Mifepristone Overcomes Tumor Resistance to Temozolomide Associated with DNA Damage Repair and Apoptosis in an Orthotopic Model of Glioblastoma.
Monserrat Llaguno-MuniveMario Romero-PiñaJaneth Serrano-BelloLuis Alberto MedinaNorma Uribe-UribeAna Maria SalazarMauricio Rodríguez-DorantesPatricia Garcia-LopezPublished in: Cancers (2018)
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.
Keyphrases
- oxidative stress
- dna damage
- pet ct
- endoplasmic reticulum stress
- cell death
- newly diagnosed
- combination therapy
- circulating tumor
- locally advanced
- signaling pathway
- photodynamic therapy
- poor prognosis
- case report
- radiation therapy
- squamous cell carcinoma
- dna repair
- early stage
- lymph node
- drug delivery
- cell proliferation
- quantum dots
- diffuse large b cell lymphoma
- mesenchymal stem cells
- rectal cancer
- radiation induced
- positron emission tomography
- atrial fibrillation
- cancer therapy
- bone marrow
- long non coding rna
- replacement therapy
- electronic health record
- cell therapy