|
1
|
Ramzy GM, Meister I, Rudaz S, Boccard J, Nowak-Sliwinska P. Identification of Lipid Species Signatures in FOLFOXIRI-Resistant Colorectal Cancer Cells. Int J Mol Sci 2025; 26:1169. [PMID: 39940937 PMCID: PMC11818583 DOI: 10.3390/ijms26031169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 01/22/2025] [Accepted: 01/27/2025] [Indexed: 02/16/2025] Open
Abstract
Chronic drug treatment can alter the lipidome of cancer cells, potentially leading to significant biological changes, such as drug resistance or increased tumor aggressiveness. This study examines the lipidome profiles of four human colorectal cancer (CRC) cell lines, comparing treatment-naïve cells with the same cells after chronic exposure to a clinically used combination therapy (FOLFOXIRI: folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan). Lipidomic profiling was obtained with untargeted liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS). For data deconvolution and to interpret the multifactorial dataset generated, Analysis of Variance Multiblock Orthogonal Partial Least Squares (AMOPLS) was used. Our results indicate specific shifts in triglycerides (TGs), sphingolipids, and phospholipids in CRC cells resistant to FOLFOXIRI. The overall shift in TGs, phosphatidylcholine, and cholesteryl ester species was notably linked to FOLFOXIRI resistance (-R) in SW620 cells, whereas an increased abundance of phospholipids, mainly hexosylceramide and sphingomyelin, was present in the signatures of HCT116-R, LS174T-R, and DLD1-R cells. These altered lipid species may serve as potential prognostic markers in CRC following chemotherapy. Furthermore, lipid-targeting therapies aimed at reprogramming the lipid profiles of drug-resistant cells could play a crucial role in restoring drug sensitivity and improving patient survival.
Collapse
Affiliation(s)
- George M. Ramzy
- Molecular Pharmacology Group, School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva, Switzerland;
- Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1211 Geneva, Switzerland; (I.M.); (S.R.)
- Translational Research Center in Oncohaematology, 1211 Geneva, Switzerland
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
| | - Isabel Meister
- Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1211 Geneva, Switzerland; (I.M.); (S.R.)
- Biomedical and Metabolomics Analysis Group, School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva, Switzerland
- Swiss Centre for Applied Human Toxicology (SCAHT), 4055 Basel, Switzerland
| | - Serge Rudaz
- Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1211 Geneva, Switzerland; (I.M.); (S.R.)
- Biomedical and Metabolomics Analysis Group, School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva, Switzerland
- Swiss Centre for Applied Human Toxicology (SCAHT), 4055 Basel, Switzerland
| | - Julien Boccard
- Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1211 Geneva, Switzerland; (I.M.); (S.R.)
- Biomedical and Metabolomics Analysis Group, School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva, Switzerland
- Swiss Centre for Applied Human Toxicology (SCAHT), 4055 Basel, Switzerland
| | - Patrycja Nowak-Sliwinska
- Molecular Pharmacology Group, School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva, Switzerland;
- Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1211 Geneva, Switzerland; (I.M.); (S.R.)
- Translational Research Center in Oncohaematology, 1211 Geneva, Switzerland
- Swiss Centre for Applied Human Toxicology (SCAHT), 4055 Basel, Switzerland
| |
Collapse
|
|
2
|
Scott NR, Kang S, Parekh SH. Mechanosensitive nuclear uptake of chemotherapy. SCIENCE ADVANCES 2024; 10:eadr5947. [PMID: 39693448 DOI: 10.1126/sciadv.adr5947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 11/14/2024] [Indexed: 12/20/2024]
Abstract
The nucleus is at the nexus of mechanotransduction and the final barrier for most first line chemotherapeutics. Here, we study the intersection between nuclear-cytoskeletal coupling and chemotherapy nuclear internalization. We find that chronic and acute modulation of intracellular filaments changes nuclear influx of doxorubicin (DOX). Rapid changes in cell strain by disruption of cytoskeletal and nuclear filaments sensitize nuclei to DOX, whereas chronic reduction of cell strain desensitize nuclei to DOX. Extracted nuclei from invasive cancer cells lines from different tissues have distinct nuclear permeability to DOX. Last, we show that mechano-priming of cells by paclitaxel markedly improves DOX nuclear internalization, rationalizing the observed drug synergies. Our findings reveal that nuclear uptake is a critical, previously unquantified aspect of drug resistance. With nuclear permeability to chemotherapy being tunable via modulation of nuclear mechanotransduction, mechano-priming may be useful to help overcome drug resistance in the future.
Collapse
Affiliation(s)
- Nicholas R Scott
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA
| | - Sowon Kang
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA
| | - Sapun H Parekh
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA
| |
Collapse
|
|
3
|
Blokhin V, Zavarykina T, Kotsuba V, Kapralova M, Gutner U, Shupik M, Kozyrko E, Luzina E, Lomskova P, Bajgazieva D, Khokhlova S, Alessenko A. The Role of Sphingolipid Metabolism in Pregnancy-Associated Breast Cancer After Chemotherapy. Biomedicines 2024; 12:2843. [PMID: 39767749 PMCID: PMC11673991 DOI: 10.3390/biomedicines12122843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 11/30/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND The aim of our study was to determine the role of sphingolipids, which control proliferation and apoptosis, in the placenta of pregnant women with pregnancy-associated breast cancer (PABC) after chemotherapy compared with healthy patients. METHODS We analyzed (by the PCR method) the gene expression of key sphingolipid metabolism enzymes (sphingomyelinases (SMPD1 and SMPD3), acid ceramidase (ASAH1), ceramide synthases (CERS 1-6), sphingosine kinase1 (SPHK1), sphingosine-1-phosphate lyase 1 (SGPL1), and sphingosine-1-phosphate receptors (S1PR1, S1PR2, and S1PR3)) and the content of subspecies of ceramides, sphingosine, and sphingosine-1-phosphate in seven patients with PABC after chemotherapy and eight healthy pregnant women as a control group. RESULTS We found a significant increase in the expression of genes of acid ceramidase (ASAH1), sphingosine-1-phosphate lyase 1 (SGPL1), sphingosine kinase (SPHK1), and ceramide synthases (CERS 1-3, 5, 6) in the samples of patients with PABC during their treatment with cytostatic chemotherapy. The increase in the expression of the enzymes' genes was not accompanied by changes in the content of the studied sphingolipids. Such significant changes in the expression of genes controlling the level of CER, sphingosine, and S1P may indicate their ability to initiate the metabolism of pro-apoptotic and anti-apoptotic sphingolipids in the placenta of pregnant women with cancer undergoing chemotherapy in order to maintain levels typical of the placenta of healthy women. CONCLUSIONS Our results may indicate the promising mechanism of placenta protection during chemotherapy for pregnant women with breast cancer and, consequently, of the newborn. This protective effect of the placenta and especially for the newborn has been discovered for the first time and requires more careful study.
Collapse
Affiliation(s)
- Victor Blokhin
- Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, Moscow 119334, Russia;
| | - Tatiana Zavarykina
- Emanuel Institute of Biochemical Physics of Russian Academy of Sciences, Moscow 119334, Russia; (T.Z.); (M.K.); (U.G.); (M.S.); (P.L.)
- B.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology of the Ministry of Health of the Russian Federation, Moscow 117997, Russia; (E.K.); (E.L.); (D.B.); (S.K.)
| | - Vasily Kotsuba
- Federal Research Center “Fundamentals of Biotechnology” Russian Academy of Sciences, Moscow 119334, Russia;
- Department of Theoretical and Applied Chemistry, Federal State University of Education, Moscow 105005, Russia
| | - Maria Kapralova
- Emanuel Institute of Biochemical Physics of Russian Academy of Sciences, Moscow 119334, Russia; (T.Z.); (M.K.); (U.G.); (M.S.); (P.L.)
| | - Uliana Gutner
- Emanuel Institute of Biochemical Physics of Russian Academy of Sciences, Moscow 119334, Russia; (T.Z.); (M.K.); (U.G.); (M.S.); (P.L.)
| | - Maria Shupik
- Emanuel Institute of Biochemical Physics of Russian Academy of Sciences, Moscow 119334, Russia; (T.Z.); (M.K.); (U.G.); (M.S.); (P.L.)
| | - Elena Kozyrko
- B.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology of the Ministry of Health of the Russian Federation, Moscow 117997, Russia; (E.K.); (E.L.); (D.B.); (S.K.)
| | - Evgenia Luzina
- B.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology of the Ministry of Health of the Russian Federation, Moscow 117997, Russia; (E.K.); (E.L.); (D.B.); (S.K.)
| | - Polina Lomskova
- Emanuel Institute of Biochemical Physics of Russian Academy of Sciences, Moscow 119334, Russia; (T.Z.); (M.K.); (U.G.); (M.S.); (P.L.)
| | - Darya Bajgazieva
- B.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology of the Ministry of Health of the Russian Federation, Moscow 117997, Russia; (E.K.); (E.L.); (D.B.); (S.K.)
| | - Svetlana Khokhlova
- B.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology of the Ministry of Health of the Russian Federation, Moscow 117997, Russia; (E.K.); (E.L.); (D.B.); (S.K.)
| | - Alice Alessenko
- Emanuel Institute of Biochemical Physics of Russian Academy of Sciences, Moscow 119334, Russia; (T.Z.); (M.K.); (U.G.); (M.S.); (P.L.)
| |
Collapse
|
|
4
|
Ung J, Kassai M, Tan SF, Loughran TP, Feith DJ, Cabot MC. The Drug Transporter P-Glycoprotein and Its Impact on Ceramide Metabolism-An Unconventional Ally in Cancer Treatment. Int J Mol Sci 2024; 25:9825. [PMID: 39337312 PMCID: PMC11432138 DOI: 10.3390/ijms25189825] [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: 07/26/2024] [Revised: 09/06/2024] [Accepted: 09/09/2024] [Indexed: 09/30/2024] Open
Abstract
The tumor-suppressor sphingolipid ceramide is recognized as a key participant in the cytotoxic mechanism of action of many types of chemotherapy drugs, including anthracyclines, Vinca alkaloids, the podophyllotoxin etoposide, taxanes, and the platinum drug oxaliplatin. These drugs can activate de novo synthesis of ceramide or stimulate the production of ceramide via sphingomyelinases to limit cancer cell survival. On the contrary, dysfunctional sphingolipid metabolism, a prominent factor in cancer survival and therapy resistance, blunts the anticancer properties of ceramide-orchestrated cell death pathways, especially apoptosis. Although P-glycoprotein (P-gp) is famous for its role in chemotherapy resistance, herein, we propose alternate interpretations and discuss the capacity of this multidrug transporter as a "ceramide neutralizer", an unwelcome event, highlighting yet another facet of P-gp's versatility in drug resistance. We introduce sphingolipid metabolism and its dysfunctional regulation in cancer, present a summary of factors that contribute to chemotherapy resistance, explain how P-gp "neutralizes" ceramide by hastening its glycosylation, and consider therapeutic applications of the P-gp-ceramide connection in the treatment of cancer.
Collapse
Affiliation(s)
- Johnson Ung
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA;
| | - Miki Kassai
- Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, The East Carolina Diabetes and Obesity Institute, Greenville, NC 27834, USA;
| | - Su-Fern Tan
- University of Virginia Cancer Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; (S.-F.T.); (D.J.F.)
- Department of Medicine, Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Thomas P. Loughran
- University of Virginia Cancer Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; (S.-F.T.); (D.J.F.)
- Department of Medicine, Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - David J. Feith
- University of Virginia Cancer Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; (S.-F.T.); (D.J.F.)
- Department of Medicine, Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Myles C. Cabot
- Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, The East Carolina Diabetes and Obesity Institute, Greenville, NC 27834, USA;
| |
Collapse
|
|
5
|
Hu T, Chen X, Lu S, Zeng H, Guo L, Han Y. Biological Role and Mechanism of Lipid Metabolism Reprogramming Related Gene ECHS1 in Cancer. Technol Cancer Res Treat 2022; 21:15330338221140655. [PMID: 36567598 PMCID: PMC9806408 DOI: 10.1177/15330338221140655] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Cancer is a major threat to human health today. Although the existing anticancer treatments have effectively improved the prognosis of some patients, there are still other patients who cannot benefit from these well-established strategies. Reprogramming of lipid metabolism is one of the typical features of cancers. Recent studies have revealed that key enzymes involved in lipid metabolism may be effective anticancer therapeutic targets, but the development of therapeutic lipid metabolism targets is still insufficient. ECHS1 (enoyl-CoA hydratase, short chain 1) is a key enzyme mediating the hydration process of mitochondrial fatty acid β-oxidation and has been observed to be abnormally expressed in a variety of cancers. Therefore, with ECHS1 and cancer as the main keywords, we searched the relevant studies of ECHS1 in the field of cancer in Pubmed, summarized the research status and functions of ECHS1 in different cancer contexts, and explored its potential regulatory mechanisms, with a view to finding new therapeutic targets for anti-metabolic therapy. By reviewing and summarizing the retrieved literatures, we found that ECHS1 regulates malignant biological behaviors such as cell proliferation, metastasis, apoptosis, autophagy, and drug resistance by remodeling lipid metabolism and regulating intercellular oncogenic signaling pathways. Not only that, ECHS1 exhibits early diagnostic and prognostic value in clear cell renal cell carcinoma, and small-molecule inhibitors that regulate ECHS1 also show therapeutic significance in preclinical studies. Taken together, we propose that ECHS1 has the potential to serve as a therapeutic target of lipid metabolism.
