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Now showing 1 - 18 of 18

Citation - WoS: 8
An answer to colon cancer treatment by mesenchymal stem cell originated from adipose tissue
(Mashhad Univ Med Sciences, 2018) Iplik, Elif Sinem; Ertugrul, Baris; Kozanoglu, Ilknur; Baran, Yusuf; Cakmakoglu, Bedia; Baran, Yusuf
Objective(s): Colon cancer is risen up with its complex mechanism that directly impacts on its treatment as well as its common prevalence. Mesenchymal stem cells (MSCs) have been considered as a therapeutic candidate for conventional disease including cancer. In this research, we have focused on apoptotic effects of adipose tissue-derived MSCs in colon cancer. Materials and Methods: MSCs were obtained from adipose tissue and characterized by Flowcytometer using suitable antibodies. MSCs, HT-29, HCT-116, RKO and healthy cell line MRC5 were cultured by different seeding procedure. After cell viability assay, changes in caspase 3 enzyme activity and the level of phosphatidylserine were measured. Results: For cell viability assay, a 48 hr incubation period was chosen to seed all cells together. There was a 1.36-fold decrease in caspase 3 enzyme activity by co-treatment of RKO and MSCs in addition to 2.02-fold decrease in HT-29 and MSCs co-treatment, and 1.103-fold increase in HCT-116 and MSCs. The results demonstrated that HCT-116 led to the highest rate of apoptotic cell death (7.5%) compared with other cells. Conclusion: We suggest that MSCs might remain a new treatment option for cancer by its differentiation and repair capacity.
Citation - WoS: 11
Bisphosphonate treatment and radiotherapy in metastatic breast cancer
(Humana Press inc, 2008) Ural, A. Ugur; Avcu, Ferit; Baran, Yusuf; Baran, Yusuf
Patients with advanced breast cancer frequently develop metastasis to bone. Bone metastasis results in intractable pain and high risk of pathologic fractures due to osteolysis. The treatment of breast cancer patients with bone metastases requires a multidisciplinary approach. Radiotherapy is an established treatment for metastatic bone pain. It may be delivered either as a localized low dose treatment for localized bone pain or systemically for more widespread symptoms. Bisphosphonates have been shown to reduce morbidity and bone pain from bone metastases when given to patients with metastatic bone disease. In vivo studies indicate that early bisphosphonates administration in combination with radiotherapy improves remineralization and restabilization of osteolytic bone metastases in animal tumor models. This review focused on a brief discussion about biology of bone metastases, the effects of radiotherapy and bisphosphonate therapy, and possible mechanisms of combination therapy in metastatic breast cancer patients.
Citation - WoS: 350
Cell Proliferation and Cytotoxicity Assays
(Bentham Science Publ Ltd, 2016) Adan, Aysun; Kiraz, Yagmur; Baran, Yusuf; Baran, Yusuf
Cell viability is defined as the number of healthy cells in a sample and proliferation of cells is a vital indicator for understanding the mechanisms in action of certain genes, proteins and pathways involved cell survival or death after exposing to toxic agents. Generally, methods used to determine viability are also common for the detection of cell proliferation. Cell cytotoxicity and proliferation assays are generally used for drug screening to detect whether the test molecules have effects on cell proliferation or display direct cytotoxic effects. Regardless of the type of cell-based assay being used, it is important to know how many viable cells are remaining at the end of the experiment. There are a variety of assay methods based on various cell functions such as enzyme activity, cell membrane permeability, cell adherence, ATP production, co-enzyme production, and nucleotide uptake activity. These methods could be basically classified into different categories: (I) dye exclusion methods such as trypan blue dye exclusion assay, (II) methods based on metabolic activity, (III) ATP assay, (IV) sulforhodamine B assay, (V) protease viability marker assay, (VI) clonogenic cell survival assay, (VII) DNA synthesis cell proliferation assays and (V) raman micro-spectroscopy. In order to choose the optimal viability assay, the cell type, applied culture conditions, and the specific questions being asked should be considered in detail. This particular review aims to provide an overview of common cell proliferation and cytotoxicity assays together with their own advantages and disadvantages, their methodologies, comparisons and intended purposes.
