Betulinic Acid Derivatives NVX-207 and B10 for Treatment of Glioblastoma—An in Vitro Study of Cytotoxicity and Radiosensitization

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.

Betulinic acid increases radiosensitization of oral squamous cell carcinoma through inducing Sp1 sumoylation and PTEN expression

“…Bache et al used BetA at a concentration of 10 µM and demonstrated that radiosensitization ability of BetA could be enhanced in hypoxic condition (51); our study agreed with theirs, while whether Sp1/PTEN pathway involves in hypoxic-induced radiosensitization ability enhancement of BetA is still unknown. Furthermore, there are also several mechanisms reveled underlying BetA-induced radiosensitization (50,51,59). However, our funding could be another important mechanism underlying the BetA enhancement of radiosensitization besides the other previously reported mechanisms (50,51,59), and further supported the assumption that BetA could be a clinically available and promising enhancer of tumor radiotherapy.…”

“…2C-E). Actually, this concentration of BetA was used also by some other teams in the study of BetA inducing radiosensitization (50,51). Therefore, we chose the concentration of 10 µM.…”

“…Considering that PTEN plays a crucial role in radiosensitization (34,57,58), our results suggested that inhibition of Sp1 expression and induction of PTEN expression by BetA contributed to the radiosensitization of OSCC. Actually BetA and its derivatives have already been demonstrated to regulate radiosensitization (50,51,59). Bache et al used BetA at a concentration of 10 µM and demonstrated that radiosensitization ability of BetA could be enhanced in hypoxic condition (51); our study agreed with theirs, while whether Sp1/PTEN pathway involves in hypoxic-induced radiosensitization ability enhancement of BetA is still unknown.…”

Betulin, a Pentacyclic Tri-Terpenoid: An Hour to Rethink the Compound

“…As mentioned in Figure 1: betulin has three most prominent positions where chemical modifications can be easily accomplished, namely primary hydroxyl group at position C-28, secondary hydroxyl group at position C-3, and alkene moiety at position C-20.The bio-chemical modifications at positions C-28 of the parent structure of betulin produces betulinic acid [12,27,[38][39][40][41]. The chief source of Betulin is bark of Birch trees, belonging to family Betulaceae the family of flowering plants.…”

An efficient process for the transformation of betulin to betulinic acid by a strain of Bacillus megaterium

“…The bio-chemical modifications at positions C-28 of the parent structure of betulin can produce betulinic acid (Fig. 1b) (Yogeeswari and Sriram 2005;Csuk et al 2006;Baratto et al 2013;Bache et al 2014;Csuk 2014). Betulinic acid is commercially produced via chemical synthesis where betulin is used as raw material (Csuk et al 2006).…”