Collapse
Affiliation(s)
- Teng Hu
- Department of Oncology, The Affiliated Hospital of Southwest
Medical University, Luzhou, Sichuan, China
| | - Xiaojing Chen
- Department of Oncology, The Affiliated Hospital of Southwest
Medical University, Luzhou, Sichuan, China
| | - Simin Lu
- Department of Oncology, The Affiliated Hospital of Southwest
Medical University, Luzhou, Sichuan, China
| | - Hao Zeng
- Department of Oncology, The Affiliated Hospital of Southwest
Medical University, Luzhou, Sichuan, China
| | - Lu Guo
- Department of Ophthalmology, The Affiliated Hospital of Southwest
Medical University, Luzhou, Sichuan, China
| | - Yunwei Han
- Department of Oncology, The Affiliated Hospital of Southwest
Medical University, Luzhou, Sichuan, China,Yunwei Han, Department of Oncology, The
Affiliated Hospital of Southwest Medical University, Taiping Street, No. 25,
Luzhou, Sichuan Province 646000, China.
| |
Collapse
|
|
6
|
Kim SO, Kim BY, Lee KH. Synergistic effect of anticancer drug resistance and Wnt3a on primary ciliogenesis in A549 cell-derived anticancer drug-resistant subcell lines. Biochem Biophys Res Commun 2022; 635:1-11. [DOI: 10.1016/j.bbrc.2022.10.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 10/05/2022] [Indexed: 11/02/2022]
|
|
7
|
Mixed lineage kinase 3 and CD70 cooperation sensitize trastuzumab-resistant HER2 + breast cancer by ceramide-loaded nanoparticles. Proc Natl Acad Sci U S A 2022; 119:e2205454119. [PMID: 36095190 PMCID: PMC9499572 DOI: 10.1073/pnas.2205454119] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Trastuzumab is the first-line therapy for human epidermal growth factor receptor 2-positive (HER2+) breast cancer, but often patients develop acquired resistance. Although other agents are in clinical use to treat trastuzumab-resistant (TR) breast cancer; still, the patients develop recurrent metastatic disease. One of the primary mechanisms of acquired resistance is the shedding/loss of the HER2 extracellular domain, where trastuzumab binds. We envisioned any new agent acting downstream of the HER2 should overcome trastuzumab resistance. The mixed lineage kinase 3 (MLK3) activation by trastuzumab is necessary for promoting cell death in HER2+ breast cancer. We designed nanoparticles loaded with MLK3 agonist ceramide (PPP-CNP) and tested their efficacy in sensitizing TR cell lines, patient-derived organoids, and patient-derived xenograft (PDX). The PPP-CNP activated MLK3, its downstream JNK kinase activity, and down-regulated AKT pathway signaling in TR cell lines and PDX. The activation of MLK3 and down-regulation of AKT signaling by PPP-CNP induced cell death and inhibited cellular proliferation in TR cells and PDX. The apoptosis in TR cells was dependent on increased CD70 protein expression and caspase-9 and caspase-3 activities by PPP-CNP. The PPP-CNP treatment alike increased the expression of CD70, CD27, cleaved caspase-9, and caspase-3 with a concurrent tumor burden reduction of TR PDX. Moreover, the expressions of CD70 and ceramide levels were lower in TR than sensitive HER2+ human breast tumors. Our in vitro and preclinical animal models suggest that activating the MLK3-CD70 axis by the PPP-CNP could sensitize/overcome trastuzumab resistance in HER2+ breast cancer.
Collapse
|
|
8
|
Chen S, Bian H, Duan J. High-Intensity Focused Ultrasound Enhanced Anti-Tumor Activities of Paclitaxel in Breast Cancer in vitro and in vivo. Cancer Manag Res 2022; 14:1303-1312. [PMID: 35386184 PMCID: PMC8978695 DOI: 10.2147/cmar.s349409] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 01/31/2022] [Indexed: 12/21/2022] Open
Abstract
Background Paclitaxel (PTX) is an important oncologic chemotherapeutic agent against breast cancer, but breast cancer patients develop significant resistance to PTX during chemotherapy. Alterations in tubulin and associated proteins have been implicated in resistance to PTX. High-intensity focused ultrasound (HIFU) induces deep tumor penetration of anti-tumor agents in solid tumors. Methods We investigated the influence of HIFU on the anti-tumor activities of PTX in breast cancer. Both in vivo and in vitro experiments were performed in this research: mice were treated with 2 mg/Kg PTX through tail vein injection, while breast cancer cells were treated with 400 nM PTX. Cell viability was analyzed through Cell Counting Kit-8. Cell apoptosis was evaluated through Annexin-V/PI Apoptosis Analysis Kit. The activities of catalase (CAT) and superoxide dismutase (SOD) and the concentration of malondialdehyde (MDA) were evaluated by relative commercial kits. Results HIFU enhanced PTX-inhibited breast cancer cell viability and PTX-induced cell apoptosis. Simultaneous treatment of HIFU and PTX decreased the activities of CAT and SOD and increased the concentration of MDA. In mice bearing MDA-MB-231 tumors, the treatment of HIFU and PTX significantly decreased tumor size, increased body weight and elevated animal survival. HIFU enhanced the distribution of PTX in tumor tissues. Conclusion The performance of HIFU promoted the distribution of PTX and enhanced its anti-tumor activities in breast cancer.
Collapse
Affiliation(s)
- Sha Chen
- Department 2 of Ultrasound, Cangzhou Central Hospital, Cangzhou, 061000, Hebei, People’s Republic of China
- Correspondence: Sha Chen, Department 2 of Ultrasound, Cangzhou Central Hospital, No. 16, Xinhua West Road, Yunhe District, Cangzhou, 061000, Hebei, People’s Republic of China, Tel +86-18232858958, Email
| | - Hao Bian
- Magnetic Resonance Imaging Department, Cangzhou Central Hospital, Cangzhou, 061000, Hebei, People’s Republic of China
| | - Jingyu Duan
- Department 2 of Ultrasound, Cangzhou Central Hospital, Cangzhou, 061000, Hebei, People’s Republic of China
| |
Collapse
|
|
9
|
Bataller M, Sánchez-García A, Garcia-Mayea Y, Mir C, Rodriguez I, LLeonart ME. The Role of Sphingolipids Metabolism in Cancer Drug Resistance. Front Oncol 2022; 11:807636. [PMID: 35004331 PMCID: PMC8733468 DOI: 10.3389/fonc.2021.807636] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 12/07/2021] [Indexed: 12/25/2022] Open
Abstract
Drug resistance continues to be one of the major challenges to cure cancer. As research in this field evolves, it has been proposed that numerous bioactive molecules might be involved in the resistance of cancer cells to certain chemotherapeutics. One well-known group of lipids that play a major role in drug resistance are the sphingolipids. Sphingolipids are essential components of the lipid raft domains of the plasma membrane and this structural function is important for apoptosis and/or cell proliferation. Dysregulation of sphingolipids, including ceramide, sphingomyelin or sphingosine 1-phosphate, has been linked to drug resistance in different types of cancer, including breast, melanoma or colon cancer. Sphingolipid metabolism is complex, involving several lipid catabolism with the participation of key enzymes such as glucosylceramide synthase (GCS) and sphingosine kinase 1 (SPHK1). With an overview of the latest available data on this topic and its implications in cancer therapy, this review focuses on the main enzymes implicated in sphingolipids metabolism and their intermediate metabolites involved in cancer drug resistance.
Collapse
Affiliation(s)
- Marina Bataller
- Biomedical Research in Cancer Stem Cells Group, Vall d´Hebron Research Institute (VHIR), Barcelona, Spain
| | - Almudena Sánchez-García
- Biomedical Research in Cancer Stem Cells Group, Vall d´Hebron Research Institute (VHIR), Barcelona, Spain
| | - Yoelsis Garcia-Mayea
- Biomedical Research in Cancer Stem Cells Group, Vall d´Hebron Research Institute (VHIR), Barcelona, Spain
| | - Cristina Mir
- Biomedical Research in Cancer Stem Cells Group, Vall d´Hebron Research Institute (VHIR), Barcelona, Spain
| | - Isabel Rodriguez
- Assistant Director of Nursing, Nursing Management Service Hospital Vall d'Hebron, Barcelona, Spain
| | - Matilde Esther LLeonart
- Biomedical Research in Cancer Stem Cells Group, Vall d´Hebron Research Institute (VHIR), Barcelona, Spain.,Spanish Biomedical Research Network Centre in Oncology, CIBERONC, Madrid, Spain
| |
Collapse
|
|
10
|
Fisher-Wellman KH, Hagen JT, Kassai M, Kao LP, Nelson MAM, McLaughlin KL, Coalson HS, Fox TE, Tan SF, Feith DJ, Kester M, Loughran TP, Claxton DF, Cabot MC. Alterations in sphingolipid composition and mitochondrial bioenergetics represent synergistic therapeutic vulnerabilities linked to multidrug resistance in leukemia. FASEB J 2021; 36:e22094. [PMID: 34888943 DOI: 10.1096/fj.202101194rrr] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 11/11/2021] [Accepted: 11/24/2021] [Indexed: 12/23/2022]
Abstract
Modifications in sphingolipid (SL) metabolism and mitochondrial bioenergetics are key factors implicated in cancer cell response to chemotherapy, including chemotherapy resistance. In the present work, we utilized acute myeloid leukemia (AML) cell lines, selected to be refractory to various chemotherapeutics, to explore the interplay between SL metabolism and mitochondrial biology supportive of multidrug resistance (MDR). In agreement with previous findings in cytarabine or daunorubicin resistant AML cells, relative to chemosensitive wildtype controls, HL-60 cells refractory to vincristine (HL60/VCR) presented with alterations in SL enzyme expression and lipidome composition. Such changes were typified by upregulated expression of various ceramide detoxifying enzymes, as well as corresponding shifts in ceramide, glucosylceramide, and sphingomyelin (SM) molecular species. With respect to mitochondria, despite consistent increases in both basal respiration and maximal respiratory capacity, direct interrogation of the oxidative phosphorylation (OXPHOS) system revealed intrinsic deficiencies in HL60/VCR, as well as across multiple MDR model systems. Based on the apparent requirement for augmented SL and mitochondrial flux to support the MDR phenotype, we explored a combinatorial therapeutic paradigm designed to target each pathway. Remarkably, despite minimal cytotoxicity in peripheral blood mononuclear cells (PBMC), co-targeting SL metabolism, and respiratory complex I (CI) induced synergistic cytotoxicity consistently across multiple MDR leukemia models. Together, these data underscore the intimate connection between cellular sphingolipids and mitochondrial metabolism and suggest that pharmacological intervention across both pathways may represent a novel treatment strategy against MDR.
Collapse
Affiliation(s)
- Kelsey H Fisher-Wellman
- Department of Physiology, Brody School of Medicine, and the East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina, USA
| | - James T Hagen
- Department of Physiology, Brody School of Medicine, and the East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina, USA
| | - Miki Kassai
- Department of Biochemistry & Molecular Biology, Brody School of Medicine, and the East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina, USA
| | - Li-Pin Kao
- Department of Biochemistry & Molecular Biology, Brody School of Medicine, and the East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina, USA
| | - Margaret A M Nelson
- Department of Physiology, Brody School of Medicine, and the East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina, USA
| | - Kelsey L McLaughlin
- Department of Physiology, Brody School of Medicine, and the East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina, USA
| | - Hannah S Coalson
- Department of Physiology, Brody School of Medicine, and the East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina, USA
| | - Todd E Fox
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Su-Fern Tan
- Department of Medicine, Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - David J Feith
- Department of Medicine, Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.,University of Virginia Cancer Center, Charlottesville, Virginia, USA
| | - Mark Kester
- Department of Medicine, Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.,University of Virginia Cancer Center, Charlottesville, Virginia, USA
| | - Thomas P Loughran
- Department of Medicine, Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.,University of Virginia Cancer Center, Charlottesville, Virginia, USA
| | - David F Claxton
- Department of Medicine, Division of Hematology and Oncology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.,Penn state Cancer Institute, Hershey, Pennsylvania, USA
| | - Myles C Cabot
- Department of Biochemistry & Molecular Biology, Brody School of Medicine, and the East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina, USA
| |
Collapse
|
|
11
|
Kim M, Park SC, Lee DY. Glycyrrhizin as a Nitric Oxide Regulator in Cancer Chemotherapy. Cancers (Basel) 2021; 13:cancers13225762. [PMID: 34830916 PMCID: PMC8616433 DOI: 10.3390/cancers13225762] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/12/2021] [Accepted: 11/15/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Glycyrrhizin (GL) has anti-cancer, anti-inflammatory, anti-viral, and anti-oxidant activity. In particular, GL reduces multidrug resistance (MDR) in cancer cells, which is a major obstacle to chemotherapy. Nitric oxide (NO) also plays an important role in MDR, and GL affects NO concentration in the tumor microenvironment. However, the effects of GL and NO interaction on MDR have not been reviewed. Here, we review the role of GL as an NO regulator in cancer cells and its subsequent anti-MDR effect and posit that GL is a promising MDR inhibitor for cancer chemotherapy. Abstract Chemotherapy is used widely for cancer treatment; however, the evolution of multidrug resistance (MDR) in many patients limits the therapeutic benefits of chemotherapy. It is important to overcome MDR for enhanced chemotherapy. ATP-dependent efflux of drugs out of cells is the main mechanism of MDR. Recent studies have suggested that nitric oxide (NO) can be used to overcome MDR by inhibiting the ATPase function of ATP-dependent pumps. Several attempts have been made to deliver NO to the tumor microenvironment (TME), however there are limitations in delivery. Glycyrrhizin (GL), an active compound of licorice, has been reported to both reduce the MDR effect by inhibiting ATP-dependent pumps and function as a regulator of NO production in the TME. In this review, we describe the potential role of GL as an NO regulator and MDR inhibitor that efficiently reduces the MDR effect in cancer chemotherapy.