Citation - WoS: 10
Effects of cell-mediated osteoprotegerin gene transfer and mesenchymal stem cell applications on orthodontically induced root resorption of rat teeth
(Oxford Univ Press, 2017) Amuk, Nisa Gul; Kurt, Gokmen; Baran, Yusuf; Seyrantepe, Volkan; Yandim, Melis Kartal; Adan, Aysun; Sonmez, Mehmet Fatih; Baran, Yusuf
Aim: The aim of this study is to evaluate and compare therapeutic effects of mesenchymal stem cell (MSCs) and osteoprotegerin (OPG) gene transfer applications on inhibition and/or repair of orthodontically induced inflammatory root resorption (OIIRR). Materials and methods: Thirty Wistar rats were divided into four groups as untreated group (negative control), treated with orthodontic appliance group (positive control), MSCs injection group, and OPG transfected MSCs [gene therapy (GT) group]. About 100 g of orthodontic force was applied to upper first molar teeth of rats for 14 days. MSCs and transfected MSC injections were performed at 1st, 6th, and 11th days to the MSC and GT group rats. At the end of experiment, upper first molar teeth were prepared for genetical, scanning electron microscopy (SEM), fluorescent microscopy, and haematoxylin eosin-tartrate resistant acid phosphatase staining histological analyses. Number of total cells, number of osteoclastic cells, number of resorption lacunae, resorption area ratio, SEM resorption ratio, OPG, RANKL, Cox-2 gene expression levels at the periodontal ligament (PDL) were calculated. Paired t-test, Kruskal-Wallis, and chi-square tests were performed. Results: Transferred MSCs showed marked fluorescence in PDL. The results revealed that number of osteoclastic cells, resorption lacunae, resorption area ratio, RANKL, and Cox-2 were reduced after single MSC injections significantly (P < 0.05). GT group showed the lowest number of osteoclastic cells (P < 0.01), number of resorption lacunae, resorption area ratio, and highest OPG expression (P < 0.001). Conclusions: Taken together all these results, MSCs and GT showed marked inhibition and/or repair effects on OIIRR during orthodontic treatment on rats.
Citation - WoS: 12
Gossypol Interferes with Both Type I and Type II Topoisomerase Activities Without Generating Strand Breaks
(Humana Press inc, 2013) Senarisoy, Muge; Canturk, Pakize; Zencir, Sevil; Baran, Yusuf; Topcu, Zeki; Baran, Yusuf
A considerable number of agents with chemotherapeutic potentials reported over the past years were shown to interfere with the reactions of DNA topoisomerases, the essential enzymes that regulate conformational changes in DNA topology. Gossypol, a naturally occurring bioactive phytochemical is a chemopreventive agent against various types of cancer cell growth with a reported activity on mammalian topoisomerase II. The compounds targeting topoisomerases vary in their mode of action; class I compounds act by stabilizing covalent topoisomerase-DNA complexes resulting in DNA strand breaks while class II compounds interfere with the catalytic function of topoisomerases without generating strand breaks. In this study, we report Gossypol as the interfering agent with type I topoisomerases as well. We also carried out an extensive set of assays to analyze the type of interference manifested by Gossypol on DNA topoisomerases. Our results strongly suggest that Gossypol is a potential class II inhibitor as it blocked DNA topoisomerase reactions with no consequently formed strand breaks.
Citation - WoS: 0
Investigating the potential therapeutic role of targeting STAT3 for overcoming drug resistance by regulating energy metabolism in chronic myeloid leukemia cells
(Mashhad Univ Med Sciences, 2022) Kaymaz, Burcin Tezcanli; Gunel, Nur Selvi; Sogutlu, Fatma; Ay, Neslihan Pinar Ozates; Baran, Yusuf; Gunduz, Cumhur; Avci, Cigir Biray; Baran, Yusuf
Objective(s): STATs are one of the initial targets of emerging anti-cancer agents due to their regulatory roles in survival, apoptosis, drug response, and cellular metabolism in CML. Aberrant STAT3 activity promotes malignancy, and acts as a metabolic switcher in cancer cell metabolism, contributing to resistance to TKI nilotinib. To investigate the possible therapeutic effects of targeting STAT3 to overcome nilotinib resistance by evaluating various cellular responses in both sensitive and nilotinib resistant CML cells and to test the hypothesis that energy metabolism modulation could be a mechanism for re-sensitization to nilotinib in resistant cells. Materials and Methods: By using RNAi-mediated STAT3 gene silencing, cell viability and proliferation assays, apoptotic analysis, expressional regulations of STAT mRNA transcripts, STAT3 total, pTyr705, pSer727 protein expression levels, and metabolic activity as energy metabolism was determined in CML model K562 cells, in vitro. Results: Targeting STAT3 sensitized both parental and especially nilotinib resistant cells by decreasing leukemic cell survival; inducing leukemic cell apoptosis, and decreasing STAT3 mRNA and protein expression levels. Besides, cell energy phenotype was modulated by switching energy metabolism from aerobic glycolysis to mitochondrial respiration in resistant cells. RNAi-mediated STAT3 silencing accelerated the sensitization of leukemia cells to nilotinib treatment, and STAT3-dependent energy metabolism regulation could be another underlying mechanism for regaining nilotinib response. Conclusion: Targeting STAT3 is an efficient strategy for improving the development of novel CML therapeutics for regaining nilotinib response, and re-sensitization of resistant cells could be mediated by induced apoptosis and regulation in energy metabolism.
