Smith
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom
| | - Su M. Phyu
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom
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Loukil A, Cheung CT, Bendris N, Lemmers B, Peter M, Blanchard JM. Cyclin A2: At the crossroads of cell cycle and cell invasion. World J Biol Chem 2015; 6:346-50. [PMID: 26629317 PMCID: PMC4657123 DOI: 10.4331/wjbc.v6.i4.346] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Revised: 09/18/2015] [Accepted: 10/12/2015] [Indexed: 02/05/2023] Open
Abstract
Cyclin A2 is an essential regulator of the cell division cycle through the activation of kinases that participate to the regulation of S phase as well as the mitotic entry. However, whereas its degradation by the proteasome in mid mitosis was thought to be essential for mitosis to proceed, recent observations show that a small fraction of cyclin A2 persists beyond metaphase and is degraded by autophagy. Its implication in the control of cytoskeletal dynamics and cell movement has unveiled its role in the modulation of RhoA activity. Since this GTPase is involved in both cell rounding early in mitosis and later, in the formation of the cleavage furrow, this suggests that cyclin A2 is a novel actor in cytokinesis. Taken together, these data point to this cyclin as a potential mediator of cell-niche interactions whose dysregulation could be taken as a hallmark of metastasis.
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Ozawa T, Osaka I, Ihozaki T, Hamada S, Kuroda Y, Murakami T, Miyazato A, Kawasaki H, Arakawa R. Simultaneous detection of phosphatidylcholines and glycerolipids using matrix-enhanced surface-assisted laser desorption/ionization-mass spectrometry with sputter-deposited platinum film. JOURNAL OF MASS SPECTROMETRY : JMS 2015; 50:1264-1269. [PMID: 26505771 DOI: 10.1002/jms.3700] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 07/31/2015] [Accepted: 08/26/2015] [Indexed: 06/05/2023]
Abstract
Matrix-assisted laser desorption/ionisation (MALDI) imaging mass spectrometry (IMS) allows for the simultaneous detection and imaging of several molecules in brain tissue. However, the detection of glycerolipids such as diacylglycerol (DAG) and triacylglycerol (TAG) in brain tissues is hindered in MALDI-IMS because of the ion suppression effect from excessive ion yields of phosphatidylcholine (PC). In this study, we describe an approach that employs a homogeneously deposited metal nanoparticle layer (or film) for the detection of glycerolipids in rat brain tissue sections using IMS. Surface-assisted laser desorption/ionisation IMS with sputter-deposited Pt film (Pt-SALDI-IMS) for lipid analysis was performed as a solvent-free and organic matrix-free method. Pt-SALDI produced a homogenous layer of nanoparticles over the surface of the rat brain tissue section. Highly selective detection of lipids was possible by MALDI-IMS and Pt-SALDI-IMS; MALDI-IMS detected the dominant ion peak of PC in the tissue section, and there were no ion peaks representing glycerolipids such as DAG and TAG. In contrast, Pt-SALDI-IMS allowed the detection of these glycerolipids, but not PC. Therefore, using a hybrid method combining MALDI and Pt-SALDI (i.e., matrix-enhanced [ME]-Pt-SALDI-IMS), we achieved the simultaneous detection of PC, PE and DAG in rat brain tissue sections, and the sensitivity for the detection of these molecules was better than that of MALDI-IMS or Pt-SALDI alone. The present simple ME-Pt-SALDI approach for the simultaneous detection of PC and DAG using two matrices (sputter-deposited Pt film and DHB matrix) would be useful in imaging analyses of biological tissue sections.