Collapse
Affiliation(s)
- Minsu Kim
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul 04763, Korea; (M.K.); (S.C.P.)
| | - Seok Chan Park
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul 04763, Korea; (M.K.); (S.C.P.)
| | - Dong Yun Lee
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul 04763, Korea; (M.K.); (S.C.P.)
- Institute of Nano Science & Technology (INST), Hanyang University, Seoul 04763, Korea
- Elixir Pharmatech Inc., Seoul 04763, Korea
- Correspondence:
| |
Collapse
|
|
12
|
Abstract
Rates of obesity and diabetes have increased significantly over the past decades and the prevalence is expected to continue to rise further in the coming years. Many observations suggest that obesity and diabetes are associated with an increased risk of developing several types of cancers, including liver, pancreatic, endometrial, colorectal, and post-menopausal breast cancer. The path towards developing obesity and diabetes is affected by multiple factors, including adipokines, inflammatory cytokines, growth hormones, insulin resistance, and hyperlipidemia. The metabolic abnormalities associated with changes in the levels of these factors in obesity and diabetes have the potential to significantly contribute to the development and progression of cancer through the regulation of distinct signaling pathways. Here, we highlight the cellular and molecular pathways that constitute the links between obesity, diabetes, cancer risk and mortality. This includes a description of the existing evidence supporting the obesity-driven morphological and functional alternations of cancer cells and adipocytes through complex interactions within the tumor microenvironment.
Collapse
Affiliation(s)
- Dae-Seok Kim
- Touchstone Diabetes Center, Department of Internal Medicine, Dallas, TX, USA
| | - Philipp E. Scherer
- Touchstone Diabetes Center, Department of Internal Medicine, Dallas, TX, USA
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Corresponding author: Philipp E. Scherer https://orcid.org/0000-0003-0680-3392 Touchstone Diabetes Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, USA E-mail:
| |
Collapse
|
|
13
|
Shammout ODA, Ashmawy NS, Shakartalla SB, Altaie AM, Semreen MH, Omar HA, Soliman SSM. Comparative sphingolipidomic analysis reveals significant differences between doxorubicin-sensitive and -resistance MCF-7 cells. PLoS One 2021; 16:e0258363. [PMID: 34637456 PMCID: PMC8509934 DOI: 10.1371/journal.pone.0258363] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 09/25/2021] [Indexed: 12/09/2022] Open
Abstract
Drug resistance is responsible for the failure of many available anticancer drugs. Several studies have demonstrated the association between the alteration in sphingolipids (SPLs) and the development of drug resistance. To investigate the association between SPLs metabolism and doxorubicin (dox)-resistance in MCF-7 cells, a comparative sphingolipidomics analysis between dox-sensitive (parental) and -resistant MCF-7 cell lines along with validation by gene expression analysis were conducted. A total of 31 SPLs representing 5 subcategories were identified. The data obtained revealed that SPLs were clustered into two groups differentiating parental from dox-resistant cells. Eight SPLs were significantly altered in response to dox-resistance including SM (d18:1/16), SM (d18:1/24:2), SM (d18:1/24:0), SM (d18:1/20:0), SM (d18:1/23:1), HexCer (d18:1/24:0), SM (d18:1/15:0), DHSM (d18:0/20:0). The current study is the first to conclusively ascertain the potential involvement of dysregulated SPLs in dox-resistance in MCF-7 cells. SPLs metabolism in dox-resistant MCF-7 cells is oriented toward the downregulation of ceramides (Cer) and the concomitant increase in sphingomyelin (SM). Gene expression analysis has revealed that dox-resistant cells tend to escape from the Cer-related apoptosis by the activation of SM-Cer and GluCer-LacCer-ganglioside pathways. The enzymes that were correlated to the alteration in SPLs metabolism of dox-resistant MCF-7 cells and significantly altered in gene expression can represent potential targets that can represent a winning strategy for the future development of promising anticancer drugs.
Collapse
Affiliation(s)
- Ola D. A. Shammout
- College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Naglaa S. Ashmawy
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Faculty of Pharmacy, Department of Pharmacognosy, Ain Shams University, Cairo, Egypt
- Pharmacy Department, City University College of Ajman, Ajman, UAE
| | - Sarra B. Shakartalla
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Faculty of Pharmacy, University of Gezira, Wadmedani, Sudan
| | - Alaa M. Altaie
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Mohammad H. Semreen
- College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Hany A. Omar
- College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Sameh S. M. Soliman
- College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- * E-mail:
| |
Collapse
|
|
14
|
Patel H, Wu ZX, Chen Y, Bo L, Chen ZS. Drug resistance: from bacteria to cancer. MOLECULAR BIOMEDICINE 2021; 2:27. [PMID: 35006446 PMCID: PMC8607383 DOI: 10.1186/s43556-021-00041-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 04/22/2021] [Indexed: 12/14/2022] Open
Abstract
The phenomenon of drug resistance has been a hindrance to therapeutic medicine since the late 1940s. There is a plethora of factors and mechanisms contributing to progression of drug resistance. From prokaryotes to complex cancers, drug resistance is a prevailing issue in clinical medicine. Although there are numerous factors causing and influencing the phenomenon of drug resistance, cellular transporters contribute to a noticeable majority. Efflux transporters form a huge family of proteins and are found in a vast number of species spanning from prokaryotes to complex organisms such as humans. During the last couple of decades, various approaches in analyses of biochemistry and pharmacology of transporters have led us to understand much more about drug resistance. In this review, we have discussed the structure, function, potential causes, and mechanisms of multidrug resistance in bacteria as well as cancers.
Collapse
Affiliation(s)
- Harsh Patel
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, NY, 11439, USA
| | - Zhuo-Xun Wu
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, NY, 11439, USA
| | - Yanglu Chen
- Columbia University Vagelos College of Physicians and Surgeons, New York, NY, 10032, USA
| | - Letao Bo
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, NY, 11439, USA
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, NY, 11439, USA.
| |
Collapse
|
|
15
|
Reza S, Ugorski M, Suchański J. Glucosylceramide and galactosylceramide, small glycosphingolipids with significant impact on health and disease. Glycobiology 2021; 31:1416-1434. [PMID: 34080016 PMCID: PMC8684486 DOI: 10.1093/glycob/cwab046] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 05/18/2021] [Accepted: 05/20/2021] [Indexed: 11/26/2022] Open
Abstract
Numerous clinical observations and exploitation of cellular and animal models indicate that glucosylceramide (GlcCer) and galactosylceramide (GalCer) are involved in many physiological and pathological phenomena. In many cases, the biological importance of these monohexosylcermides has been shown indirectly as the result of studies on enzymes involved in their synthesis and degradation. Under physiological conditions, GalCer plays a key role in the maintenance of proper structure and stability of myelin and differentiation of oligodendrocytes. On the other hand, GlcCer is necessary for the proper functions of epidermis. Such an important lysosomal storage disease as Gaucher disease (GD) and a neurodegenerative disorder as Parkinson’s disease are characterized by mutations in the GBA1 gene, decreased activity of lysosomal GBA1 glucosylceramidase and accumulation of GlcCer. In contrast, another lysosomal disease, Krabbe disease, is associated with mutations in the GALC gene, resulting in deficiency or decreased activity of lysosomal galactosylceramidase and accumulation of GalCer and galactosylsphingosine. Little is known about the role of both monohexosylceramides in tumor progression; however, numerous studies indicate that GlcCer and GalCer play important roles in the development of multidrug-resistance by cancer cells. It was shown that GlcCer is able to provoke immune reaction and acts as a self-antigen in GD. On the other hand, GalCer was recognized as an important cellular receptor for HIV-1. Altogether, these two molecules are excellent examples of how slight differences in chemical composition and molecular conformation contribute to profound differences in their physicochemical properties and biological functions.
Collapse
Affiliation(s)
- Safoura Reza
- Department of Biochemistry and Molecular Biology, Wroclaw University of Environmental and Life Sciences, C.K. Norwida 31, 50-375, Wroclaw, Poland
| | - Maciej Ugorski
- Department of Biochemistry and Molecular Biology, Wroclaw University of Environmental and Life Sciences, C.K. Norwida 31, 50-375, Wroclaw, Poland
| | - Jarosław Suchański
- Department of Biochemistry and Molecular Biology, Wroclaw University of Environmental and Life Sciences, C.K. Norwida 31, 50-375, Wroclaw, Poland
| |
Collapse
|
|
16
|
Mynott RL, Wallington-Beddoe CT. Drug and Solute Transporters in Mediating Resistance to Novel Therapeutics in Multiple Myeloma. ACS Pharmacol Transl Sci 2021; 4:1050-1065. [PMID: 34151200 DOI: 10.1021/acsptsci.1c00074] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Indexed: 02/06/2023]
Abstract
Multiple myeloma remains an incurable malignancy of plasma cells. Novel therapies, notably proteasome inhibitors and immunomodulatory drugs, have improved the survival of multiple myeloma patients; however, patients either present with, or develop resistance to, these therapies. Resistance to traditional chemotherapeutic agents can be caused by cellular drug efflux via adenosine triphosphate (ATP)-binding cassette (ABC) transporters, but it is still not clear whether these transporters mediate resistance to proteasome inhibitors and immunomodulatory drugs in multiple myeloma. Solute carrier (SLC) transporters also play a role in cancer drug resistance due to changes in cell homeostasis caused by their abnormal expression and changes in the solutes they transport. In this review, we evaluate resistance to novel therapies used to treat multiple myeloma, as mediated by drug and solute transporters.
Collapse
Affiliation(s)
- Rachel L Mynott
- College of Medicine and Public Health, Flinders University, Bedford Park, South Australia 5042, Australia
| | - Craig T Wallington-Beddoe
- College of Medicine and Public Health, Flinders University, Bedford Park, South Australia 5042, Australia.,Flinders Medical Centre, Bedford Park, South Australia 5042, Australia.,Centre for Cancer Biology, University of South Australia and SA Pathology, UniSA CRI Building, North Tce, Adelaide, South Australia 5000, Australia.,Adelaide Medical School, University of Adelaide, Adelaide, South Australia 5000, Australia
| |
Collapse
|
|
17
|
Gupta P, Taiyab A, Hussain A, Alajmi MF, Islam A, Hassan MI. Targeting the Sphingosine Kinase/Sphingosine-1-Phosphate Signaling Axis in Drug Discovery for Cancer Therapy. Cancers (Basel) 2021; 13:1898. [PMID: 33920887 PMCID: PMC8071327 DOI: 10.3390/cancers13081898] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 03/11/2021] [Accepted: 04/03/2021] [Indexed: 02/07/2023] Open
Abstract
Sphingolipid metabolites have emerged as critical players in the regulation of various physiological processes. Ceramide and sphingosine induce cell growth arrest and apoptosis, whereas sphingosine-1-phosphate (S1P) promotes cell proliferation and survival. Here, we present an overview of sphingolipid metabolism and the compartmentalization of various sphingolipid metabolites. In addition, the sphingolipid rheostat, a fine metabolic balance between ceramide and S1P, is discussed. Sphingosine kinase (SphK) catalyzes the synthesis of S1P from sphingosine and modulates several cellular processes and is found to be essentially involved in various pathophysiological conditions. The regulation and biological functions of SphK isoforms are discussed. The functions of S1P, along with its receptors, are further highlighted. The up-regulation of SphK is observed in various cancer types and is also linked to radio- and chemoresistance and poor prognosis in cancer patients. Implications of the SphK/S1P signaling axis in human pathologies and its inhibition are discussed in detail. Overall, this review highlights current findings on the SphK/S1P signaling axis from multiple angles, including their functional role, mechanism of activation, involvement in various human malignancies, and inhibitor molecules that may be used in cancer therapy.
Collapse
Affiliation(s)
- Preeti Gupta
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India; (P.G.); (A.T.); (A.I.)
| | - Aaliya Taiyab
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India; (P.G.); (A.T.); (A.I.)
| | - Afzal Hussain
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (A.H.); (M.F.A.)
| | - Mohamed F. Alajmi
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (A.H.); (M.F.A.)
| | - Asimul Islam
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India; (P.G.); (A.T.); (A.I.)
| | - Md. Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India; (P.G.); (A.T.); (A.I.)
| |
Collapse
|
|
18
|
Mynott RL, Wallington-Beddoe CT. Inhibition of P-Glycoprotein Does Not Increase the Efficacy of Proteasome Inhibitors in Multiple Myeloma Cells. ACS Pharmacol Transl Sci 2021; 4:713-729. [PMID: 33860196 DOI: 10.1021/acsptsci.0c00200] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Indexed: 12/14/2022]
Abstract
P-Glycoprotein is a well-known drug transporter associated with chemotherapy resistance in a number of cancers, but its role in modulating proteasome inhibitor efficacy in multiple myeloma is not well understood. The second-generation proteasome inhibitor carfilzomib is thought to be a substrate of P-glycoprotein whose efficacy may correlate with P-glycoprotein activity; however, research concerning the first-in-class proteasome inhibitor bortezomib is inconsistent. We show that while P-glycoprotein gene expression increases with the disease stages leading to multiple myeloma it does not affect the survival of newly diagnosed patients treated with bortezomib. Moreover, RNA-seq on LP-1 cells demonstrated minimal basal P-glycoprotein expression which did not increase after exposure to bortezomib or carfilzomib. Only one (KMS-18) of nine multiple myeloma cell lines expressed P-glycoprotein, including RPMI-8226 cells that are resistant to bortezomib or carfilzomib. We hypothesized that by inhibiting P-glycoprotein multiple myeloma cell sensitivity to proteasome inhibitors would increase; however, the sensitivity of multiple myeloma cells lines to proteasome inhibition was not enhanced by the specific P-glycoprotein inhibitor tariquidar. In addition, targeting glucosylceramide synthase with eliglustat did not inhibit P-glycoprotein activity nor improve proteasome inhibitor efficacy except at a high concentration. To confirm these negative findings, tariquidar did not substantially increase the cytotoxicity of bortezomib or carfilzomib in P-glycoprotein-expressing K562/ADM cells. We conclude the following: P-glycoprotein expression may not correlate with the survival of newly diagnosed multiple myeloma patients treated with proteasome inhibitors. P-glycoprotein is poorly expressed in many multiple myeloma cell lines, and its inhibition does not appreciably enhance the efficacy of proteasome inhibitors.