Citation - WoS: 8
Citation - Scopus: 8
Long Noncoding RNAs in Human Cancer and Apoptosis
(Bentham Science Publ Ltd, 2023) Erdogan, Ipek; Sweef, Osama; Akgul, Bunyamin; Akgül, Bünyamin
Genome annotations have uncovered the production of at least one transcript from nearly all loci in the genome at some given time throughout the development. Surprisingly, many of these transcripts do not code for proteins and are relatively long in size, thus called long noncoding RNAs (lncRNAs). Next- and third-generation sequencing technologies have amassed numerous lncRNAs expressed under different phenotypic conditions, yet many remain to be functionally characterized. LncRNAs regulate gene expression by functioning as scaffold, decoy, signaling, and guide molecules both at the transcriptional and post-transcriptional levels, interacting with different types of macromolecules, such as proteins, DNA, and RNA. Here, we review the potential regulatory role of lncRNAs in apoptosis and cancer as some of these lncRNAs may have the diagnostic and therapeutic potential in cancer.
Citation - WoS: 12
Macromolecular Changes in Nilotinib Resistant K562 Cells; an In vitro Study by Fourier Transform Infrared Spectroscopy
(Sage Publications inc, 2012) Ceylan, Cagatay; Camgoz, Aylin; Baran, Yusuf; Baran, Yusuf
Nilotinib is a second generation tyrosine kinase inhibitor which is used in both first and second line treatment of chronic myeloid leukemia (CML). In the present work, the effects of nilotinib resistance on K562 cells were investigated at the molecular level using Fourier transform infrared (FT-IR) spectroscopy. Human K562 CML cells were exposed to step-wise increasing concentrations of nilotinib, and sub-clones of K562 cells resistant to 50 nM nilotinib were generated and referred to as K562/NIL-50 cells. Antiproliferative effects of nilotinib were determined by XTT cell proliferation assay. Changes in macromolecules in parental and resistant cells were studied by FT-IR spectroscopy. Nilotinib resistance caused significant changes which indicated increases in the level of glycogen and membrane/lipid order. The amount of unsaturated lipids increased in the nilotinib resistant cells indicating lipid peroxidation. The total amount of lipids did not change significantly but the relative proportion of cholesterol and triglycerides altered considerably. Moreover, the transcriptional status decreased but metabolic turn-over increased as revealed by the FT-IR spectra. In addition, changes in the proteome and structural changes in both proteins and the nucleus were observed in the K562/NIL-50 cells. Protein secondary structural analyses revealed that alpha helix structure and random coil structure decreased, however, anti-parallel beta sheet structure, beta sheet structure and turns structure increased. These results indicate that the FT-IR technique provides a method for analyzing drug resistance related structural changes in leukemia and other cancer types.
Citation - WoS: 22
Mechanisms responsible for nilotinib resistance in human chronic myeloid leukemia cells and reversal of resistance
(Taylor & Francis Ltd, 2013) Camgoz, Aylin; Gencer, Emel Basak; Ural, Ali Ugur; Baran, Yusuf; Baran, Yusuf
Multidrug resistance remains a significant obstacle to successful chemotherapy. The ability to determine the possible resistance mechanisms and surmount the resistance is likely to improve chemotherapy. Nilotinib is a very effective drug in the treatment of imatinib-sensitive or -resistant patients. Although very successful hematologic and cytogenetic responses have been obtained in nilotinib-treated patients, in recent years cases showing resistance to nilotinib have been observed. We aimed to examine the mechanisms underlying nilotinib resistance and to provide new targets for the treatment of chronic myeloid leukemia (CML). There was an up-regulation of antiapoptotic BCR/ABL, GCS and SK-1 genes and MRP1 transporter gene and down-regulation of apoptotic Bax and CerS1 genes in nilotinib-resistant cells. There was no mutation in the nilotinib-binding region of BCR/ABL in resistant cells. Inhibiton of GCS and SK-1 restored nilotinib sensitivity. Targeting the proteins that are involved in nilotinib resistance in addition to the inhibition of BCR/ABL could be a better method of treatment in CML.
