Abstract
Abstract
Idarubicin (IDA) is a very potent second generation anthracycline that has shown high efficacy against glioma in vitro. However, this agent has failed to exert satisfactory therapeutic response in patients with brain tumors.
Phosphodiesterase (PDE-5), an enzyme which hydrolyzes intracellular cyclic guanosine monophosphate (cGMP), is highly expressed in many brain tumor cell lines. We proposed that increasing cGMP in the brain by the potent PDE-5 inhibitor vardenafil (VAR) will augment the antitumor efficacy of IDA against glioma. We also proposed that VAR will induce apoptosis of glioma cells. Here we show for the first time that VAR (10 mg/kg) enhanced the antitumor activity of IDA (0.1mg/kg). VAR alone inhibited tumor growth and prolonged survival of glioma bearing rats. Histopathological examination revealed that tumors from glioma bearing rats treated with VAR alone or VAR+ IDA presented a significant reduction in mitotic index, indicating less proliferative tumors, as compared to those which received PBS (control) or IDA. Real time PCR results demonstrated that VAR inhibited mRNA expression of PDE-5 in the brains of animals treated with VAR, compared to control-treated group, implicating an important role for the inhibition of PDE-5 in the antitumor activity of VAR. Interestingly, the antitumor activity of VAR was similar to that of IDA. Moreover, animals receiving either VAR alone or VAR+IDA demonstrated statistically significant improvement in overall survival when compared with control (PBS) or IDA groups. In order to explain such an unexpected finding, we examined the antiproliferative, pro-apoptotic and anti-invasive activities VAR in vitro. MTT assay results showed that VAR significantly inhibited the growth of rat C6 glioma cells. Annexin V propidium iodide assay results revealed that the inhibition of C6 cell growth is mediated at least in part by inducing C6 apoptosis. Wound healing and soft agar colony formation assays showed that VAR inhibited the migration and anchorage-independent growth of C6 cells, respectively. This suggests that the enhanced antitumor effect of VAR could be due to a combined antiproliferative, pro-apoptotic and anti-invasive activities.
Together, our data support anti-glioma properties of VAR, and provide a proof-of-concept basis for further development of VAR as potential adjuvant for treatment of brain tumors.
Citation Format: Abdelkader E. Ashour, Abdulrahman Z. Alzahrani, Hala E. Abdel-Hamied, Khairy M. Zoheir, Sheikh F. Ahmed, Salem S. Al-Rejaie, Adel R. Abd-Allah. Vardenafil is superior to idarubicin in treatment of glioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2528. doi:10.1158/1538-7445.AM2015-2528