Mifepristone Overcomes Tumor Resistance to Temozolomide Associated with DNA Damage Repair and Apoptosis in an Orthotopic Model of Glioblastoma
The standard treatment for glioblastoma multiforme (GBM) is surgery followed by chemo/radiotherapy. A major limitation on patient improvement is the high resistance of tumors to drug treatment, likely responsible for their subsequent recurrence and rapid progression. Therefore, alternatives to the s...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2018-12-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | http://www.mdpi.com/2072-6694/11/1/16 |
| _version_ | 1797713650900795392 |
|---|---|
| author | Monserrat Llaguno-Munive Mario Romero-Piña Janeth Serrano-Bello Luis A. Medina Norma Uribe-Uribe Ana Maria Salazar Mauricio Rodríguez-Dorantes Patricia Garcia-Lopez |
| author_facet | Monserrat Llaguno-Munive Mario Romero-Piña Janeth Serrano-Bello Luis A. Medina Norma Uribe-Uribe Ana Maria Salazar Mauricio Rodríguez-Dorantes Patricia Garcia-Lopez |
| author_sort | Monserrat Llaguno-Munive |
| collection | DOAJ |
| description | The standard treatment for glioblastoma multiforme (GBM) is surgery followed by chemo/radiotherapy. A major limitation on patient improvement is the high resistance of tumors to drug treatment, likely responsible for their subsequent recurrence and rapid progression. Therefore, alternatives to the standard therapy are necessary. The aim of the present study was to evaluate whether mifepristone, an antihormonal agent, has a synergistic effect with temozolomide (used in standard therapy for gliomas). Whereas the mechanism of temozolomide involves damage to tumor DNA leading to apoptosis, tumor resistance is associated with DNA damage repair through the O6-methylguanine-DNA-methyltransferase (MGMT) enzyme. Temozolomide/mifepristone treatment, herein examined in Wistar rats after orthotopically implanting C6 glioma cells, markedly reduced proliferation. This was evidenced by a decreased level of the following parameters: a proliferation marker (Ki-67), a tumor growth marker (18F-fluorothymidine uptake, determined by PET/CT images), and the MGMT enzyme. Increased apoptosis was detected by the relative expression of related proteins, (e.g. Bcl-2 (B-cell lymphoma 2), Bax (bcl-2-like protein 4) and caspase-3). Thus, greater apoptosis of tumor cells caused by their diminished capacity to repair DNA probably contributed significantly to the enhanced activity of temozolomide. The results suggest that mifepristone could possibly act as a chemo-sensitizing agent for temozolomide during chemotherapy for GBM. |
| first_indexed | 2024-03-12T07:39:51Z |
| format | Article |
| id | doaj.art-d6ef2c4df4c249079da9160ddf8b8498 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T07:39:51Z |
| publishDate | 2018-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-d6ef2c4df4c249079da9160ddf8b84982023-09-02T21:22:56ZengMDPI AGCancers2072-66942018-12-011111610.3390/cancers11010016cancers11010016Mifepristone Overcomes Tumor Resistance to Temozolomide Associated with DNA Damage Repair and Apoptosis in an Orthotopic Model of GlioblastomaMonserrat Llaguno-Munive0Mario Romero-Piña1Janeth Serrano-Bello2Luis A. Medina3Norma Uribe-Uribe4Ana Maria Salazar5Mauricio Rodríguez-Dorantes6Patricia Garcia-Lopez7Laboratorio de Farmacología, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Ciudad de México 14080, MexicoLaboratorio de Farmacología, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Ciudad de México 14080, MexicoFacultad de Odontología, Universidad Nacional Autónoma de México (UNAM), Ciudad de México 04510, MexicoInstituto de Física, Universidad Nacional Autónoma de México (UNAM), Unidad de Investigación Biomédica en Cáncer INCan-UNAM, Ciudad de México, 14080, MexicoInstituto Nacional de Ciencias Médicas y de la Nutrición Salvador Zubirán, Ciudad de México 14080, MexicoInstituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Ciudad de México 04510, MexicoInstituto de Medicina Genómica, Ciudad de México 14080, MexicoLaboratorio de Farmacología, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Ciudad de México 14080, MexicoThe standard treatment for glioblastoma multiforme (GBM) is surgery followed by