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Affiliation(s)
- Tomoyuki Ozawa
- Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials, and Bioengineering, Kansai University, 3-3-35 Yamate-cho, Suita-shi, Osaka, Japan
| | - Issey Osaka
- Center for Nano Materials and Technology, Japan Advanced Institute of Science and Technology, 1-1 Asahidai, Nomi, Ishikawa, Japan
| | - Taisuke Ihozaki
- Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials, and Bioengineering, Kansai University, 3-3-35 Yamate-cho, Suita-shi, Osaka, Japan
| | - Satoshi Hamada
- Analysis Research Department, Chemical Research Laboratories, Nissan Chemical Industries, Ltd., 10-1, Tsuboi-Nishi 2-chome, Funabashi, Chiba, Japan
| | - Yusuke Kuroda
- Toxicology and Environmental Science Department Biological Research Laboratories, Nissan Chemical Industries, Ltd., 10-1, Tsuboi-Nishi 2-chome, Funabashi, Chiba, Japan
| | - Tatsuya Murakami
- Center for Nano Materials and Technology, Japan Advanced Institute of Science and Technology, 1-1 Asahidai, Nomi, Ishikawa, Japan
| | - Akio Miyazato
- Center for Nano Materials and Technology, Japan Advanced Institute of Science and Technology, 1-1 Asahidai, Nomi, Ishikawa, Japan
| | - Hideya Kawasaki
- Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials, and Bioengineering, Kansai University, 3-3-35 Yamate-cho, Suita-shi, Osaka, Japan
| | - Ryuichi Arakawa
- Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials, and Bioengineering, Kansai University, 3-3-35 Yamate-cho, Suita-shi, Osaka, Japan
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Cecchetti S, Bortolomai I, Ferri R, Mercurio L, Canevari S, Podo F, Miotti S, Iorio E. Inhibition of Phosphatidylcholine-Specific Phospholipase C Interferes with Proliferation and Survival of Tumor Initiating Cells in Squamous Cell Carcinoma. PLoS One 2015; 10:e0136120. [PMID: 26402860 PMCID: PMC4581859 DOI: 10.1371/journal.pone.0136120] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Accepted: 07/29/2015] [Indexed: 12/31/2022] Open
Abstract
Purpose The role of phosphatidylcholine-specific phospholipase C (PC-PLC), the enzyme involved in cell differentiation and proliferation, has not yet been explored in tumor initiating cells (TICs). We investigated PC-PLC expression and effects of PC-PLC inhibition in two adherent (AD) squamous carcinoma cell lines (A431 and CaSki), with different proliferative and stemness potential, and in TIC-enriched floating spheres (SPH) originated from them. Results Compared with immortalized non-tumoral keratinocytes (HaCaT) A431-AD cells showed 2.5-fold higher PC-PLC activity, nuclear localization of a 66-kDa PC-PLC isoform, but a similar distribution of the enzyme on plasma membrane and in cytoplasmic compartments. Compared with A431-AD, A431-SPH cells showed about 2.8-fold lower PC-PLC protein and activity levels, but similar nuclear content. Exposure of adherent cells to the PC-PLC inhibitor D609 (48h) induced a 50% reduction of cell proliferation at doses comprised between 33 and 50 μg/ml, without inducing any relevant cytotoxic effect (cell viability 95±5%). In A431-SPH and CaSki-SPH D609 induced both cytostatic and cytotoxic effects at about 20 to 30-fold lower doses (IC50 ranging between 1.2 and 1.6 μg/ml). Furthermore, D609 treatment of A431-AD and CaSki-AD cells affected the sphere-forming efficiency, which dropped in both cells, and induced down-modulation of stem-related markers mRNA levels (Oct4, Nestin, Nanog and ALDH1 in A431; Nestin and ALDH1 in CaSki cells). Conclusions These data suggest that the inhibition of PC-PLC activity may represent a new therapeutic approach to selectively target the most aggressive and tumor promoting sub-population of floating spheres originated from squamous cancer cells possessing different proliferative and stemness potential.
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Affiliation(s)
- Serena Cecchetti
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
| | - Ileana Bortolomai
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Renata Ferri
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Laura Mercurio
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
| | - Silvana Canevari
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- * E-mail: (FP); (SC)
| | - Franca Podo
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
- * E-mail: (FP); (SC)
| | - Silvia Miotti
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Egidio Iorio
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
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Cheung CT, Bendris N, Paul C, Hamieh A, Anouar Y, Hahne M, Blanchard JM, Lemmers B. Cyclin A2 modulates EMT via β-catenin and phospholipase C pathways. Carcinogenesis 2015; 36:914-24. [PMID: 25993989 DOI: 10.1093/carcin/bgv069] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 05/06/2015] [Indexed: 12/15/2022] Open
Abstract
We have previously demonstrated that Cyclin A2 is involved in cytoskeletal dynamics, epithelial-mesenchymal transition (EMT) and metastasis. This phenotype was potentiated by activated oncogenic H-Ras. However, the mechanisms governing EMT in these cells have not yet been elucidated. Here, we dissected the pathways that are responsible for EMT in cells deficient for Cyclin A2. In Cyclin A2-depleted normal murine mammary gland (NMuMG) cells expressing RasV12, we found that β-catenin was liberated from the cell membrane and cell-cell junctions and underwent nuclear translocation and activation. Components of the canonical wingless (WNT) pathway, including WNT8b, WNT10a, WNT10b, frizzled 1 and 2 and TCF4 were upregulated at the messenger RNA and protein levels following Cyclin A2 depletion. However, suppression of the WNT pathway using the acetyltransferase porcupine inhibitor C59 did not reverse EMT whereas a dominant negative form of TCF4 as well as inhibition of phospholipase C using U73122 were able to do so. This suggests that a WNT-independent mechanism of β-catenin activation via phospholipase C is involved in the EMT induced by Cyclin A2 depletion. Our findings will broaden our knowledge on how Cyclin A2 contributes to EMT and metastasis.