Collapse
Affiliation(s)
- Rachel L Mynott
- College of Medicine and Public Health, Flinders University, Bedford Park, South Australia 5042, Australia
| | - Craig T Wallington-Beddoe
- College of Medicine and Public Health, Flinders University, Bedford Park, South Australia 5042, Australia.,Flinders Medical Centre, Bedford Park, South Australia 5042, Australia.,Centre for Cancer Biology, University of South Australia and SA Pathology, UniSA CRI Building, North Tce, Adelaide, South Australia 5000, Australia.,Adelaide Medical School, University of Adelaide, Adelaide, South Australia 5000, Australia
| |
Collapse
|
|
19
|
Abstract
Chemotherapy represents the current mainstay therapeutic approach for most types of cancer. Despite the development of targeted chemotherapeutic strategies, the efficacy of anti-cancer drugs is severely limited by the development of drug resistance. Multidrug resistance (MDR) consists of the simultaneous resistance to various unrelated cytotoxic drugs and is one of the main causes of anticancer treatment failure. One of the principal mechanisms by which cancer cells become MDR involves the overexpression of ATP Binding Cassette (ABC) transporters, such as P-glycoprotein (P-gp), mediating the active efflux of cytotoxic molecules from the cytoplasm. Extracellular vesicles (EVs) are submicron lipid-enclosed vesicles that are released by all cells and which play a fundamental role in intercellular communication in physiological and pathological contexts. EVs have fundamental function at each step of cancer development and progression. They mediate the transmission of MDR through the transfer of vesicle cargo including functional ABC transporters as well as nucleic acids, proteins and lipids. Furthermore, EVs mediate MDR by sequestering anticancer drugs and stimulate cancer cell migration and invasion. EVs also mediate the communication with the tumour microenvironment and the immune system, resulting in increased angiogenesis, metastasis and immune evasion. All these actions contribute directly and indirectly to the development of chemoresistance and treatment failure. In this chapter, we describe the many roles EVs play in the acquisition and spread of chemoresistance in cancer. We also discuss possible uses of EVs as pharmacological targets to overcome EV-mediated drug resistance and the potential that the analysis of tumour-derived EVs offers as chemoresistance biomarkers.
Collapse
Affiliation(s)
- Gabriele De Rubis
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, Australia
| | - Mary Bebawy
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, Australia.
| |
Collapse
|
|
20
|
Zhang X, Shan S, Shi J, Li H, Li Z. Polyphenol from millet bran increases the sensitivity of colorectal cancer cells to oxaliplatin by blocking the ganglioside GM3 catabolism. Food Funct 2021; 12:291-301. [DOI: 10.1039/d0fo02232b] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The study implies that bound polyphenol from millet bran dramatically prevents ganglioside GM3 catabolism followed by the suppression of P-gp, which eventually reverse drug-resistance in colorectal cancer cells to oxaliplatin.
Collapse
Affiliation(s)
- Xiaoli Zhang
- Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education
- Institute of Biotechnology
- Shanxi University
- Taiyuan
- China
| | - Shuhua Shan
- Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education
- Institute of Biotechnology
- Shanxi University
- Taiyuan
- China
| | - Jiangying Shi
- Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education
- Institute of Biotechnology
- Shanxi University
- Taiyuan
- China
| | - Hanqing Li
- School of Life Science
- Shanxi University
- Taiyuan
- China
| | - Zhuoyu Li
- Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education
- Institute of Biotechnology
- Shanxi University
- Taiyuan
- China
| |
Collapse
|
|
21
|
Fisher-Wellman KH, Hagen JT, Neufer PD, Kassai M, Cabot MC. On the nature of ceramide-mitochondria interactions - Dissection using comprehensive mitochondrial phenotyping. Cell Signal 2020; 78:109838. [PMID: 33212155 DOI: 10.1016/j.cellsig.2020.109838] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/12/2020] [Accepted: 11/13/2020] [Indexed: 02/06/2023]
Abstract
Sphingolipids are a unique class of lipids owing to their non-glycerol-containing backbone, ceramide, that is constructed from a long-chain aliphatic amino alcohol, sphinganine, to which a fatty acid is attached via an amide bond. Ceramide plays a star role in the initiation of apoptosis by virtue of its interactions with mitochondria, a control point for a downstream array of signaling cascades culminating in apoptosis. Many pathways converge on mitochondria to elicit mitochondrial outer membrane permeabilization (MOMP), a step that corrupts bioenergetic service. Although much is known regarding ceramides interaction with mitochondria and the ensuing cell signal transduction cascades, how ceramide impacts the elements of mitochondrial bioenergetic function is poorly understood. The objective of this review is to introduce the reader to sphingolipid metabolism, present a snapshot of mitochondrial respiration, elaborate on ceramides convergence on mitochondria and the upstream players that collaborate to elicit MOMP, and introduce a mitochondrial phenotyping platform that can be of utility in dissecting the fine-points of ceramide impact on cellular bioenergetics.
Collapse
Affiliation(s)
- Kelsey H Fisher-Wellman
- Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, United States of America; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, United States of America.
| | - James T Hagen
- Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, United States of America; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, United States of America
| | - P Darrell Neufer
- East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, United States of America
| | - Miki Kassai
- Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC, United States of America; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, United States of America
| | - Myles C Cabot
- Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC, United States of America; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, United States of America.
| |
Collapse
|
|
22
|
Baliou S, Kyriakopoulos AM, Spandidos DA, Zoumpourlis V. Role of taurine, its haloamines and its lncRNA TUG1 in both inflammation and cancer progression. On the road to therapeutics? (Review). Int J Oncol 2020; 57:631-664. [PMID: 32705269 PMCID: PMC7384849 DOI: 10.3892/ijo.2020.5100] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 07/14/2020] [Indexed: 12/11/2022] Open
Abstract
For one century, taurine is considered as an end product of sulfur metabolism. In this review, we discuss the beneficial effect of taurine, its haloamines and taurine upregulated gene 1 (TUG1) long non‑coding RNA (lncRNA) in both cancer and inflammation. We outline how taurine or its haloamines (N‑Bromotaurine or N‑Chlorotaurine) can induce robust and efficient responses against inflammatory diseases, providing insight into their molecular mechanisms. We also provide information about the use of taurine as a therapeutic approach to cancer. Taurine can be combined with other chemotherapeutic drugs, not only mediating durable responses in various malignancies, but also circumventing the limitations met from chemotherapeutic drugs, thus improving the therapeutic outcome. Interestingly, the lncRNA TUG1 is regarded as a promising therapeutic approach, which can overcome acquired resistance of cancer cells to selected strategies. In this regard, we can translate basic knowledge about taurine and its TUG1 lncRNA into potential therapeutic options directed against specific oncogenic signaling targets, thereby bridging the gap between bench and bedside.
Collapse
Affiliation(s)
| | | | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, Heraklion 71003, Greece
| | | |
Collapse
|
|
23
|
Inhibitors of Ceramide- and Sphingosine-Metabolizing Enzymes as Sensitizers in Radiotherapy and Chemotherapy for Head and Neck Squamous Cell Carcinoma. Cancers (Basel) 2020; 12:cancers12082062. [PMID: 32722626 PMCID: PMC7463798 DOI: 10.3390/cancers12082062] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 07/21/2020] [Accepted: 07/23/2020] [Indexed: 02/07/2023] Open
Abstract
In the treatment of advanced head and neck squamous cell carcinoma (HNSCC), including oral SCC, radiotherapy is a commonly performed therapeutic modality. The combined use of radiotherapy with chemotherapy improves therapeutic effects, but it also increases adverse events. Ceramide, a central molecule in sphingolipid metabolism and signaling pathways, mediates antiproliferative responses, and its level increases in response to radiotherapy and chemotherapy. However, when ceramide is metabolized, prosurvival factors, such as sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), and glucosylceramide, are produced, reducing the antitumor effects of ceramide. The activities of ceramide- and sphingosine-metabolizing enzymes are also associated with radio- and chemo-resistance. Ceramide analogs and low molecular-weight compounds targeting these enzymes exert anticancer effects. Synthetic ceramides and a therapeutic approach using ultrasound have also been developed. Inhibitors of ceramide- and sphingosine-metabolizing enzymes and synthetic ceramides can function as sensitizers of radiotherapy and chemotherapy for HNSCC.
Collapse
|
|
24
|
Zhang T, van Die I, Tefsen B, van Vliet SJ, Laan LC, Zhang J, Ten Dijke P, Wuhrer M, Belo AI. Differential O- and Glycosphingolipid Glycosylation in Human Pancreatic Adenocarcinoma Cells With Opposite Morphology and Metastatic Behavior. Front Oncol 2020; 10:732. [PMID: 32582529 PMCID: PMC7280451 DOI: 10.3389/fonc.2020.00732] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 04/16/2020] [Indexed: 01/15/2023] Open
Abstract
Changes in the glycosylation profile of cancer cells have been strongly associated with cancer progression. To increase our insights into the role of glycosylation in human pancreatic ductal adenocarcinoma (PDAC), we performed a study on O-glycans and glycosphingolipid (GSL) glycans of the PDAC cell lines Pa-Tu-8988T (PaTu-T) and Pa-Tu-8988S (PaTu-S). These cell lines are derived from the same patient, but show an almost opposite phenotype, morphology and capacity to metastasize, and may thus provide an attractive model to study the role of glycosylation in progression of PDAC. Gene-array analysis revealed that 24% of the glycosylation-related genes showed a ≥ 1.5-fold difference in expression level between the two cell lines. Subsequent validation of the data by porous graphitized carbon nano-liquid chromatography coupled to a tandem ion trap mass spectrometry and flow cytometry established major differences in O-glycans and GSL-glycans between the cell lines, including lower levels of T and sialylated Tn (sTn) antigens, neoexpression of globosides (Gb3 and Gb4), and higher levels of gangliosides in the mesenchymal-like PaTu-T cells compared to the epithelial-like PaTu-S. In addition, PaTu-S cells demonstrated a significantly higher binding of the immune-lectins macrophage galactose-type lectin and galectin-4 compared to PaTu-T. In summary, our data provide a comprehensive and differential glycan profile of two PDAC cell lines with disparate phenotypes and metastatic behavior. This will allow approaches to modulate and monitor the glycosylation of these PDAC cell lines, which opens up avenues to study the biology and metastatic behavior of PDAC.
Collapse
Affiliation(s)
- Tao Zhang
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, Netherlands
| | - Irma van Die
- Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Boris Tefsen
- Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.,Department of Biological Sciences, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Sandra J van Vliet
- Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Lisa C Laan
- Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Jing Zhang
- Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, Leiden, Netherlands
| | - Peter Ten Dijke
- Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, Leiden, Netherlands
| | - Manfred Wuhrer
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, Netherlands
| | - Ana I Belo
- Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| |
Collapse
|
|
25
|
Zhong P, Chen X, Guo R, Chen X, Chen Z, Wei C, Li Y, Wang W, Zhou Y, Qin L. Folic Acid-Modified Nanoerythrocyte for Codelivery of Paclitaxel and Tariquidar to Overcome Breast Cancer Multidrug Resistance. Mol Pharm 2020; 17:1114-1126. [PMID: 32176509 DOI: 10.1021/acs.molpharmaceut.9b01148] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The efflux of anticancer agents mediated by P-glycoprotein (P-gp) is one of the main causes of multidrug resistance (MDR) and eventually leads to chemotherapy failure. To overcome this problem, the delivery of anticancer agents in combination with a P-gp inhibitor using nanocarrier systems is considered an effective strategy. On the basis of the physiological compatibility and excellent drug loading ability of erythrocytes, we hypothesized that nanoerythrocytes could be used for the codelivery of an anticancer agent and a P-gp inhibitor to overcome MDR in breast cancer. Herein, a folic acid-modified nanoerythrocyte system (PTX/TQR NPs@NanoRBC-PEG/FA) was prepared to simultaneously transport paclitaxel and tariquidar, and the in vitro and in vivo characteristics of this delivery system were evaluated through several experiments. The results indicated that the average diameter and surface potential of this nanocarrier system were 159.8 ± 1.4 nm and -10.98 mV, respectively. Within 120 h, sustained release of paclitaxel was observed in both pH 6.5 media and pH 7.4 media. Tariquidar release from this nanocarrier suppressed the P-gp function of MCF-7/Taxol cells and significantly increased the intracellular paclitaxel level (p < 0.01 versus the PTX group). The results of the MTT assay indicated that the simultaneous transportation of paclitaxel and tariquidar could significantly inhibit the growth of MCF-7 cells or MCF-7/Taxol cells. After 48 h of incubation with PTX/TQR NPs@NanoRBC-PEG/FA, the viability of MCF-7 cells and MCF-7/Taxol cells decreased to 7.37% and 30.2%, respectively, and the IC50 values were 2.49 μM and 6.30 μM. Pharmacokinetic results illustrated that, compared with free paclitaxel, all test paclitaxel nanoformulations prolonged the drug release time and showed similar plasma concentration-time profiles. The peak concentration (Cmax), area under the curve (AUC0-∞), and half-life (t1/2) of PTX/TQR NPs@NanoRBC-PEG/FA were 3.33 mg/L, 6.02 mg/L·h, and 5.84 h, respectively. Moreover, this active targeting nanocarrier dramatically increased the paclitaxel level in tumor tissues. Furthermore, compared with those of the other paclitaxel formulations, the cellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels of the PTX/TQR NPs@NanoRBC-PEG/FA group increased by 1.38-fold (p < 0.01) and 1.36-fold (p < 0.01), respectively, and the activities of superoxide dismutase (SOD) and catalase (CAT) decreased to 67.8% (p < 0.01) and 65.4% (p < 0.001), respectively. More importantly, in vivo antitumor efficacy results proved that the PTX/TQR NPs@NanoRBC-PEG/FA group exerted an outstanding tumor inhibition effect with no marked body weight loss and fewer adverse effects. In conclusion, by utilizing the inherent and advantageous properties of erythrocytes and surface modification strategies, this biomimetic targeted drug delivery system provides a promising platform for the codelivery of an anticancer agent and a P-gp inhibitor to treat MDR in breast cancer.
