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The Synergistic Effect of DZ‑NEP, Panobinostat and Temozolomide Reduces Clonogenicity and Induces Apoptosis in Glioblastoma Cells

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The Synergistic Effect of DZ‑NEP, Panobinostat and Temozolomide Reduces Clonogenicity and Induces Apoptosis in Glioblastoma Cells INTERNATIONAL JOURNAL OF ONCOLOGY 56: 283-300, 2020 The synergistic effect of DZ‑NEP, panobinostat and temozolomide reduces clonogenicity and induces apoptosis in glioblastoma cells JAVIER DE LA ROSA1, ALEJANDRO URDICIAIN1, IDOYA ZAZPE2, MARÍA V. ZELAYA3, BÁRBARA MELÉNDEZ4, JUAN A. REY5, MIGUEL A. IDOATE6 and JAVIER S. CASTRESANA1 1Department of Biochemistry and Genetics, University of Navarra School of Sciences; Departments of 2Neurosurgery and 3Pathology, Hospital Complex of Navarra, 31008 Pamplona; 4Molecular Pathology Research Unit, Department of Pathology, Virgen de la Salud Hospital, 45005 Toledo; 5IdiPaz Research Unit, La Paz University Hospital, 28046 Madrid; 6Department of Pathology, University of Navarra Clinic, 31008 Pamplona, Spain Received March 26, 2019; Accepted August 29, 2019 DOI: 10.3892/ijo.2019.4905 Abstract. Current treatment against glioblastoma consists of Introduction surgical resection followed by temozolomide, with or without combined radiotherapy. Glioblastoma frequently acquires Glioblastoma (1,2) is the most common form of malignant brain resistance to chemotherapy and/or radiotherapy. Novel thera- cancer in adults. It is highly lethal, with a median survival of peutic approaches are thus required. The inhibition of enhancer <15 months (3). Surgery, radiation therapy and temozolomide of zeste homolog 2 (EZH2; a histone methylase) and histone are the main therapeutic options against glioblastoma. A lack of deacetylases (HDACs) are possible epigenetic treatments. expression of methyl guanyl methyltransferase [MGMT; a DNA Temozolomide, 3-deazaneplanocin A (DZ-Nep; an EZH2 repair enzyme (4) that reverses the temozolomide-induced O6 inhibitor) and panobinostat (an HDAC inhibitor) were tested guanine methylation] due to MGMT promoter methylation is in regular and temozolomide-resistant glioblastoma cells to associated with improved clinical response to temozolomide, confirm whether the compounds could behave in a synergistic, whereas patients with unmethylated MGMT promoters exhibit additive or antagonistic manner. A total of six commercial resistance to temozolomide (4). Temozolomide resistance and cell lines, two temozolomide-induced resistant cell lines and radiotherapy resistance represent major challenges in the treat- two primary cultures derived from glioblastoma samples were ment of this disease (3,5,6). used. Cell lines were exposed to single treatments of the drugs Brain tumors are not only developed by gene mutation, but in addition to all possible two- and three-drug combinations. also by epigenetic changes, mainly DNA methylation, histone Colony formation assays, synergistic assays and reverse tran- acetylation, histone methylation and microRNA dysregula- scription-quantitative PCR analysis of apoptosis-associated tion (7-11). Unlike genetic alterations, epigenetic changes are genes were performed. The highest synergistic combination reversible, and as such are considered attractive targets for was DZ-Nep + panobinostat. Triple treatment was also syner- cancer therapy. Two main epigenetic modulators were investi- gistic. Reduced clonogenicity and increased apoptosis were gated in the present study, one that targets the enhancer of zeste both induced. It was concluded that the therapeutic potential homolog 2 (EZH2) histone methyltransferase [3-deazanepla- of the combination of these three drugs in glioblastoma was nocin A (DZ-Nep) (12)], and a second one that targets histone evident and should be further explored. deacetylases (HDACs), panobinostat (13). EZH2, the catalytically active component of polycomb repressive complex 2, trimethylates lysine 27 of histone H3 (H3K27met3) (14). EZH2 is overexpressed in ovarian carci- noma (15), prostate cancer (16), glioblastoma (17) and other tumors, and predicts poor prognosis, high tumor grade and high clinical stage (18) by favoring cell invasion and tumor angiogenesis. DZ-Nep, an inhibitor of EZH2, demonstrated Correspondence to: Professor Javier S. Castresana, Department antitumor activity against breast (19), lung (20), brain (21), of Biochemistry and Genetics, University of Navarra School of Sciences, Irunlarrea 1, 31008 Pamplona, Spain prostate (22) and liver (23) cancer cells, blocked cancer E-mail: [email protected] cell migration and invasion in prostate cancer cells (22), and reduced tumor-associated blood vessel formation in a Key words: 3-deazaneplanocin A, epigenetics, enhancer of zeste glioblastoma xenograft model, suggesting antiangiogenic homolog 2, glioblastoma, histone deacetylase, panobinostat activity in vivo (18,24). Recent studies have reinforced the value of EZH2 as a target in cancer, even associated microRNAs and long non coding RNAs with the regulation of EZH2 (25-27). 