Mifepristone as a Potential Therapy to Reduce Angiogenesis and P-Glycoprotein Associated With Glioblastoma Resistance to Temozolomide

Abstract

Glioblastoma, the most common primary central nervous system tumor, is characterized by extensive vascular neoformation and an area of necrosis generated by rapid proliferation. The standard treatment for this type of tumor is surgery followed by chemotherapy based on temozolomide and radiotherapy, resulting in poor patient survival. Glioblastoma is known for strong resistance to treatment, frequent recurrence and rapid progression. The aim of this study was to evaluate whether mifepristone, an antihormonal agent, can enhance the effect of temozolomide on C6 glioma cells orthotopically implanted in Wistar rats. The levels of the vascular endothelial growth factor (VEGF), and P-glycoprotein (P-gp) were examined, the former a promoter of angiogenesis that facilitates proliferation, and the latter an efflux pump transporter linked to drug resistance. After a 3-week treatment, the mifepristone/temozolomide regimen had decreased the level of VEGF and P-gp and significantly reduced tumor proliferation (detected by PET/CT images based on 18F-fluorothymidine uptake). Additionally, mifepristone proved to increase the intracerebral concentration of temozolomide. The lower level of O6-methylguanine-DNA-methyltransferase (MGMT) (related to DNA repair in tumors) previously reported for this combined treatment was herein confirmed. After the mifepristone/temozolomide treatment ended, however, the values of VEGF, P-gp, and MGMT increased and reached control levels by 14 weeks post-treatment. There was also tumor recurrence, as occurred when administering temozolomide alone. On the other hand, temozolomide led to 100% mortality within 26 days after beginning the drug treatment, while mifepristone/temozolomide enabled 70% survival 60–70 days and 30% survived over 100 days, suggesting that mifepristone could possibly act as a chemo-sensitizing agent for temozolomide.

Application of intraoperative B-mode ultrasound and shear wave elastography for glioma grading

“…Multivariate logistic regression analysis showed that age, cystic tumor degeneration, degree of edema around the tumor, and uneven internal echogenicity of the tumor were independent risk factors for high-grade glioma, which indicated that the older the patient was and the more severe the degree of peritumoral edema, the greater the probability of high-grade glioma. These results are partly consistent with the findings obtained by MRI (22), and they may relate to the growth pattern of high-grade gliomas, which grow rapidly and have an insufficient blood supply, leading to necrosis of the emergent tissues (23). Also, highgrade glioma's growth process often leads to the destruction of the blood-brain barrier and an increase in vascular permeability (24), causing edema in the surrounding brain tissue.…”

Mifepristone Repurposing in Treatment of High-Grade Gliomas

“…The tumor growth rate was slower than that found with temozolomide alone, indicating a chemo-sensitizing effect. According to the current results, mifepristone could contribute to the modulation of tumor relapse in glioblastoma by decreasing the levels of VEGF, MGMT, and P-gp ( 34 ). Further research is needed to explore other mechanisms of drug resistance of glioblastoma tumors.…”

“…As a result, these proteins have become an important therapeutic target to improve patient response to glioblastoma treatment. As we have mentioned, several studies reported that mifepristone decreased MGMT and P-gp expression ( 33 , 34 ) ( Figure 2 ). Future research is required to determine whether mifepristone can regulate glioma stem cells, offer greater benefits during tumor recurrence and improve the prognosis of patients with glioma.…”

“…In the last few years, our group has investigated mifepristone (an abortifacient drug) as a plausible repurposing candidate for treating a wide range of cancers. A synergistic action has been demonstrated when it is combined with cisplatin or temozolomide plus radiation ( 30 – 34 ).…”

“…In C6 glioma cells implanted intracranially in rats, our group recently described the capacity of mifepristone to reduce the expression of the MGMT protein. This led to a higher rate of apoptosis and consequently to diminish tumor proliferation in rats treated with the mifepristone/temozolomide combination ( 33 , 34 ). Consequently, one of the mechanisms possibly involved in the mifepristone-induced sensitization to temozolomide is the modulation of the expression of the MGMT enzyme.…”