Collapse
Affiliation(s)
- Ping Zhong
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Xuehong Chen
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Rishuo Guo
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Xiaomei Chen
- Department of Pharmacy, Puning People's Hospital, Puning 515300, China
| | - Zhihao Chen
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Cui Wei
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yusheng Li
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Wanting Wang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yi Zhou
- School of Pharmacy, Guangzhou Medical University, Guangzhou 510436, China
| | - Linghao Qin
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| |
Collapse
|
|
26
|
Tea MN, Poonnoose SI, Pitson SM. Targeting the Sphingolipid System as a Therapeutic Direction for Glioblastoma. Cancers (Basel) 2020; 12:cancers12010111. [PMID: 31906280 PMCID: PMC7017054 DOI: 10.3390/cancers12010111] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 12/28/2019] [Accepted: 12/30/2019] [Indexed: 02/06/2023] Open
Abstract
Glioblastoma (GBM) is the most commonly diagnosed malignant brain tumor in adults. The prognosis for patients with GBM remains poor and largely unchanged over the last 30 years, due to the limitations of existing therapies. Thus, new therapeutic approaches are desperately required. Sphingolipids are highly enriched in the brain, forming the structural components of cell membranes, and are major lipid constituents of the myelin sheaths of nerve axons, as well as playing critical roles in cell signaling. Indeed, a number of sphingolipids elicit a variety of cellular responses involved in the development and progression of GBM. Here, we discuss the role of sphingolipids in the pathobiology of GBM, and how targeting sphingolipid metabolism has emerged as a promising approach for the treatment of GBM.
Collapse
Affiliation(s)
- Melinda N. Tea
- Centre for Cancer Biology, University of South Australia and SA Pathology, UniSA CRI Building, North Tce, Adelaide, SA 5001, Australia;
| | - Santosh I. Poonnoose
- Department of Neurosurgery, Flinders Medical Centre, Adelaide, SA 5042, Australia;
| | - Stuart M. Pitson
- Centre for Cancer Biology, University of South Australia and SA Pathology, UniSA CRI Building, North Tce, Adelaide, SA 5001, Australia;
- Adelaide Medical School and School of Biological Sciences, University of Adelaide, SA 5001, Australia
- Correspondence: ; Tel.: +61-8-8302-7832; Fax: +61-8-8302-9246
| |
Collapse
|
|
27
|
Gomez-Zepeda D, Taghi M, Scherrmann JM, Decleves X, Menet MC. ABC Transporters at the Blood-Brain Interfaces, Their Study Models, and Drug Delivery Implications in Gliomas. Pharmaceutics 2019; 12:pharmaceutics12010020. [PMID: 31878061 PMCID: PMC7022905 DOI: 10.3390/pharmaceutics12010020] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 12/13/2019] [Accepted: 12/20/2019] [Indexed: 12/22/2022] Open
Abstract
Drug delivery into the brain is regulated by the blood-brain interfaces. The blood-brain barrier (BBB), the blood-cerebrospinal fluid barrier (BCSFB), and the blood-arachnoid barrier (BAB) regulate the exchange of substances between the blood and brain parenchyma. These selective barriers present a high impermeability to most substances, with the selective transport of nutrients and transporters preventing the entry and accumulation of possibly toxic molecules, comprising many therapeutic drugs. Transporters of the ATP-binding cassette (ABC) superfamily have an important role in drug delivery, because they extrude a broad molecular diversity of xenobiotics, including several anticancer drugs, preventing their entry into the brain. Gliomas are the most common primary tumors diagnosed in adults, which are often characterized by a poor prognosis, notably in the case of high-grade gliomas. Therapeutic treatments frequently fail due to the difficulty of delivering drugs through the brain barriers, adding to diverse mechanisms developed by the cancer, including the overexpression or expression de novo of ABC transporters in tumoral cells and/or in the endothelial cells forming the blood-brain tumor barrier (BBTB). Many models have been developed to study the phenotype, molecular characteristics, and function of the blood-brain interfaces as well as to evaluate drug permeability into the brain. These include in vitro, in vivo, and in silico models, which together can help us to better understand their implication in drug resistance and to develop new therapeutics or delivery strategies to improve the treatment of pathologies of the central nervous system (CNS). In this review, we present the principal characteristics of the blood-brain interfaces; then, we focus on the ABC transporters present on them and their implication in drug delivery; next, we present some of the most important models used for the study of drug transport; finally, we summarize the implication of ABC transporters in glioma and the BBTB in drug resistance and the strategies to improve the delivery of CNS anticancer drugs.
Collapse
Affiliation(s)
- David Gomez-Zepeda
- Inserm, UMR-S 1144, Optimisation Thérapeutique en Neuropsychopharmacologie, 75006 Paris, France; (M.T.); (J.-M.S.); (X.D.)
- Sorbonne Paris Cité, Université Paris Descartes, 75006 Paris, France
- Sorbonne Paris Cité, Université Paris Diderot, 75013 Paris, France
- Correspondence: (D.G.-Z.); (M.-C.M.)
| | - Méryam Taghi
- Inserm, UMR-S 1144, Optimisation Thérapeutique en Neuropsychopharmacologie, 75006 Paris, France; (M.T.); (J.-M.S.); (X.D.)
- Sorbonne Paris Cité, Université Paris Descartes, 75006 Paris, France
- Sorbonne Paris Cité, Université Paris Diderot, 75013 Paris, France
| | - Jean-Michel Scherrmann
- Inserm, UMR-S 1144, Optimisation Thérapeutique en Neuropsychopharmacologie, 75006 Paris, France; (M.T.); (J.-M.S.); (X.D.)
- Sorbonne Paris Cité, Université Paris Descartes, 75006 Paris, France
- Sorbonne Paris Cité, Université Paris Diderot, 75013 Paris, France
| | - Xavier Decleves
- Inserm, UMR-S 1144, Optimisation Thérapeutique en Neuropsychopharmacologie, 75006 Paris, France; (M.T.); (J.-M.S.); (X.D.)
- Sorbonne Paris Cité, Université Paris Descartes, 75006 Paris, France
- Sorbonne Paris Cité, Université Paris Diderot, 75013 Paris, France
- UF Biologie du médicament et toxicologie, Hôpital Cochin, AP HP, 75006 Paris, France
| | - Marie-Claude Menet
- Inserm, UMR-S 1144, Optimisation Thérapeutique en Neuropsychopharmacologie, 75006 Paris, France; (M.T.); (J.-M.S.); (X.D.)
- Sorbonne Paris Cité, Université Paris Descartes, 75006 Paris, France
- Sorbonne Paris Cité, Université Paris Diderot, 75013 Paris, France
- UF Hormonologie adulte, Hôpital Cochin, AP HP, 75006 Paris, France
- Correspondence: (D.G.-Z.); (M.-C.M.)
| |
Collapse
|
|
28
|
Nagarajan N, Yapp EKY, Le NQK, Kamaraj B, Al-Subaie AM, Yeh HY. Application of Computational Biology and Artificial Intelligence Technologies in Cancer Precision Drug Discovery. BIOMED RESEARCH INTERNATIONAL 2019; 2019:8427042. [PMID: 31886259 PMCID: PMC6925679 DOI: 10.1155/2019/8427042] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 10/14/2019] [Indexed: 02/08/2023]
Abstract
Artificial intelligence (AI) proves to have enormous potential in many areas of healthcare including research and chemical discoveries. Using large amounts of aggregated data, the AI can discover and learn further transforming these data into "usable" knowledge. Being well aware of this, the world's leading pharmaceutical companies have already begun to use artificial intelligence to improve their research regarding new drugs. The goal is to exploit modern computational biology and machine learning systems to predict the molecular behaviour and the likelihood of getting a useful drug, thus saving time and money on unnecessary tests. Clinical studies, electronic medical records, high-resolution medical images, and genomic profiles can be used as resources to aid drug development. Pharmaceutical and medical researchers have extensive data sets that can be analyzed by strong AI systems. This review focused on how computational biology and artificial intelligence technologies can be implemented by integrating the knowledge of cancer drugs, drug resistance, next-generation sequencing, genetic variants, and structural biology in the cancer precision drug discovery.
Collapse
Affiliation(s)
| | - Edward K. Y. Yapp
- Singapore Institute of Manufacturing Technology, 2 Fusionopolis Way, Singapore 138634
| | - Nguyen Quoc Khanh Le
- School of Humanities, Nanyang Technological University, 14 Nanyang Dr, Singapore 637332
| | - Balu Kamaraj
- Department of Neuroscience Technology, College of Applied Medical Sciences, Imam Abdulrahman Bin Faisal University, Jubail 35816, Saudi Arabia
| | - Abeer Mohammed Al-Subaie
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Hui-Yuan Yeh
- School of Humanities, Nanyang Technological University, 14 Nanyang Dr, Singapore 637332
| |
Collapse
|
|
29
|
Varela-López A, Battino M, Navarro-Hortal MD, Giampieri F, Forbes-Hernández TY, Romero-Márquez JM, Collado R, Quiles JL. An update on the mechanisms related to cell death and toxicity of doxorubicin and the protective role of nutrients. Food Chem Toxicol 2019; 134:110834. [PMID: 31577924 DOI: 10.1016/j.fct.2019.110834] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 09/10/2019] [Accepted: 09/21/2019] [Indexed: 12/11/2022]
Abstract
Doxorubicin (DOX), is a very effective chemotherapeutic agent against cancer whose clinical use is limited by toxicity. Different strategies have been proposed to attenuate toxicity, including combined therapy with bioactive compounds. This review update mechanisms of action and toxicity of doxorubicin and the role of nutrients like vitamins (A, C, E), minerals (selenium) and n-3 polyunsaturated fatty acids. Protective activities against DOX toxicity in liver, kidney, skin, bone marrow, testicles or brain have been reported, but these have not been evaluated for all of the reviewed nutrients. In most cases oxidation-related effects were present either, by reducing ROS levels and/or increasing antioxidant defenses. Antiapoptotic and anti-inflammatory mechanisms are also commonly reported. In some cases, interferences with autophagy and calcium homeostasis also have shown to be affected. Notwithstanding, there is a wide variety in duration and doses of treatment tested for both, compounds and DOX, which make difficult to compare the results of the studies. In spite of the reduction of DOX cardiotoxicity in health models, DOX anti-cancer activity in cancer cell lines or xenograft models usually did not result compromised when this has been evaluated. Importantly, clinical studies are needed to confirm all the observed effects.