Citation - WoS: 6
Citation - Scopus: 5
MicroRNAs and Long Non-coding RNAs as Novel Targets in Anti-cancer Drug Development
(Bentham Science Publ Ltd, 2023) Cetinkaya, Melisa; Baran, Yusuf; Baran, Yusuf
Non-coding RNAs comprise the majority of RNAs that have been transcribed from the human genome, and these non-coding RNAs have essential regulatory roles in the cellular processes. They have been discovered to influence the expression of the genes, including tumor-suppressive and oncogenes, that establish the non-coding RNAs as novel targets for anti-cancer drug development. Among non-coding RNAs, microRNAs have been extensively studied in terms of cancer biology, and some microRNA-based therapeutics have been reached in clinical studies. Even though most of the research regarding targeting non-coding RNAs for anti-cancer drug development focused on microRNAs, long non-coding RNAs have also started to gain importance as potential therapeutic targets for cancer therapy. In this chapter, the strategies and importance of targeting microRNAs and long non-coding RNAs will be described, along with the clinical studies that involve microRNA-based cancer therapeutics and preclinical studies that involve long non-coding RNA-based therapeutics. Finally, the delivery strategies that have great importance in the effective delivery of the non-coding RNA-based cancer therapeutics, hence the therapy's effectiveness, will be described.
Citation - WoS: 4
Citation - Scopus: 4
Noncoding RNAs: A New Layer of Functional RNAs
(Bentham Science Publ Ltd, 2023) Gurer, Dilek Cansu; Akgul, Bunyamin; Akgül, Bünyamin
The conventional central dogma of molecular biology dictates that the genetic information contained within deoxyribonucleic acid (DNA) is passed onto messenger ribonucleic acids (mRNAs), which are then used as templates to synthesize proteins. Although these types of protein-coding genes have been historically prioritized in typical phenotype-genotype studies with a parallel disregard to the rest of the genome, the completion of genome projects has unveiled a surprising layer of genetic information that can play critical roles in cellular processes without coding for proteins. These types of genes are called noncoding genes as they do not code for proteins. Noncoding genes come in different sizes and shapes, and they are just as versatile in carrying out cellular biochemical processes as proteins. In this review, we cover a comprehensive review of housekeeping and regulatory noncoding genes and their mode of action.
Citation - WoS: 35
Citation - Scopus: 41
Protoporphyrin IX-loaded magnetoliposomes as a potential drug delivery system for photodynamic therapy: Fabrication, characterization and in vitro study
(Elsevier, 2016) Basoglu, Harun; Bilgin, Mehmet Dincer; Demir, Mustafa Muammer; Demir, Mustafa
Background: Protoporphyrin IX (PpIX) is a well-known photosensitizer that has great potential for use in photodynamic therapy (PDT). However, aggregation behavior of PpIX in neutral water makes it inappropriate for physiological studies. PpIX-loaded magnetoliposomes (MLs) were fabricated to increase PpIX biocompatibility. PpIX-loaded ML physical properties were characterized, and PpIX-loaded ML drug release behavior was investigated under the influence of an external magnetic field and heat. Toxicity and photodynamic effects of the complex were also examined using in vitro experiments with MCF-7 human breast cancer cells. Methods: The magnetoliposomes were prepared with DPPC, DSPE-PEG2000 lipids and Fe3O4 nanoparticles. The toxicity and in vitro photodynamic effects of the PpIX-loaded MLs at various concentrations were studied using the MCF-7 cell line. Results: The produced PpIX-loaded MLs exhibited an average hydrodynamic diameter of 221 nm; however, TEM measurements indicated that the diameter of the PpIX-loaded MLs varied between 166 and 720 nm. The iron content of the MLs affected cell viability less than the content of the iron free liposomes. Cell viability was reduced to 66% when the concentration of the PpIX-loaded MLs was 350 nM, but when white light was applied for 5 min, all of the cells that were exposed to concentrations of 250 nM and higher PpIX died within 24 h. Conclusion: The results of this study demonstrated the effective application of PpIX-loaded MLs for in vitro photodynamic therapy at nanomolar concentrations. The results also indicated that an LED light source provided sufficient energy to stimulate the PpIX molecules. (C) 2015 Elsevier B.V. All rights reserved.