284 DE LA ROSA et al: SYNERGY OF DZ-NEP, PANOBINOSTAT AND TEMOZOLOMIDE IN GLIOBLASTOMA Histone acetylation by histone acetyltransferases induces Table I. Molecular profile of PTEN and p53 genes in cell lines a relaxed status of chromatin and promotes the expression and primary cell cultures. of adjacent genes, whereas HDACs condense chromatin and inhibit gene expression. One proposed strategy against cancer Cell line Type PTEN p53 is the use of inhibitors of HDACs, such as panobinostat (28-33), that target certain pathways that serve important roles in A172 GB MUT (60) WT (61) cancer development (13,34-36) at the level of the cell cycle, A172-TMZR GB MUT (60) WT (61) apoptosis, DNA damage responses, metastasis, angiogenesis U87MG GB MUT (62) WT (61) or autophagy. LN405 GB MUTa MUTa The aim of the present study was to investigate the LN405-TMZR GB MUTa MUTa therapeutic potential of different combinations of DZ-Nep, T98G GB MUT (63) MUT (61) panobinostat and temozolomide for the in vitro treatment of GOS-3 GB hemi-METH (64) WT (65) glioblastoma, as well as the possible synergistic effects that MOG-G-CCM GB hemi-METH (64) MUT (66) could exist between them. PE8 GB-1 ND ND PE9 GB-1 ND ND Materials and methods aInformation obtained from https://amp.pharm.mssm.edu/ In vitro culture of cell lines and primary tumors Harmonizome/gene_set/LN-405/COSMIC+Cell+Line+Gene+Mutat Cell lines. A172 (CRL1620), U87MG (HTB14), T98G ion+Profiles. GB, glioblastoma; GB‑1, primary glioblastoma; MUT, (92090213), MOG-C-CCM (86022702), LN405 (ACC189), mutated; WT, wild type; ND, not determined; METH, methylated. and GOS-3 (ACC408) human glioblastoma cell lines were used for the study. A172 and U87MG (glioblastoma of unknown origin) were obtained from the American Type Culture Collection. T98G and MOG-C-CCM were but that the resistant lines exhibited greater resistance to the obtained from the European Collection of Authenticated drug (particularly A172, as LN405 started with a large basal Cell Cultures. LN405 and GOS-3 were obtained from the resistance). German Collection of Microorganisms and Cell Cultures Culture of primary tumors. The study was authorized GmbH. A172, GOS-3, T98G, MOG-C-CCM, LN405 cells by the Ethics Committee of the University of Navarra (ref. were cultured using RPMI L-Glutamax medium (Gibco; no. CEI0502012) for conducting research on the genetics Thermo Fisher Scientific, Inc.), supplemented with 10% of tumors of the nervous system. All samples were fully fetal bovine serum (FBS; Gibco; Thermo Fisher Scientific, anonymized prior to accessing; therefore, patient details Inc.), 1% penicillin/streptomycin (Gibco; Thermo Fisher were not known. Patients provided informed consent for the Scientific, Inc.) and 0.1% amphotericin B (Gibco; Thermo use of their samples for research. Primary tumors obtained Fisher Scientific, Inc.). U87MG cells were cultured using from the Hospital Complex of Navarra were cultured. Tumor DMEM L‑Glutamax (Gibco; Thermo Fisher Scientific, Inc.) fragments were completely frozen in vials at ‑80˚C and in supplemented with 10% FBS, 4% non-essential amino acids, liquid nitrogen. The remainder of the tumor tissue was cut 1% penicillin/streptomycin and 0.1% amphotericin B. Cells with scalpels into ~22-mm thick fragments, which were were maintained under normoxic conditions at 37˚C with a treated with 0.1% trypsin and later mechanically processed humid atmosphere of 5% CO2. Subcultures were performed until tumor tissue was disintegrated into individual cells. upon reaching ~80% confluence using trypsin/EDTA The cells were cultured in flasks pretreated with laminin in (Gibco; Thermo Fisher Scientific, Inc.), after a previous wash neurosphere medium (composition described below). Starting with phosphate buffered saline (PBS; Gibco; Thermo Fisher with 1 mg/ml laminin (Sigma-Aldrich; Merck KGaA), a Scientific, Inc.). Table I presents the molecular profiles of the 10 µg/ml final concentration solution was prepared using cell lines used. PBS. The culture flasks were treated by adding 3 ml of this Obtaining temozolomide‑resistant cell lines. Cell lines solution. After incubating the flasks overnight at 4˚C, excess A172 and LN405 were exposed to 500 µM temozolomide for laminin was removed and three washes were made with 3 ml 72 h at 37˚C in an atmosphere of 5% CO2. The surviving cells of PBS. The culture medium used was DMEM + F12 (Gibco; were subsequently allowed to grow until they developed colo- Thermo Fisher Scientific, Inc.) in the absence of serum and nies. The colonies were trypsinized and reseeded. Once the supplemented with 1X B27 (Gibco; Thermo Fisher Scientific, cells reached ~70% confluence, they were treated again with Inc.), 20 ng/ml epidermal growth factor (Sigma-Aldrich; temozolomide as aforementioned. There were three total expo- Merck
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