Collapse
Affiliation(s)
- Alfonso Varela-López
- Department of Physiology, Institute of Nutrition and Food Technology ''José Mataix", Biomedical Research Centre, University of Granada, 18071, Granada, Spain
| | - Maurizio Battino
- Dipartimento di Scienze Cliniche Specialistiche Ed Odontostomatologiche (DISCO)-Sez, Biochimica, Facoltà di Medicina, Università Politecnica Delle Marche, 60131, Ancona, Italy; Nutrition and Food Science Group. Department of Analytical and Food Chemistry, CITACA, CACTI, University of Vigo, Vigo, Spain; International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang, China
| | - María D Navarro-Hortal
- Department of Physiology, Institute of Nutrition and Food Technology ''José Mataix", Biomedical Research Centre, University of Granada, 18071, Granada, Spain
| | - Francesca Giampieri
- Dipartimento di Scienze Cliniche Specialistiche Ed Odontostomatologiche (DISCO)-Sez, Biochimica, Facoltà di Medicina, Università Politecnica Delle Marche, 60131, Ancona, Italy
| | - Tamara Y Forbes-Hernández
- Nutrition and Food Science Group. Department of Analytical and Food Chemistry, CITACA, CACTI, University of Vigo, Vigo, Spain
| | - José M Romero-Márquez
- Department of Physiology, Institute of Nutrition and Food Technology ''José Mataix", Biomedical Research Centre, University of Granada, 18071, Granada, Spain
| | - Ricardo Collado
- Complejo Hospitalario Universitario de Cáceres, Cáceres, Spain
| | - José L Quiles
- Department of Physiology, Institute of Nutrition and Food Technology ''José Mataix", Biomedical Research Centre, University of Granada, 18071, Granada, Spain.
| |
Collapse
|
|
30
|
Kao LP, Morad SAF, Davis TS, MacDougall MR, Kassai M, Abdelmageed N, Fox TE, Kester M, Loughran TP, Abad JL, Fabrias G, Tan SF, Feith DJ, Claxton DF, Spiegel S, Fisher-Wellman KH, Cabot MC. Chemotherapy selection pressure alters sphingolipid composition and mitochondrial bioenergetics in resistant HL-60 cells. J Lipid Res 2019; 60:1590-1602. [PMID: 31363040 PMCID: PMC6718434 DOI: 10.1194/jlr.ra119000251] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 07/27/2019] [Indexed: 12/15/2022] Open
Abstract
The combination of daunorubicin (dnr) and cytarabine (Ara-C) is a cornerstone of treatment for acute myelogenous leukemia (AML); resistance to these drugs is a major cause of treatment failure. Ceramide, a sphingolipid (SL), plays a critical role in cancer cell apoptosis in response to chemotherapy. Here, we investigated the effects of chemotherapy selection pressure with Ara-C and dnr on SL composition and enzyme activity in the AML cell line HL-60. Resistant cells, those selected for growth in Ara-C- and dnr-containing medium (HL-60/Ara-C and HL-60/dnr, respectively), demonstrated upregulated expression and activity of glucosylceramide synthase, acid ceramidase (AC), and sphingosine kinase 1 (SPHK1); were more resistant to ceramide than parental cells; and displayed sensitivity to inhibitors of SL metabolism. Lipidomic analysis revealed a general ceramide deficit and a profound upswing in levels of sphingosine 1-phosphate (S1P) and ceramide 1-phosphate (C1P) in HL-60/dnr cells versus parental and HL-60/Ara-C cells. Both chemotherapy-selected cells also exhibited comprehensive upregulations in mitochondrial biogenesis consistent with heightened reliance on oxidative phosphorylation, a property that was partially reversed by exposure to AC and SPHK1 inhibitors and that supports a role for the phosphorylation system in resistance. In summary, dnr and Ara-C selection pressure induces acute reductions in ceramide levels and large increases in S1P and C1P, concomitant with cell resilience bolstered by enhanced mitochondrial remodeling. Thus, strategic control of ceramide metabolism and further research to define mitochondrial perturbations that accompany the drug-resistant phenotype offer new opportunities for developing therapies that regulate cancer growth.
Collapse
Affiliation(s)
- Li-Pin Kao
- Department of Biochemistry and Molecular Biology Brody School of Medicine, East Carolina University, and the East Carolina Diabetes and Obesity Institute, Greenville, NC
| | - Samy A F Morad
- Department of Biochemistry and Molecular Biology Brody School of Medicine, East Carolina University, and the East Carolina Diabetes and Obesity Institute, Greenville, NC; Department of Pharmacology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
| | - Traci S Davis
- Department of Biochemistry and Molecular Biology Brody School of Medicine, East Carolina University, and the East Carolina Diabetes and Obesity Institute, Greenville, NC
| | - Matthew R MacDougall
- Department of Biochemistry and Molecular Biology Brody School of Medicine, East Carolina University, and the East Carolina Diabetes and Obesity Institute, Greenville, NC
| | - Miki Kassai
- Department of Biochemistry and Molecular Biology Brody School of Medicine, East Carolina University, and the East Carolina Diabetes and Obesity Institute, Greenville, NC
| | - Noha Abdelmageed
- Department of Pharmacology, Faculty of Veterinary Medicine, Sohag University, Sohag, Egypt
| | - Todd E Fox
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA
| | - Mark Kester
- University of Virginia Cancer Center Charlottesville, VA
| | - Thomas P Loughran
- University of Virginia Cancer Center Charlottesville, VA; Department of Medicine, Hematology/Oncology, University of Virginia, Charlottesville, VA
| | - Jose' L Abad
- Instituto de Quimica Avanzada de Cataluña, Barcelona, Spain
| | - Gemma Fabrias
- Instituto de Quimica Avanzada de Cataluña, Barcelona, Spain
| | - Su-Fern Tan
- Department of Medicine, Hematology/Oncology, University of Virginia, Charlottesville, VA
| | - David J Feith
- University of Virginia Cancer Center Charlottesville, VA; Department of Medicine, Hematology/Oncology, University of Virginia, Charlottesville, VA
| | | | - Sarah Spiegel
- Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA
| | - Kelsey H Fisher-Wellman
- Department of Physiology, Brody School of Medicine, East Carolina University, and the East Carolina Diabetes and Obesity Institute, Greenville, NC.
| | - Myles C Cabot
- Department of Biochemistry and Molecular Biology Brody School of Medicine, East Carolina University, and the East Carolina Diabetes and Obesity Institute, Greenville, NC.
| |
Collapse
|
|
31
|
Alrbyawi H, Poudel I, Dash RP, Srinivas NR, Tiwari AK, Arnold RD, Babu RJ. Role of Ceramides in Drug Delivery. AAPS PharmSciTech 2019; 20:287. [PMID: 31410612 DOI: 10.1208/s12249-019-1497-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 07/31/2019] [Indexed: 12/20/2022] Open
Abstract
Ceramides belong to the sphingolipid group of lipids, which serve as both intracellular and intercellular messengers and as regulatory molecules that play essential roles in signal transduction, inflammation, angiogenesis, and metabolic disorders such as diabetes, neurodegenerative diseases, and cancer cell degeneration. Ceramides also play an important structural role in cell membranes by increasing their rigidity, creating micro-domains (rafts and caveolae), and altering membrane permeability; all these events are involved in the cell signaling. Ceramides constitute approximately half of the lipid composition in the human skin contributing to barrier function as well as epidermal signaling as they affect both proliferation and apoptosis of keratinocytes. Incorporation of ceramides in topical preparations as functional lipids appears to alter skin barrier functions. Ceramides also appear to enhance the bioavailability of drugs by acting as lipid delivery systems. They appear to regulate the ocular inflammation signaling, and external ceramides have shown relief in the anterior and posterior eye disorders. Ceramides play a structural role in liposome formulations and enhance the cellular uptake of amphiphilic drugs, such as chemotherapies. This review presents an overview of the various biological functions of ceramides, and their utility in topical, oral, ocular, and chemotherapeutic drug delivery.
Collapse
|
|
32
|
Roy KR, Khiste SK, Liu Z, Liu YY. Fluorescence HPLC Analysis of the in-vivo Activity of Glucosylceramide Synthase. Bio Protoc 2019; 9:e3269. [PMID: 33654788 DOI: 10.21769/bioprotoc.3269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 05/23/2019] [Accepted: 05/23/2019] [Indexed: 01/13/2023] Open
Abstract
Almost all functions of cells or organs rely on the activities of cellular enzymes. Indeed, the in-vivo activities that directly represent the cellular effects of enzymes in live organs are critical importance to appreciate the roles enzymes play in modulating physiological or pathological processes, although assessments of such in-vivo enzyme activity are more difficult than typical test-tube assays. Recently, we, for the first time, developed a direct and easy-handling method for HPLC analyzing the in-vivo activity of glucosylceramide synthase (GCS). GCS that converts ceramide into glucosylceramide is a limiting-enzyme in the syntheses of glycosphingolipids and is one cause of cancer drug resistance. In our method developed, rubusoside nanomicelles delivers fluorescence N-[6-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]hexanoyl]-d-erythro-sphingosine (NBD C6-ceramide) into mice, tissues uptake the cell-permeable substrate, and GCS converts it into NBD C6-glucosylceramide in all organs simultaneously. Further, HPLC analyzes the extracted NBD C6-glucosylceramide to assess alterations of the in-vivo GCS activities in tissues. This method can be broadly used to assess the in-vivo GCS activities in any kind of animal models to appreciate either the role GCS plays in diseases or the therapeutic efficacies of GCS inhibitors.
Collapse
Affiliation(s)
- Kartik R Roy
- School of Basic Pharmaceutical and Toxicological Sciences, University of Louisiana at Monroe, Monroe, LA 71209, USA
| | - Sachin K Khiste
- School of Basic Pharmaceutical and Toxicological Sciences, University of Louisiana at Monroe, Monroe, LA 71209, USA
| | - Zhijun Liu
- School of Renewable Resources, Louisiana State University Agriculture Center, Baton Rouge, LA 70803, USA
| | - Yong-Yu Liu
- School of Basic Pharmaceutical and Toxicological Sciences, University of Louisiana at Monroe, Monroe, LA 71209, USA
| |
Collapse
|
|
33
|
Cao Y, Li Z, Mao L, Cao H, Kong J, Yu B, Yu C, Liao W. The use of proteomic technologies to study molecular mechanisms of multidrug resistance in cancer. Eur J Med Chem 2019; 162:423-434. [PMID: 30453249 DOI: 10.1016/j.ejmech.2018.10.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 09/27/2018] [Accepted: 10/01/2018] [Indexed: 01/18/2023]
Abstract
Multidrug resistance (MDR), defined as the cross-resistance of cancer cells toward a broad range of chemotherapeutic agents, is a universal and intractable problem in chemotherapy. The understanding of MDR mechanisms is essential to discover the potential biomarkers for predicting multidrug resistance and more importantly, tackling and preventing multidrug resistance. Multiple technologies have been used to study MDR mechanisms including comparative genomic hybridization, DNA array, differential display RT-PCR and various immunoassays. Compared with these approaches, proteomic technologies allow a high through-put analysis of protein detection, protein quantification and protein interaction with high accuracy. With the rapid development of proteomic studies in recent years, proteomic technologies have made substantial contributions to the characterization of MDR mechanisms including MDR-related protein detection and quantification, as well as the characterization of drug-transporter binding sites. This review offers a comprehensive illustration of MDR, proteomic technologies and the discoveries made in understanding MDR mechanisms using proteomic approaches.
Collapse
Affiliation(s)
- Yi Cao
- Key Laboratory of Environment-Friendly Chemistry and Application of Ministry of Education, Lab of Biochemistry, College of Chemistry, Xiangtan University, Xiangtan, 411105, China
| | - Ziyin Li
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China
| | - Lianzhi Mao
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China
| | - Hehe Cao
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China
| | - Jingjing Kong
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China
| | - Bin Yu
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Changmin Yu
- Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced Materials (IAM), Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing Tech University (Nanjing Tech), Nanjing, 211816, China.
| | - Wenzhen Liao
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China.
| |
Collapse
|
|
34
|
Vázquez L, Corzo-Martínez M, Arranz-Martínez P, Barroso E, Reglero G, Torres C. Bioactive Lipids. BIOACTIVE MOLECULES IN FOOD 2019. [DOI: 10.1007/978-3-319-78030-6_58] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
|
|
35
|
Xu J, Zhao W, Sun J, Huang Y, Wang P, Venkataramanan R, Yang D, Ma X, Rana A, Li S. Novel glucosylceramide synthase inhibitor based prodrug copolymer micelles for delivery of anticancer agents. J Control Release 2018; 288:212-226. [PMID: 30223045 PMCID: PMC6177216 DOI: 10.1016/j.jconrel.2018.09.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 09/07/2018] [Accepted: 09/12/2018] [Indexed: 01/04/2023]
Abstract
In order to improve the efficacy of chemotherapy for cancers, we have developed a novel prodrug micellar formulation to co-deliver ceramide-generating anticancer agents and ceramide degradation inhibitor (PPMP). The prodrug nanocarrier is based on a well-defined POEG-b-PPPMP diblock copolymer. The hydrophilic block of POEG-b-PPPMP is POEG, and the hydrophobic block is composed of a number of PPMP units, which could work synergistically with loaded anticancer drugs. POEG-b-PPPMP was readily synthesized via a one-step reversible addition-fragment transfer (RAFT) polymerization from a PPMP monomer. The newly synthesized polymers were self-assembled into micelles and served as a carrier for several hydrophobic anticancer drugs including DOX, PTX and C6-ceramide. POEG-b-PPPMP prodrug polymer exhibited intrinsic antitumor activity in vitro and in vivo. In addition, POEG-b-PPPMP prodrug polymer was comparable to free PPMP in selectively enhancing the production of pro-apoptotic ceramide species as well as down-regulating the mRNA expression of GCS. DOX-loaded POEG-b-PPPMP micelles exhibited an excellent stability of 42 days at 4 °C. Moreover, DOX loaded in POEG-b-PPPMP micelles showed higher levels of cytotoxicity than DOX loaded in a pharmacologically inert polymer (POEG-b-POM) and Doxil formulation in several tumor cell lines. Consistently, in a 4T1.2 murine breast cancer model, the tumor inhibition followed the order of DOX/POEG-b-PPPMP > DOX/POEG-b-POM ≥ Doxil > POEG-b-PPPMP > POEG-b-POM. Our data suggest that POEG-b-PPPMP micelles are a promising dual-functional carrier that warrants more studies in the future.
Collapse
Affiliation(s)
- Jieni Xu
- Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA; University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Whenchen Zhao
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Jingjing Sun
- Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA; University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Yixian Huang
- Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA; University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Pengcheng Wang
- Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Raman Venkataramanan
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Da Yang
- Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Xiaochao Ma
- Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Ajay Rana
- Department of Surgery/Surgical Oncology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Song Li
- Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA; University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| |
Collapse
|
|
36
|
Kreitzburg KM, van Waardenburg RCAM, Yoon KJ. Sphingolipid metabolism and drug resistance in ovarian cancer. ACTA ACUST UNITED AC 2018; 1:181-197. [PMID: 31891125 PMCID: PMC6936734 DOI: 10.20517/cdr.2018.06] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Despite progress in understanding molecular aberrations that contribute to the development and progression of ovarian cancer, virtually all patients succumb to drug resistant disease at relapse. Emerging data implicate bioactive sphingolipids and regulation of sphingolipid metabolism as components of response to chemotherapy or development of resistance. Increases in cytosolic ceramide induce apoptosis in response to therapy with multiple classes of chemotherapeutic agents. Aberrations in sphingolipid metabolism that accelerate the catabolism of ceramide or that prevent the production and accumulation of ceramide contribute to resistance to standard of care platinum- and taxane-based agents. The aim of this review is to highlight current literature and research investigating the influence of the sphingolipids and enzymes that comprise the sphingosine-1-phosphate pathway on the progression of ovarian cancer. The focus of the review is on the utility of sphingolipid-centric therapeutics as a mechanism to circumvent drug resistance in this tumor type.
