SMALL MOLECULE, TOLFENAMIC ACID INHIBITS MEDULLOBALSTOMA CELL GROWTH AND ENHANCES RESPONSE TO RADIATION OR CHEMOTHERAPY
Riyaz Basha and Don Eslin
Arnold Palmer Hospital for Children, Orlando FL 32806, USA
Medulloblastoma (MB) is the most common brain tumor in children. MB requires intensive multimodality treatment that often causes extensive/long term side-effects. Therefore, developing novel therapeutic approaches involving strategies to achieve higher efficacy with less toxicity are urgently needed for treating children with MB. Small molecule, Tolfenamic Acid (TA) is known to inhibit Specificity protein (Sp) transcription factors and suevivin, an inhibitor of apoptosis protein. Sp proteins regulate the critical genes associated with several malignancies including MB. The over-expression of survivin showed a strong association with tumor morphology and poor clinical outcome in MB. Our results demonstrate that TA inhibits the growth of MB cells in a dose/time-dependent manner and significantly decreases Sp1 and survivin expression. Apart from cell cycle arrest, TA causes significant increase in the apoptotic cell population, caspase 3/7 activity and c-PARP expression. These results confirm that TA effectively inhibits MB cell growth potentially through suppressing mitosis, Sp1 and survivin expression, and inducing apoptosis. Pre-clinical testing to evaluate the response of TA in combination therapy reveals that TA sensitizes MB cells and mice tumors to irradiation and enhances the response of certain chemotherapeutic agents. These studies are critical for developing robust strategies while minimizing morbidity in medulloblastoma therapy.
Financial assistance: This study is supported by MD Anderson Cancer Center Orlando, Run Way to Hope, and Hyundai Hope on Wheels grant.