532P - Nitric oxide is a target by a combo-drug for glioblastoma treatment

Background

Glioblastoma is the most common and aggressive type of primary brain tumor, with a high morbidity and mortality rate. Nitric oxide (NO) has been shown to have diverse effects on various cancers, including glioblastoma. Nitric oxide synthase (NOS) activation has been implicated in the growth and progression of glioblastoma. In this study, we investigated the effects of our novel two drugs HU-53 and HU-54, on the U87-MG cell line and a xenograft model of glioblastoma. Both drugs attenuate nitrative stress through different mechanisms.

Methods

NOD.CB17-Prkdc-scid/NCrHsd mice were used for the xenograft subcutaneous tumor model to evaluate the ability of HU-53 and HU-54 treatment regimens. Both treatments were given intraperitoneally. Tumor weight and volume were measured during the study. The experiments were also carried out on the human-derived U87-MG cells. Nitrite content was measured biochemically by Griess assay. Immunofluorescence and immunoblotting assessed nitrosative stress.

Results

We found that treatment with the combo-drug resulted in a significant decrease (P<0.0001) in cell viability and proliferation as compared to vehicle in the U87-MG cell line. The combo-drug also induced apoptosis as evidenced by increased caspase-3 activity. In addition, treatment with HU-53 and HU-54 resulted in a significant reduction (p<0.0001) in tumor growth in the xenograft model of glioblastoma, as demonstrated by decreased tumor volume and weight. Furthermore, we observed that the combo treatment resulted in a significant decrease in the level of nitrite content (p<0.02) and 3-Nitrotyrosine (a marker of nitrosative stress) which are important mediators of glioblastoma growth.

Conclusions

Our results suggest that targeting the nitrosative stress with HU-53 and HU-54 may be a promising therapeutic strategy for glioblastoma treatment.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The Hebrew University of Jerusalem.

Funding

The Hebrew University of Jerusalem, Israel.

Disclosure

All authors have declared no conflicts of interest.