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Affiliation(s)
- Caroline T Cheung
- Institut de Génétique Moléculaire de Montpellier, CNRS, France-Université Montpellier 2, France-Université Montpellier 1, Montpellier, France
| | - Nawal Bendris
- Institut de Génétique Moléculaire de Montpellier, CNRS, France-Université Montpellier 2, France-Université Montpellier 1, Montpellier, France, UT Southwestern Medical Center, Department of Cell Biology, Dallas, TX, USA and
| | - Conception Paul
- Institut de Génétique Moléculaire de Montpellier, CNRS, France-Université Montpellier 2, France-Université Montpellier 1, Montpellier, France
| | - Abdallah Hamieh
- INSERM U982, Neuronal and Neuroendocrine Differentiation and Communication, Université de Rouen, Mont-Saint-Aignan, France
| | - Youssef Anouar
- INSERM U982, Neuronal and Neuroendocrine Differentiation and Communication, Université de Rouen, Mont-Saint-Aignan, France
| | - Michael Hahne
- Institut de Génétique Moléculaire de Montpellier, CNRS, France-Université Montpellier 2, France-Université Montpellier 1, Montpellier, France
| | - Jean-Marie Blanchard
- Institut de Génétique Moléculaire de Montpellier, CNRS, France-Université Montpellier 2, France-Université Montpellier 1, Montpellier, France,
| | - Bénédicte Lemmers
- Institut de Génétique Moléculaire de Montpellier, CNRS, France-Université Montpellier 2, France-Université Montpellier 1, Montpellier, France,
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Cocco L, Follo MY, Manzoli L, Suh PG. Phosphoinositide-specific phospholipase C in health and disease. J Lipid Res 2015; 56:1853-60. [PMID: 25821234 DOI: 10.1194/jlr.r057984] [Citation(s) in RCA: 115] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Indexed: 12/20/2022] Open
Abstract
Phospholipases are widely occurring and can be found in several different organisms, including bacteria, yeast, plants, animals, and viruses. Phospholipase C (PLC) is a class of phospholipases that cleaves phospholipids on the diacylglycerol (DAG) side of the phosphodiester bond producing DAGs and phosphomonoesters. Among PLCs, phosphoinositide-specific PLC (PI-PLC) constitutes an important step in the inositide signaling pathways. The structures of PI-PLC isozymes show conserved domains as well as regulatory specific domains. This is important, as most PI-PLCs share a common mechanism, but each of them has a peculiar role and can have a specific cell distribution that is linked to a specific function. More importantly, the regulation of PLC isozymes is fundamental in health and disease, as there are several PLC-dependent molecular mechanisms that are associated with the activation or inhibition of important physiopathological processes. Moreover, PI-PLC alternative splicing variants can play important roles in complex signaling networks, not only in cancer but also in other diseases. That is why PI-PLC isozymes are now considered as important molecules that are essential for better understanding the molecular mechanisms underlying both physiology and pathogenesis, and are also potential molecular targets useful for the development of innovative therapeutic strategies.
