Mifepristone Overcomes Tumor Resistance to Temozolomide Associated with DNA Damage Repair and Apoptosis in an Orthotopic Model of Glioblastoma

Cancers

Janeth Serrano-Bello¹  Norma Uribe-Uribe²  LuisA. Medina³  AnaMaria Salazar⁴  Mauricio Rodríguez-Dorantes⁵  Patricia Garcia-Lopez⁶  Mario Romero-Piña⁶  Monserrat Llaguno-Munive⁶ 

[1] Facultad de Odontología, Universidad Nacional Autónoma de México (UNAM), Ciudad de México 04510, Mexico;Instituto Nacional de Ciencias Médicas y de la Nutrición Salvador Zubirán, Ciudad de México 14080, Mexico;Instituto de Física, Universidad Nacional Autónoma de México (UNAM), Unidad de Investigación Biomédica en Cáncer INCan-UNAM, Ciudad de México, 14080, Mexico;Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Ciudad de México 04510, Mexico;Instituto de Medicina Genómica, Ciudad de México 14080, Mexico;Laboratorio de Farmacología, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Ciudad de México 14080, Mexico;

关键词: glioblastoma;    temozolomide;    mifepristone;    MGMT;    drug resistance;    apoptosis;   

DOI  :  10.3390/cancers11010016

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown