Hypoxia Imaging and Biological Evaluation of the Radiosensitizing Effect of Oleanolic Acid

Abstract

Background and Purpose The aim of this study was to evaluate the radiosensitizing effect of oleanolic acid (OA) on C6 rat glioma and the changes in tumor biology during radiosensitization therapy on 18F-fluoromisonidazole (18F-FMISO) positron emission tomography/computed tomography (PET/CT). Methods The radiosensitizing effect of OA on C6 tumors was assessed in vivo by measuring the tumor inhibitory rate and rat survival time. Meanwhile, rats with C6 tumors were imaged with 18F-FMISO PET/CT during radiosensitization therapy. Tumor-to-muscle ratio (TMR) of 18F-FMISO maximum uptake was calculated by region of interest analysis. Changes in tumor biology after therapy were assessed with immunohistochemical staining. 18F-FMISO uptake was analyzed in relation to expression of tumor biomarkers including hypoxia-inducible factor (HIF)-1α, glucose transporter (Glut-1), the proliferation antigen Ki67, tumor suppressor P53, and microvessel density (MVD). Results The results showed that OA combined with radiation inhibited the growth rates of tumors and prolonged the survival period of tumor-bearing rats effectively (χ2 = 12.5, p < 0.01). 18F-FMISO PET/CT indicated decreases in hypoxia after radiosensitization therapy. Statistical differences were observed in TMR of the irradiation group and OA combined with irradiation group (t = 3.32, p < 0.05). HIF-1α, Glut-1, Ki67, P53, and MVD expressions in tumors were downregulated by OA combined with radiation as well as with radiation alone. Additionally, there was a significant positive linear correlation between TMR and HIF-1α, Glut-1, Ki67, P53, and MVD. Conclusions These results suggest that OA has a radiosensitizing effect on C6 tumors in terms of tumor volume inhibition, survival extension, and multiple poor prognosis biological markers downregulation. 18F-FMISO PET/CT can be of value for tumor biology noninvasive capture and radiosensitization response evaluation.

Dual-Tracer Assessment of Dynamic Changes in Reoxygenation and Proliferation Decrease During Fractionated Radiotherapy in Murine Tumors

“…Interestingly, FMISO uptake correlates with the “gold standard” of tissue measurement using invasive polarographic oxygen electrodes ( 8 , 9 ), as well as pimonidazole uptake in animals with glioma ( 10 ). Our previous and several other studies have reported decreased FMISO uptake in hypoxic tumors during radiotherapy and post-treatment, indicating that reoxygenation occurs ( 11 – 16 ). However, cancer cells killed by irradiation no longer show FMISO uptake; thus, it is hard to correctly determine whether reduced FMISO uptake in radiotherapy results from tumor reoxygenation or reflects tumoricidal effects.…”

Ursolic and Oleanolic Acids: Plant Metabolites with Neuroprotective Potential

“…However, 15 mg/kg/d (for 10 d) of UA did not affect the tumour size in an orthotopic glioma model in vivo [ 126 ]. In another study utilizing an in vivo model of glioblastoma, the anti-tumour effects of triterpenoids have been established [ 127 ]. When C6 tumour-bearing rats were given OA solution by gavage (40 mg daily for 7 d) and underwent irradiation therapy, the combined effect of OA and radiation was demonstrated, which resulted in the decreased growth rates of tumours and the prolonged survival period of tumour-bearing rats.…”

The Roles of Hypoxia Imaging Using 18F-Fluoromisonidazole Positron Emission Tomography in Glioma Treatment

“…Wang et al used C6 glioma model rats to evaluate the radiosensitization effects of oleanolic acid with FMISO [62]. They observed slowed tumor growth by the OA treatment combined with radiotherapy, as well as a decrease in FMISO uptake, and they suggested that FMISO PET can be of value for radiosensitization response evaluations.…”