Collapse
Affiliation(s)
- Kelly M Kreitzburg
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | | | - Karina J Yoon
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| |
Collapse
|
|
37
|
Challenges and perspectives in the treatment of diabetes associated breast cancer. Cancer Treat Rev 2018; 70:98-111. [PMID: 30130687 DOI: 10.1016/j.ctrv.2018.08.004] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 08/02/2018] [Accepted: 08/09/2018] [Indexed: 12/12/2022]
Abstract
Type 2 diabetes mellitus is one of the most common chronic disease worldwide and affects all cross-sections of the society including children, women, youth and adults. Scientific evidence has linked diabetes to higher incidence, accelerated progression and increased aggressiveness of different cancers. Among the different forms of cancer, research has reinforced a link between diabetes and the risk of breast cancer. Some studies have specifically linked diabetes to the highly aggressive, triple negative breast cancers (TNBCs) which do not respond to conventional hormonal/HER2 targeted interventions, have chances of early recurrence, metastasize, tend to be more invasive in nature and develop drug resistance. Commonly used anti-diabetic drugs, such as metformin, have recently gained importance in the treatment of breast cancer due to their proposed anti-cancer properties. Here we discuss the link between diabetes and breast cancer, the metabolic disturbances in diabetes that support the development of breast cancer, the challenges involved and future perspective and directions. We link the three main metabolic disturbances (dyslipidemia, hyperinsulinemia and hyperglycemia) that occur in diabetes to potential aberrant molecular pathways that may lead to the development of an oncogenic phenotype of the breast tissue, thereby leading to acceleration of cell growth, proliferation, migration, inflammation, angiogenesis, EMT and metastasis and inhibition of apoptosis in breast cancer cells. Furthermore, managing diabetes and treating cancer using a combination of anti-diabetic and classical anti-cancer drugs should prove to be more efficient in the treatment diabetes associated cancers.
Collapse
|
|
38
|
Adamska A, Falasca M. ATP-binding cassette transporters in progression and clinical outcome of pancreatic cancer: What is the way forward? World J Gastroenterol 2018; 24:3222-3238. [PMID: 30090003 PMCID: PMC6079284 DOI: 10.3748/wjg.v24.i29.3222] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 05/31/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive diseases and is characterized by high chemoresistance, leading to the lack of effective therapeutic approaches and grim prognosis. Despite increasing understanding of the mechanisms of chemoresistance in cancer and the role of ATP-binding cassette (ABC) transporters in this resistance, the therapeutic potential of their pharmacological inhibition has not been successfully exploited yet. In spite of the discovery of potent pharmacological modulators of ABC transporters, the results obtained in clinical trials have been so far disappointing, with high toxicity levels impairing their successful administration to the patients. Critically, although ABC transporters have been mostly studied for their involvement in development of multidrug resistance (MDR), in recent years the contribution of ABC transporters to cancer initiation and progression has emerged as an important area of research, the understanding of which could significantly influence the development of more specific and efficient therapies. In this review, we explore the role of ABC transporters in the development and progression of malignancies, with focus on PDAC. Their established involvement in development of MDR will be also presented. Moreover, an emerging role for ABC transporters as prognostic tools for patients' survival will be discussed, demonstrating the therapeutic potential of ABC transporters in cancer therapy.
Collapse
Affiliation(s)
- Aleksandra Adamska
- Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth 6102, WA, Australia
| | - Marco Falasca
- Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth 6102, WA, Australia
| |
Collapse
|
|
39
|
Targeting sphingolipid metabolism as an approach for combination therapies in haematological malignancies. Cell Death Discov 2018; 4:72. [PMID: 30062053 PMCID: PMC6060109 DOI: 10.1038/s41420-018-0075-0] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Accepted: 06/12/2018] [Indexed: 12/16/2022] Open
Abstract
Conventional chemotherapy-based drug combinations have, until recently, been the backbone of most therapeutic strategies for cancer. In a time of emerging rationale drug development, targeted therapies are beginning to be added to traditional chemotherapeutics to synergistically enhance clinical responses. Of note, the importance of pro-apoptotic ceramide in mediating the anti-cancer effects of these therapies is becoming more apparent. Furthermore, reduced cellular ceramide in favour of pro-survival sphingolipids correlates with tumorigenesis and most importantly, drug resistance. Thus, agents that manipulate sphingolipid metabolism have been explored as potential anti-cancer agents and have recently demonstrated exciting potential to augment the efficacy of anti-cancer therapeutics. This review examines the biology underpinning these observations and the potential use of sphingolipid manipulating agents in the context of existing and emerging therapies for haematological malignancies. • Efficacy of many chemotherapeutics and targeted therapies is dictated by cellular ceramide levels. • Oncogene activation skews sphingolipid metabolism to favour the production of pro-survival sphingolipids. • Inhibitors of enzymes involved in ceramide metabolism exhibit promise in the relapsed-refractory setting. • Anti-cancer activity of sphingosine kinase inhibitors provides several options for new drug combinations. Open Questions • What other clinically utilised drugs rely on increases in ceramide levels for their efficacy and can they be effectively partnered with other ceramide inducing agents? • How does ceramide modulate the Bcl-2 family proteins, Mcl-1 and Bcl-2? • Are sphingolipid enzyme inhibitors best suited in the frontline or relapsed-refractory setting?
Collapse
|
|
40
|
Abstract
Chemotherapy resistance, inherent or acquired, represents a serious barrier to the successful treatment of cancer. Although drug efflux, conducted by plasma membrane-resident proteins, detoxification enzymes, cell death inhibition, and DNA damage repair are ensemble players in this unwanted biology, a full understanding of the many in concert molecular mechanisms driving drug resistance is lacking. Recent discoveries in sphingolipid (SL) metabolism have provided significant insight into the role of these lipids in cancer growth; however, considerably less is known with respect to SLs and the drug-resistant phenotype. One exception here is enhanced ceramide glycosylation, a hallmark of multidrug resistance that is believed responsible, in part, for diminishing ceramides tumor-suppressor potential. This chapter will review various aspects of SL biology that relate to chemotherapy resistance and extend this topic to acknowledge the role of chemotherapy selection pressure in promoting dysregulated SL metabolism, a characteristic in cancer and an exploitable target for therapy.
Collapse
|
|
41
|
Nikolaou M, Pavlopoulou A, Georgakilas AG, Kyrodimos E. The challenge of drug resistance in cancer treatment: a current overview. Clin Exp Metastasis 2018; 35:309-318. [DOI: 10.1007/s10585-018-9903-0] [Citation(s) in RCA: 248] [Impact Index Per Article: 35.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2017] [Accepted: 05/16/2018] [Indexed: 12/14/2022]
|
|
42
|
Qin J, Kilkus JP, Dawson G. The cross roles of sphingosine kinase 1/2 and ceramide glucosyltransferase in cell growth and death. Biochem Biophys Res Commun 2018; 500:597-602. [PMID: 29673590 DOI: 10.1016/j.bbrc.2018.04.110] [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: 04/11/2018] [Accepted: 04/13/2018] [Indexed: 11/29/2022]
Abstract
Sphingosine-1-phosphate is synthesized by two sphingosine kinases, cytosolic SK1 and nuclear SK2 but SK2 expression was much higher than SK1in mouse skin fibroblasts. However, in SK2-/- cells, SK1 expression was markedly increased to SK2 levels whereas in SK1-/- cells, SK2 expression was unaffected. Ceramide, glucosylceramide and sphingosine levels were all increased in SK1-/- but less so in SK2-/- cells and S1P levels were not significantly reduced in either SK1-/- or SK2-/- cells. Greatly increased Ceramide glucosyltransferase expression was observed in SK1-/- cells but less so in SK2-/- cells suggested a role in drug resistance. SK2-/- cells grew faster than control and SK1-/-. The cell division gene PCNA was significantly overexpressed in SK2-/- cells, suggesting a cross regulation between SKs and Ceramide glucosyltransferase.
Collapse
Affiliation(s)
- Jingdong Qin
- Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA.
| | - John P Kilkus
- Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA
| | - Glyn Dawson
- Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA.
| |
Collapse
|
|
43
|
Hosain SB, Khiste SK, Uddin MB, Vorubindi V, Ingram C, Zhang S, Hill RA, Gu X, Liu YY. Inhibition of glucosylceramide synthase eliminates the oncogenic function of p53 R273H mutant in the epithelial-mesenchymal transition and induced pluripotency of colon cancer cells. Oncotarget 2018; 7:60575-60592. [PMID: 27517620 PMCID: PMC5312403 DOI: 10.18632/oncotarget.11169] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 07/26/2016] [Indexed: 01/06/2023] Open
Abstract
Missense mutation of tumor suppressor p53, which exhibits oncogenic gain-of-function (GOF), not only promotes tumor progression, but also diminishes therapeutic efficacies of cancer treatments. However, it remains unclear how a p53 missense mutant contributes to induced pluripotency of cancer stem cells (CSCs) in tumors exposed to chemotherapeutic agents. More importantly, it may be possible to abrogate the GOF by restoring wild-type p53 activity, thereby overcoming the deleterious effects resulting from heterotetramer formation, which often compromises the efficacies of current approaches being used to reactivate p53 function. Herewith, we report that p53 R273H missense mutant urges cancer cells to spawn CSCs. SW48/TP53 cells, which heterozygously carry the p53 R273H hot-spot mutant (R273H/+, introduced by a CRISPR/Casp9 system), were subchronically exposed to doxorubicin in cell culture and in tumor-bearing mice. We found that p53-R273H (TP53-Dox) cells were drug-resistant and exhibited epithelial-mesenchymal transition (EMT) and increased numbers of CSCs (CD44v6+/CD133+), which resulted in enhanced wound healing and tumor formation. Inhibition of glucosylceramide synthase with d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) sensitized p53-R273H cancer cells and tumor xenografts to doxorubicin treatments. Intriguingly, PDMP treatments restored wild-type p53 expression in heterozygous R273H mutant cells and in tumors, decreasing CSCs and sensitizing cells and tumors to treatments. This study demonstrated that p53-R273H promotes EMT and induced pluripotency of CSCs in cancer cells exposed to doxorubicin, mainly through Zeb1 and β-catenin transcription factors. Our results further indicate that restoration of p53 through inhibition of ceramide glycosylation might be an effective treatment approach for targeting cancers heterozygously harboring TP53 missense mutations.
Collapse
Affiliation(s)
- Salman B Hosain
- Department of Basic Pharmaceutical Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA
| | - Sachin K Khiste
- Department of Basic Pharmaceutical Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA
| | - Mohammad B Uddin
- Department of Basic Pharmaceutical Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA
| | - Vindya Vorubindi
- Department of Basic Pharmaceutical Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA
| | - Catherine Ingram
- Department of Basic Pharmaceutical Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA
| | - Sifang Zhang
- Department of Integrated Chinese and Western Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Ronald A Hill
- Department of Basic Pharmaceutical Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA
| | - Xin Gu
- Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA
| | - Yong-Yu Liu
- Department of Basic Pharmaceutical Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA
| |
Collapse
|
|
44
|
Xu X, Wang Y, Deng H, Liu C, Wu J, Lai M. HMGA2 enhances 5-fluorouracil chemoresistance in colorectal cancer via the Dvl2/Wnt pathway. Oncotarget 2018. [PMID: 29515783 PMCID: PMC5839414 DOI: 10.18632/oncotarget.24133] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Drug resistance is one of the main hurdles to overcome for the improvement of cancer patient survival. However, the underlying mechanisms remain largely unknown, and therapeutic options are limited. Here, we demonstrate a strong correlation between HMGA2 expression and chemosensitivity to 5-fluorouracil (5-FU), a widely used first-line systemic chemotherapy regimen for colorectal cancer (CRC) patients. Overexpression of HMGA2 enhances chemoresistance to 5-FU of CRC both in vitro and in vivo. Further experiments indicate that HMGA2 directly binds to the promoter of Dvl2 and induces its transcription, which leads to increased activation of the Wnt/β-catenin pathway. Taken together, our data suggest that HMGA2 enhances the chemoresistance to 5-FU in CRC via activating the Dvl2/Wnt pathway. Therefore, HMGA2 may serve as a predictive biomarker and a potential therapeutic target in CRC.