chemo/radiotherapy. A major limitation on patient improvement is the high resistance of tumors to drug treatment, likely responsible for their subsequent recurrence and rapid progression. Therefore, alternatives to the standard therapy are necessary. The aim of the present study was to evaluate whether mifepristone, an antihormonal agent, has a synergistic effect with temozolomide (used in standard therapy for gliomas). Whereas the mechanism of temozolomide involves damage to tumor DNA leading to apoptosis, tumor resistance is associated with DNA damage repair through the O6-methylguanine-DNA-methyltransferase (MGMT) enzyme. Temozolomide/mifepristone treatment, herein examined in Wistar rats after orthotopically implanting C6 glioma cells, markedly reduced proliferation. This was evidenced by a decreased level of the following parameters: a proliferation marker (Ki-67), a tumor growth marker (18F-fluorothymidine uptake, determined by PET/CT images), and the MGMT enzyme. Increased apoptosis was detected by the relative expression of related proteins, (e.g. Bcl-2 (B-cell lymphoma 2), Bax (bcl-2-like protein 4) and caspase-3). Thus, greater apoptosis of tumor cells caused by their diminished capacity to repair DNA probably contributed significantly to the enhanced activity of temozolomide. The results suggest that mifepristone could possibly act as a chemo-sensitizing agent for temozolomide during chemotherapy for GBM.http://www.mdpi.com/2072-6694/11/1/16glioblastomatemozolomidemifepristoneMGMTdrug resistanceapoptosis |
| spellingShingle | Monserrat Llaguno-Munive Mario Romero-Piña Janeth Serrano-Bello Luis A. Medina Norma Uribe-Uribe Ana Maria Salazar Mauricio Rodríguez-Dorantes Patricia Garcia-Lopez Mifepristone Overcomes Tumor Resistance to Temozolomide Associated with DNA Damage Repair and Apoptosis in an Orthotopic Model of Glioblastoma Cancers glioblastoma temozolomide mifepristone MGMT drug resistance apoptosis |
| title | Mifepristone Overcomes Tumor Resistance to Temozolomide Associated with DNA Damage Repair and Apoptosis in an Orthotopic Model of Glioblastoma |
| title_full | Mifepristone Overcomes Tumor Resistance to Temozolomide Associated with DNA Damage Repair and Apoptosis in an Orthotopic Model of Glioblastoma |
| title_fullStr | Mifepristone Overcomes Tumor Resistance to Temozolomide Associated with DNA Damage Repair and Apoptosis in an Orthotopic Model of Glioblastoma |
| title_full_unstemmed | Mifepristone Overcomes Tumor Resistance to Temozolomide Associated with DNA Damage Repair and Apoptosis in an Orthotopic Model of Glioblastoma |
| title_short | Mifepristone Overcomes Tumor Resistance to Temozolomide Associated with DNA Damage Repair and Apoptosis in an Orthotopic Model of Glioblastoma |
| title_sort | mifepristone overcomes tumor resistance to temozolomide associated with dna damage repair and apoptosis in an orthotopic model of glioblastoma |
| topic | glioblastoma temozolomide mifepristone MGMT drug resistance apoptosis |
| url | http://www.mdpi.com/2072-6694/11/1/16 |
| work_keys_str_mv | AT monserratllagunomunive mifepristoneovercomestumorresistancetotemozolomideassociatedwithdnadamagerepairandapoptosisinanorthotopicmodelofglioblastoma AT marioromeropina mifepristoneovercomestumorresistancetotemozolomideassociatedwithdnadamagerepairandapoptosisinanorthotopicmodelofglioblastoma AT janethserranobello mifepristoneovercomestumorresistancetotemozolomideassociatedwithdnadamagerepairandapoptosisinanorthotopicmodelofglioblastoma AT luisamedina mifepristoneovercomestumorresistancetotemozolomideassociatedwithdnadamagerepairandapoptosisinanorthotopicmodelofglioblastoma AT normauribeuribe mifepristoneovercomestumorresistancetotemozolomideassociatedwithdnadamagerepairandapoptosisinanorthotopicmodelofglioblastoma AT anamariasalazar mifepristoneovercomestumorresistancetotemozolomideassociatedwithdnadamagerepairandapoptosisinanorthotopicmodelofglioblastoma AT mauriciorodriguezdorantes mifepristoneovercomestumorresistancetotemozolomideassociatedwithdnadamagerepairandapoptosisinanorthotopicmodelofglioblastoma AT patriciagarcialopez mifepristoneovercomestumorresistancetotemozolomideassociatedwithdnadamagerepairandapoptosisinanorthotopicmodelofglioblastoma |