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Affiliation(s)
- Lucio Cocco
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy
| | - Matilde Y Follo
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy
| | - Lucia Manzoli
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy
| | - Pann-Ghill Suh
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan 689-798, Korea
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Abstract
Tricyclodecan-9-yl-xanthogenate (D609) is an antioxidative molecule with antiproliferative and neuroprotective properties in a variety of cells. Previously, we have shown that D609 decreased the proliferation of neural progenitor cells. In this study, we examined the antioxidative property of D609 on neural progenitor cells isolated from the subventricular zone of the rat brain. Cellular oxidation was assessed by measuring the ATP content of the cells. Our results show that D609 decreased the ATP content of the neural progenitor cells by ∼40%, suggesting the possible inhibition of cellular metabolic activity. Cytochrome c oxidase (Cox), also known as complex IV of the electron transport chain, is a terminal enzyme involved in the oxidation of substrates resulting in the generation of energy required for the cellular activity. Therefore, regulating the activity of Cox could interfere with the generation of ATP, consequently affecting the proliferation of cells. Consistent with this hypothesis, we also observed a decrease in the Cox activity following the incubation of neural progenitor cells with D609. These results suggest that D609 could inhibit the activity of Cox and subsequent ATP synthesis in the neural progenitor cells.
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Ueda Y, Ishitsuka R, Hullin-Matsuda F, Kobayashi T. Regulation of the transbilayer movement of diacylglycerol in the plasma membrane. Biochimie 2014; 107 Pt A:43-50. [DOI: 10.1016/j.biochi.2014.09.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Accepted: 09/09/2014] [Indexed: 12/27/2022]
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Xin M, Dong XW, Guo XL. Role of the interaction between galectin-3 and cell adhesion molecules in cancer metastasis. Biomed Pharmacother 2014; 69:179-85. [PMID: 25661355 DOI: 10.1016/j.biopha.2014.11.024] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Accepted: 11/12/2014] [Indexed: 12/15/2022] Open
Abstract
Galectin-3, a unique chimera-type member of the β-galactoside-binding soluble lectin family, is present in both normal and cancer cells and plays a crucial role in the regulation of cell adhesion. It is involved both in accelerating detachment of cells from primary tumor sites and promoting cancer cell adhesion and survival to anoikis in the blood stream. Cell adhesion molecules (CAMs) are membrane receptors that mediate cell-cell and cell-matrix interactions, and are essential for transducing intracellular signals responsible for adhesion, migration, invasion, angiogenesis, and organ-specific metastasis. This review will discuss the recent advances in our understanding the biological functions, mechanism and therapeutic implication of the interaction between galectin-3 and CAMs in cancer metastasis.
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Affiliation(s)
- Ming Xin
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China
| | - Xin-Wen Dong
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China
| | - Xiu-Li Guo
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
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Anikeeva N, Sykulev Y, Delikatny EJ, Popov AV. Core-based lipid nanoparticles as a nanoplatform for delivery of near-infrared fluorescent imaging agents. AMERICAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 2014; 4:507-524. [PMID: 25250201 PMCID: PMC4171838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Accepted: 08/06/2014] [Indexed: 06/03/2023]
Abstract
Pyropheophorbide a (Pyro) is a near-infrared (NIR) fluorescent dye and photosensitizer with high quantum yield that makes the dye suitable for tumor treatment both as an imaging and therapy agent. We have designed and synthesized a series of a Pyro-based NIR probes, based on the conjugation of Pyro with lipids. The nature of our probes requires the use of a lipophilic carrier to deliver the probes to cancer cell membranes. To address this, we have utilized lipid-based nanoparticles (LNPs) consisting of PEGylated lipids, which form the nanoparticle shell, and a lipid core. To endow the LNPs with targeting properties, nitrilotriacetic acid (NTA) lipids were included in the composition that enables the non-covalent attachment of His-tag targeting proteins preserving their functional activity. We found that the nature of the core molecules influence the nanoparticle size, shelf-life and stability at physiological temperature. Two different Pyro-lipid conjugates were loaded either into the core or shell of the LNPs. The conjugates revealed differential ability to be accumulated in the cell membrane of the target cells with time. Thus, the modular organization of the core-shell LNPs allows facile adjustment of their composition with goal to fine tuning the nanoparticle properties for in vivo application.
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Affiliation(s)
- Nadia Anikeeva
- Department of Microbiology and Immunology and Kimmel Cancer Center, Thomas Jefferson UniversityPhiladelphia, Pennsylvania, USA
| | - Yuri Sykulev
- Department of Microbiology and Immunology and Kimmel Cancer Center, Thomas Jefferson UniversityPhiladelphia, Pennsylvania, USA
| | - Edward J Delikatny
- Department of Radiology, Perelman School of Medicine, University of PennsylvaniaPhiladelphia, Pennsylvania, USA
| | - Anatoliy V Popov
- Department of Radiology, Perelman School of Medicine, University of PennsylvaniaPhiladelphia, Pennsylvania, USA
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