Citation - WoS: 35
Resveratrol Triggers Apoptosis Through Regulating Ceramide Metabolizing Genes in Human K562 Chronic Myeloid Leukemia Cells
(Routledge Journals, Taylor & Francis Ltd, 2011) Kartal, Melis; Saydam, Guray; Sahin, Fahri; Baran, Yusuf; Baran, Yusuf
Resveratrol, an important phytoalexin in many plants, has been reported to have cytotoxic effects on various types of cancer. Ceramide is a bioactive sphingolipid that regulates many signaling pathways, including cell growth and proliferation, senescence and quiescence, apoptosis, and cell cycle. Ceramides are generated by longevity assurance genes (LASS). Glucosylceramide synthase (GCS) and sphingosine kinase-1 (SK-1) enzymes can convert ceramides to antiapoptotic molecules, glucosylceramide, and sphingosine-1-phosphate, respectively. C8:ceramide, an important cell-permeable analogue of natural ceramides, increases intracellular ceramide levels significantly, while 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) and SK-1 inhibitor increase accumulation of ceramides by inhibiting GCS and SK-1, respectively. Chronic myelogenous leukemia (CML) is a hematological disorder resulting from generation of BCR/ABL oncogene. In this study, we examined the roles of ceramide metabolizing genes in resveratrol-induced apoptosis in K562 CML cells. There were synergistic cytotoxic and apoptotic effects of resveratrol with coadministration of C8:ceramide, PDMP, and SK-1 inhibitor. Interestingly, there were also significant increases in expression levels of LASS genes and decreases in expression levels of GCS and SK-1 in K562 cells in response to resveratrol. Our data, in total, showed for the first time that resveratrol might kill CML cells through increasing intracellular generation and accumulation of apoptotic ceramides.
Citation - WoS: 16
Roles of ceramide synthase and ceramide clearence genes in nilotinib-induced cell death in chronic myeloidleukemia cells
(Taylor & Francis Ltd, 2011) Camgoz, Aylin; Gencer, Emel Basak; Ural, Ali Ugur; Avcu, Ferit; Baran, Yusuf; Baran, Yusuf
In this study, we aimed to increase the sensitivity of human K562 and Meg-01 chronic myeloid leukemia (CML) cells to nilotinib by targeting bioactive sphingolipids, in addition to investigating the roles of ceramide metabolizing genes in nilotinib induced apoptosis. Cytotoxic effects of nilotinib, C8:ceramide, glucosyle ceramide synthase (GCS) and sphingosine kinase-1 (SK-1) inhibitors were determined by XTT cell proliferation assay and synergism between the agents was determined by isobologram analysis. Also, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) results demonstrated that expression levels of longevity assurance (LASS) genes in response to nilotinib were correlated with sensitivity to nilotinib. For the first time, The results of this study showed for the first time that nilotinib induces apoptosis through upregulating ceramide synthase genes and downregulating SK-1 in CML cells in addition to inhibition of BCR/ABL. On the other hand, manipulating bioactive sphingolipids toward generation/accumulation of ceramides increased the apoptotic effects of nilotinib in CML cells.
Citation - WoS: 18
Suppression of STAT5A increases chemotherapeutic sensitivity in imatinib-resistant and imatinib-sensitive K562 cells
(Taylor & Francis Ltd, 2010) Kosova, Buket; Tezcanli, Burcin; Ekiz, Huseyin Atakan; Cakir, Zeynep; Selvi, Nur; Dalmizrak, Aysegul; Baran, Yusuf; Baran, Yusuf
STAT proteins are cytoplasmic transcription factors that are involved in the regulation of numerous cellular activities such as cell growth, differentiation, and survival. In this study, we aimed to identify the expression pattern of STAT genes in imatinib-sensitive and -resistant K562 cells, and further, to reveal the effects of STAT5A siRNA knockdown on cell growth and apoptosis induction. The XTT cell proliferation assay showed that both sensitive and resistant K562 cells were sensitized to imatinib upon transfection with STAT5A siRNA. Caspase-3 enzyme activity was increased significantly in both cells. These results may open up new opportunities to overcome chemotherapeutic resistance in leukemia.
