title: Chemotherapeutic resistance in anaplastic astrocytoma cell lines treated with a temozolomide-lomeguatrib combination.
abstract: The treatment of anaplastic astrocytoma (AA) is controversial. New chemotherapeutic approaches are needed for AA treatment. Temozolomide (TMZ) is one of the chemotherapeutic drugs for the treatment of AA. The cytotoxic effects of TMZ can be removed by the MGMT (O(6)-methylguanine-DNA methyltransferase) enzyme. Then, chemotherapeutic resistance to TMZ occurs. MGMT inhibition by MGMT inactivators (such as lomeguatrib) is an important anticancer therapeutic approach to circumvent TMZ resistance. We aim to investigate the effect of TMZ-lomeguatrib combination on MGMT expression and TMZ sensitivity of SW1783 and GOS-3 AA cell lines. The sensitivity of SW1783 and GOS-3 cell lines to TMZ and to the combination of TMZ and lomeguatrib was determined by a cytotoxicity assay. MGMT methylation was detected by MS-PCR. MGMT and p53 expression were investigated by real-time PCR after drug treatment, and the proportion of apoptotic cells was analyzed by flow cytometry. When the combination of TMZ-lomeguatrib (50 μM) was used in AA cell lines, IC50 values were reduced compared to only using TMZ. MGMT expression was decreased, p53 expression was increased, and the proportion of apoptotic cells was induced in both cell lines. The lomeguatrib-TMZ combination did not have any effect on the cell cycle and caused apoptosis by increasing p53 expression and decreasing MGMT expression. Our study is a pilot study investigating a new therapeutic approach for AA treatment, but further research is needed.
authors.affiliation: Department of Neurosurgery, School of Medicine, Ankara University, Ankara, Turkey.
authors.forename: Hasan Caglar
authors.initials: HC
authors.lastname: Ugur
authors.forename: Mehmet
authors.initials: M
authors.lastname: Taspinar
authors.forename: Seda
authors.initials: S
authors.lastname: Ilgaz
authors.forename: Fatma
authors.initials: F
authors.lastname: Sert
authors.forename: Hande
authors.initials: H
authors.lastname: Canpinar
authors.forename: Juan A
authors.initials: JA
authors.lastname: Rey
authors.forename: Javier S
authors.initials: JS
authors.lastname: Castresana
authors.forename: Asuman
authors.initials: A
authors.lastname: Sunguroglu
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001254:Astrocytoma / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000096:biosynthesis; D004260:DNA Repair / Q000187:drug effects; D045643:DNA Repair Enzymes / Q000096:biosynthesis; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D011401:Promoter Regions, Genetic; D011687:Purines / Q000008:administration & dosage*; D000077204:Temozolomide; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis
chemical_list: D011687:Purines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; C521206:lomeguatrib; D000077204:Temozolomide