Abstract
Abstract Malignant gliomas are the most common primary brain tumors with approximately 22,000 cases per year. In spite of aggressive surgery, radiotherapy and chemotherapeutic regimens, the median survival of patients with malignant gliomas is a dismal 15 months. The objective of our study was to explore the adjuvant therapeutic potential and associated molecular mechanisms of natural polyphenols stilbenes in malignant gliomas. Recent studies have demonstrated the efficacy of stilbenes in extracranial tumor models. Stilbenes, including resveratrol, were bioavailable in the brain even after low dose oral administration and there was no toxicity to normal tissue. On the contrary, these compounds were found to be neuroprotective in Alzheimer's disease models. Mechanistically, stilbenes modulate NF-κB, STAT3, wnt/β-catenin signaling and also inhibits antiapoptotic protein Bcl-xl. While these molecules are critical in imparting chemoresistance, they are also pivotal in inducing immune-resistance and pro-tumor immune infiltration in gliomas. We hypothesized that stilbenes enhance the efficacy of chemotherapy while also inhibiting immune-suppression and -resistance in malignant gliomas via overlapping molecular mechanisms. We observed significant positive interaction between Temozolomide and Resveratrol for inhibition of glioma proliferation. Resveratrol induced apoptosis in gliomas via inhibition of Bcl-2 and Bcl-xl, while STAT3 activity was also inhibited. Importantly, Resveratrol significantly enhanced the expression of TRAIL-R2 and MIC A/B in gliomas, making them vulnerable to lysis by CTLs and NK cells. Studies are underway to determine combined effect of DC-based immunotherapy and stilbenes against malignant gliomas using syngeneic, orthotopic mouse glioma models. The results can have significant impact in developing novel adjuvant studies to improve survival in patients with malignant gliomas. Citation Format: Chandramouli Mandalaparty, Andrew Huang, Sandeep Mittal, Agnes M. Rimando, Q. Ping Dou, Prahlad Parajuli. Immuno-sensitization of malignant gliomas by natural polyphenols. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3982. doi:10.1158/1538-7445.AM2013-3982
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