Citation - WoS: 5
Targeting FoxM1 transcription factor in T-cell acute lymphoblastic leukemia cell line
(Pergamon-elsevier Science Ltd, 2015) Tufekci, Ozlem; Yandim, Melis Kartal; Oren, Hale; Irken, Gulersu; Baran, Yusuf; Baran, Yusuf
The Forkhead box protein M1 (FoxM1) is an important transcription factor having significant roles in various cellular events. FoxM1 overexpression has been reported to be related with many types of cancer. However, it is not known whether it contributes to oncogenesis of acute lymphoblastic leukemia. Siomycin A, a thiazol antibiotic, is known to inhibit FoxM1 transcriptional activity. In this study, we aimed to determine gene expression levels of FoxM1 in Jurkat cells (T-cell acute lymphoblastic leukemia cell line) and therapeutic potential of targeting FoxM1 by siomycin A alone and in combination with dexamethasone which improves the survival of children with T-cell acute lymphoblastic leukemia (ALL). We also examined the molecular mechanisms of siomycin A and dexamethasone-induced cell death in Jurkat cells. We demonstrated that FoxM1 mRNA is highly expressed in Jurkat cells. Dexamethasone and siomycin A caused a significant reduction in gene expression levels of FoxM1 in Jurkat cells. Targeting FoxM1 by siomycin A and dexamethasone caused a significant decrease in T-ALL cell line proliferation through induction of G1 cell cycle arrest. All these findings suggest a possible role of FoxM1 in T-cell ALL pathogenesis and represent FoxM1 as an attractive target for T-cell ALL therapy. (C) 2014 Elsevier Ltd. All rights reserved.
Citation - WoS: 25
Therapeutic Potential of Apigenin, a Plant Flavonoid, for Imatinib-Sensitive and Resistant Chronic Myeloid Leukemia Cells
(Routledge Journals, Taylor & Francis Ltd, 2014) Solmaz, Soner; Gokbulut, Aysun Adan; Cincin, Birsu; Ozdogu, Hakan; Boga, Can; Cakmakoglu, Bedia; Baran, Yusuf; Baran, Yusuf
Despite the presence of many therapeutic regimens like imatinib and other tyrosine kinase inhibitors, the development of resistance, intolerance, and side effects makes chronic myeloid leukemia (CML) therapy challenging. Thus, there is a need to discover novel drugs for CML patients. In this study, we attempted to assess apigenin, a common plant dietary flavonoid, in terms of its cytotoxic, apoptotic, and cytostatic effects on imatinib-sensitive and resistant Philadelphia-positive CML cells. We analyzed apigenin's effects on cell proliferation, apoptosis, caspase-3 activity, loss of mitochondrial membrane potential, and cell cycle progression in K562 and K562/IMA3 cells. Furthermore, we described genes and gene networks that are modulated in CML in response to apigenin. Results of our study revealed that apigenin has cytotoxic and apoptotic effects on both cell types. We also displayed that apigenin induced G2/M arrest in K562 cells while arresting K562/IMA3 cells in S phase especially at the highest apigenin concentration. The expression analysis identified a set of genes that were regulated by apigenin in K652 and K562/IMA3 cells. Association of modulated genes with biological functional groups identified several networks affected by apigenin including cell survival, proliferation, cell death, cell cycle, and cell signalling pathways.
Citation - WoS: 42
Therapeutic potential of targeting ceramide/glucosylceramide pathway in cancer
(Springer, 2013) Yandim, Melis Kartal; Apohan, Elif; Baran, Yusuf; Baran, Yusuf
Sphingolipids including ceramides and its derivatives such as ceramide-1-phosphate, glucosylceramide (GlcCer), and sphingosine-1-phosphate are essential structural components of cell membranes. They now recognized as novel bioeffector molecules which control various aspects of cell growth, proliferation, apoptosis, and drug resistance. Ceramide, the central molecule of sphingolipid metabolism, generally mediates anti-proliferative responses such as inhibition of cell growth, induction of apoptosis, and/or modulation of senescence. There are two major classes of sphingolipids. One of them is glycosphingolipids which are synthesized from the hydrophobic molecule, ceramide. GlcCer, generated by glucosylceramide synthase (GCS) that transfers the glucose from UDP-glucose to ceramide, is an important glycosphingolipid metabolic intermediate. GCS regulates the balance between apoptotic ceramide and antiapoptotic GlcCer. Downregulation or inhibition of GCS results in increased apoptosis and decreased drug resistance. The mechanism underlying the drug resistance which develops with increased glucosylceramide expression is associated with P-glycoprotein. In various types of cancers, overexpression of GCS has been observed which renders GCS a good target for the treatment of cancer. This review summarizes our current knowledge on the structure and functions of glucosylceramide synthase and glucosylceramide and on the roles of glucosylceramide synthase in cancer therapy and drug resistance.

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