Abstract
Betulinic acid (BA), a pentacyclic triterpene, represents a new therapeutic substance that has potential benefits for treating glioblastoma. Recently, new strategies for producing BA derivatives with improved properties have evolved. However, few studies have examined the combination of BA or BA derivatives using radiotherapy. The effects of two BA derivatives, NVX-207 and B10, on cellular and radiobiological behavior were analyzed using glioblastoma cell lines (U251MG, U343MG and LN229). Based on IC50 values under normoxic conditions, we detected a 1.3–2.9-fold higher cytotoxicity of the BA derivatives B10 and NVX-207, respectively, compared to BA. Incubation using both BA derivatives led to decreased cell migration, cleavage of PARP and decreased protein expression levels of Survivin. Weak radiation sensitivity enhancement was observed in U251MG cells after treatment with both BA derivatives. The enhancement factors at an irradiation dose of 6 Gy after treatment with 5 µM NVX-207 and 5 µM B10 were 1.32 (p = 0.029) and 1.55 (p = 0.002), respectively. In contrast to BA, neither NVX-207 nor B10 had additional effects under hypoxic conditions. Our results suggest that the BA derivatives NVX-207 and B10 improve the effects of radiotherapy on human malignant glioma cells, particularly under normoxic conditions.
Highlights
Glioblastoma is the most common malignant primary brain tumor
NVX-207 and B10 had a higher cytotoxicity than Betulinic acid (BA), with IC50 values ranging from 7.6–8.5 and
NVX-207 revealed the strongest effect, with IC50 values ranging from 7.6–9.6 μM in malignant glioma cells independent of the oxygen concentration
Summary
Glioblastoma is the most common malignant primary brain tumor. Its treatment typically consists of surgery and subsequent radiotherapy with concomitant and sequential chemotherapy. Initial investigations have revealed that BA improved the effects of chemotherapy and radiotherapy and increased doxorubicin- or cisplatin-induced apoptosis in various tumor cell lines [10]. In a phase I/II study, the clinical use of NVX-207 led to complete remission of therapy-resistant tumors in dogs [19]. Another analysis indicated that glycosylation of BA significantly increased the activity and selectivity toward cancer cell lines [20]. We analyzed the effects of the BA derivatives NVX-207 and B10 on cytotoxicity, migration, protein expression of PARP, Survivin and CAIX and radiosensitivity under normoxic and hypoxic conditions in human malignant glioma cells. The chemical structures of BA derivatives NVX-207 and B10, shown in Figure 1, were previously described [21,23]
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