Collapse
Affiliation(s)
- Xi Xu
- Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.,Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, Zhejiang, 310058, China
| | - Yunfeng Wang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, 150081, China
| | - Hong Deng
- Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.,Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, Zhejiang, 310058, China
| | - Chungang Liu
- Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.,Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, Zhejiang, 310058, China.,Center of Biological Therapy, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China
| | - Jingjing Wu
- Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.,Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, Zhejiang, 310058, China
| | - Maode Lai
- Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.,Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, Zhejiang, 310058, China
| |
Collapse
|
|
45
|
Samuel P, Fabbri M, Carter DRF. Mechanisms of Drug Resistance in Cancer: The Role of Extracellular Vesicles. Proteomics 2017; 17. [PMID: 28941129 DOI: 10.1002/pmic.201600375] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 09/11/2017] [Indexed: 12/11/2022]
Abstract
Drug resistance remains a major barrier to the successful treatment of cancer. The mechanisms by which therapeutic resistance arises are multifactorial. Recent evidence has shown that extracellular vesicles (EVs) play a role in mediating drug resistance. EVs are small vesicles carrying a variety of macromolecular cargo released by cells into the extracellular space and can be taken up into recipient cells, resulting in transfer of cellular material. EVs can mediate drug resistance by several mechanisms. They can serve as a pathway for sequestration of cytotoxic drugs, reducing the effective concentration at target sites. They can act as decoys carrying membrane proteins and capturing monoclonal antibodies intended to target receptors at the cell surface. EVs from resistant tumor cells can deliver mRNA, miRNA, long noncoding RNA, and protein inducing resistance in sensitive cells. This provides a new model for how resistance that arises can then spread through a heterogeneous tumor. EVs also mediate cross-talk between cancer cells and stromal cells in the tumor microenvironment, leading to tumor progression and acquisition of therapeutic resistance. In this review, we will describe what is known about how EVs can induce drug resistance, and discuss the ways in which EVs could be used as therapeutic targets or diagnostic markers for managing cancer treatment. While further characterization of the vesiculome and the mechanisms of EV function are still required, EVs offer an exciting opportunity in the fight against cancer.
Collapse
Affiliation(s)
- Priya Samuel
- Department of Biological and Medical Sciences Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK
| | - Muller Fabbri
- Department of Pediatrics and Microbiology & Molecular Immunology University of Southern California-Keck School of Medicine Norris Comprehensive Cancer Center Children's Center for Cancer and Blood Diseases, Children's Hospital, Los Angeles, CA, USA
| | - David Raul Francisco Carter
- Department of Biological and Medical Sciences Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK
| |
Collapse
|
|
46
|
Tsurumaki H, Katano H, Sato K, Imai R, Niino S, Hirabayashi Y, Ichikawa S. WP1066, a small molecule inhibitor of the JAK/STAT3 pathway, inhibits ceramide glucosyltransferase activity. Biochem Biophys Res Commun 2017; 491:265-270. [PMID: 28739255 DOI: 10.1016/j.bbrc.2017.07.115] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 07/20/2017] [Indexed: 02/05/2023]
Abstract
WP1066 is a well-known inhibitor of the JAK/STAT3 signaling pathway. By a screen of known small molecule inhibitors of various enzymes and protein factors, we identified WP1066 as a ceramide glucosyltransferase inhibitor. Ceramide glucosyltransferase catalyzes the first glycosylation step during glycosphingolipid synthesis. We found that WP1066 inhibited the activity of ceramide glucosyltransferase with an IC50 of 7.2 μM, and that its action was independent of JAK/STAT3 pathway blockade. Moreover, the modes of inhibition of ceramide glucosyltransferase were uncompetitive with respect to both C6-NBD-cermide and UDP-glucose.
Collapse
Affiliation(s)
- Hirotaka Tsurumaki
- Laboratory for Animal Cell Engineering, Niigata University of Pharmacy and Applied Life Sciences (NUPALS), 265-1 Higashijima, Akiha-ku, Niigata-shi, Niigata 956-8603, Japan
| | - Hikaru Katano
- Laboratory for Animal Cell Engineering, Niigata University of Pharmacy and Applied Life Sciences (NUPALS), 265-1 Higashijima, Akiha-ku, Niigata-shi, Niigata 956-8603, Japan
| | - Kousuke Sato
- Laboratory for Animal Cell Engineering, Niigata University of Pharmacy and Applied Life Sciences (NUPALS), 265-1 Higashijima, Akiha-ku, Niigata-shi, Niigata 956-8603, Japan
| | - Ryou Imai
- Laboratory for Animal Cell Engineering, Niigata University of Pharmacy and Applied Life Sciences (NUPALS), 265-1 Higashijima, Akiha-ku, Niigata-shi, Niigata 956-8603, Japan
| | - Satomi Niino
- Laboratory for Animal Cell Engineering, Niigata University of Pharmacy and Applied Life Sciences (NUPALS), 265-1 Higashijima, Akiha-ku, Niigata-shi, Niigata 956-8603, Japan
| | - Yoshio Hirabayashi
- Laboratory for Molecular Membrane Neuroscience, Brain Science Institute (BSI), The Institute of Physical and Chemical Research (RIKEN), 2-1 Hirosawa, Wako-shi, Saitama 351-01, Japan
| | - Shinichi Ichikawa
- Laboratory for Animal Cell Engineering, Niigata University of Pharmacy and Applied Life Sciences (NUPALS), 265-1 Higashijima, Akiha-ku, Niigata-shi, Niigata 956-8603, Japan.
| |
Collapse
|
|
47
|
Lee WK, Kolesnick RN. Sphingolipid abnormalities in cancer multidrug resistance: Chicken or egg? Cell Signal 2017; 38:134-145. [PMID: 28687494 DOI: 10.1016/j.cellsig.2017.06.017] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Revised: 06/25/2017] [Accepted: 06/25/2017] [Indexed: 12/12/2022]
Abstract
The cancer multidrug resistance (MDR) phenotype encompasses a myriad of molecular, genetic and cellular alterations resulting from progressive oncogenic transformation and selection. Drug efflux transporters, in particular the MDR P-glycoprotein ABCB1, play an important role in MDR but cannot confer the complete phenotype alone indicating parallel alterations are prerequisite. Sphingolipids are essential constituents of lipid raft domains and directly participate in functionalization of transmembrane proteins, including providing an optimal lipid microenvironment for multidrug transporters, and are also perturbed in cancer. Here we postulate that increased sphingomyelin content, developing early in some cancers, recruits and functionalizes plasma membrane ABCB1 conferring a state of partial MDR, which is completed by glycosphingolipid disturbance and the appearance of intracellular vesicular ABCB1. In this review, the independent and interdependent roles of sphingolipid alterations and ABCB1 upregulation during the transformation process and resultant conferment of partial and complete MDR phenotypes are discussed.
Collapse
Affiliation(s)
- Wing-Kee Lee
- Laboratory of Signal Transduction, Sloan Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, United States; Institute for Physiology, Pathophysiology and Toxicology, Centre for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Witten, Germany.
| | - Richard N Kolesnick
- Laboratory of Signal Transduction, Sloan Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, United States
| |
Collapse
|
|
48
|
Incorporation of Fluorescence Ceramide-Based HPLC Assay for Rapidly and Efficiently Assessing Glucosylceramide Synthase In Vivo. Sci Rep 2017; 7:2976. [PMID: 28592871 PMCID: PMC5462733 DOI: 10.1038/s41598-017-03320-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 04/26/2017] [Indexed: 12/16/2022] Open
Abstract
Glucosylceramide synthase (GCS) is a rate-limiting enzyme catalyzing ceramide glycosylation, thereby regulating cellular ceramide levels and the synthesis of glycosphingolipids (GSLs) in cellular membranes. Alterations of GCS not only affect membrane integrity, but also closely correlate with stem cell pluripotency, cancer drug resistance, GSL storage disorders and other diseases. Enzyme activities measured conventionally with currently available ex-vivo methods do not enable reliable assessment of the roles played by GCS in vivo. We report herein a substrate-incorporation method enabling rapid and efficient assessment of GCS in-vivo activity. Upon nanoparticle-based delivery, fluorescent NBD C6-ceramide was efficiently converted to NBD C6-glucosylceramide in live cells or in mouse tissues, whereupon an HPLC assay enabled detection and quantification of NBD C6-glucosylceramide in the low-femtomolar range. The enzyme kinetics of GCS in live cells and mouse liver were well-described by the Michaelis-Menten model. GCS activities were significantly higher in drug-resistant cancer cells and in tumors overexpressing GCS, but reduced after silencing GCS expression or inhibiting this enzyme. Our studies indicate that this rapid and efficient method provides a valuable means for accurately assessing the roles played by GCS in normal vs. pathological states, including ones involving cancer drug resistance.
Collapse
|
|
49
|
Dupre TV, Doll MA, Shah PP, Sharp CN, Siow D, Megyesi J, Shayman J, Bielawska A, Bielawski J, Beverly LJ, Hernandez-Corbacho M, Clarke CJ, Snider AJ, Schnellmann RG, Obeid LM, Hannun YA, Siskind LJ. Inhibiting glucosylceramide synthase exacerbates cisplatin-induced acute kidney injury. J Lipid Res 2017; 58:1439-1452. [PMID: 28490444 DOI: 10.1194/jlr.m076745] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 04/28/2017] [Indexed: 12/26/2022] Open
Abstract
Acute kidney injury (AKI), resulting from chemotherapeutic agents such as cisplatin, remains an obstacle in the treatment of cancer. Cisplatin-induced AKI involves apoptotic and necrotic cell death, pathways regulated by sphingolipids such as ceramide and glucosylceramide. Results from this study indicate that C57BL/6J mice treated with cisplatin had increased ceramide and hexosylceramide levels in the renal cortex 72 h following cisplatin treatment. Pretreatment of mice with inhibitors of acid sphingomyelinase and de novo ceramide synthesis (amitriptyline and myriocin, respectively) prevented accumulation of ceramides and hexosylceramide in the renal cortex and protected from cisplatin-induced AKI. To determine the role of ceramide metabolism to hexosylceramides in kidney injury, we treated mice with a potent and highly specific inhibitor of glucosylceramide synthase, the enzyme responsible for catalyzing the glycosylation of ceramides to form glucosylceramides. Inhibition of glucosylceramide synthase attenuated the accumulation of the hexosylceramides and exacerbated ceramide accumulation in the renal cortex following treatment of mice with cisplatin. Increasing ceramides and decreasing glucosylceramides in the renal cortex sensitized mice to cisplatin-induced AKI according to markers of kidney function, kidney injury, inflammation, cell stress, and apoptosis. Under conditions of high ceramide generation, data suggest that metabolism of ceramides to glucosylceramides buffers kidney ceramides and helps attenuate kidney injury.-Dupre, T. V., M. A. Doll, P. P. Shah, C. N. Sharp, D. Siow, J. Megyesi, J. Shayman, A. Bielawska, J. Bielawski, L. J. Beverly, M. Hernandez-Corbacho, C. J. Clarke, A. J. Snider, R. G. Schnellmann, L. M. Obeid, Y. A. Hannun, and L. J. Siskind. Inhibiting glucosylceramide synthase exacerbates cisplatin-induced acute kidney injury. J. Lipid Res 2017. 58: 1439-1452.
Collapse
Affiliation(s)
- Tess V Dupre
- Departments of Pharmacology and Toxicology University of Louisville, Louisville, KY
| | - Mark A Doll
- Departments of Pharmacology and Toxicology University of Louisville, Louisville, KY
| | - Parag P Shah
- Departments of Pharmacology and Medicine, University of Louisville, Louisville, KY; James Graham Brown Cancer Center, University of Louisville, Louisville, KY
| | - Cierra N Sharp
- Departments of Pharmacology and Toxicology University of Louisville, Louisville, KY
| | - Deanna Siow
- Departments of Pharmacology and Toxicology University of Louisville, Louisville, KY
| | - Judit Megyesi
- Department of Internal Medicine, Division of Nephrology, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR
| | - James Shayman
- Department Internal Medicine, University of Michigan, Ann Arbor, MI
| | - Alicja Bielawska
- Department of Biochemistry and Molecular Biology, Lipidomics Shared Resources, Medical University of South Carolina, Charleston, SC
| | - Jacek Bielawski
- Department of Biochemistry and Molecular Biology, Lipidomics Shared Resources, Medical University of South Carolina, Charleston, SC
| | - Levi J Beverly
- Departments of Pharmacology and Toxicology University of Louisville, Louisville, KY; Departments of Pharmacology and Medicine, University of Louisville, Louisville, KY; James Graham Brown Cancer Center, University of Louisville, Louisville, KY
| | | | - Christopher J Clarke
- Department of Medicine and Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY
| | - Ashley J Snider
- Department of Medicine and Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY; Northport Veterans Affairs Medical Center, Northport, NY
| | - Rick G Schnellmann
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ
| | - Lina M Obeid
- Department of Medicine and Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY; Northport Veterans Affairs Medical Center, Northport, NY
| | - Yusuf A Hannun
- Department of Medicine and Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY
| | - Leah J Siskind
- Departments of Pharmacology and Toxicology University of Louisville, Louisville, KY; James Graham Brown Cancer Center, University of Louisville, Louisville, KY.
| |
Collapse
|
|
50
|
Bugde P, Biswas R, Merien F, Lu J, Liu DX, Chen M, Zhou S, Li Y. The therapeutic potential of targeting ABC transporters to combat multi-drug resistance. Expert Opin Ther Targets 2017; 21:511-530. [DOI: 10.1080/14728222.2017.1310841] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Piyush Bugde
- School of Science, Auckland University of Technology, Auckland, New Zealand
| | - Riya Biswas
- School of Science, Auckland University of Technology, Auckland, New Zealand
| | - Fabrice Merien
- School of Science, Auckland University of Technology, Auckland, New Zealand
- School of Science, AUT Roche Diagnostic Laboratory, Auckland University of Technology, Auckland, New Zealand
| | - Jun Lu
- School of Science, Auckland University of Technology, Auckland, New Zealand
- School of Interprofessional Health Studies, Auckland University of Technology, Auckland, New Zealand
| | - Dong-Xu Liu
- School of Science, Auckland University of Technology, Auckland, New Zealand
| | - Mingwei Chen
- Department of Respiratory Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Shufeng Zhou
- Department of Biotechnology and Bioengineering, College of Chemical Engineering, Huaqiao University, Xiamen, China
| | - Yan Li
- School of Science, Auckland University of Technology, Auckland, New Zealand
- School of Interprofessional Health Studies, Auckland University of Technology, Auckland, New Zealand
| |
Collapse
|