Tolfenamic Acid Induces Therapeutic Efficacy of Chemotherapeutic Agents in Medulloblastoma Cells

Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Currently, MB is treated using a multimodal approach consisting of surgery, craniospinal irradiation, and chemotherapy. Among the most commonly used chemotherapeutic agents are vincristine (Vinc), etoposide (Etop) and Cisplatin (Cis), while doxorubicin (Dox) is also used rarely. All of these agents carry significant delayed consequences for the patients including cognitive deficits. It is imperative that the strategies to improve the therapeutic efficacy of standard chemotherapy will include reduction of side effects in order to have a significant impact for treating MB patients. The primary objective of this study is to determine the effectiveness of a combination treatment to enhance the therapeutic efficacy of chemotherapeutic agents using MB cell lines. We have tested the combination of Tolfenamic Acid (TA), a small molecule and non-steroidal anti-inflammatory drug along with Vinc or Etop or Cis or Dox using MB cell lines, DAOY and D283. These cell lines were purchased from American Type Culture Collection (ATCC), Manassas, VA. TA has been shown to inhibit cell proliferation, induce apoptosis, and decrease the expression of Sp1 and Survivin which play roles in growth and cell survival in MB cells. Our results show that each drug together with TA causes a time and dose dependent decrease of MB cell viability which is more than that of single drug treatment. The cell growth inhibition is accompanied by an induction of apoptotic markers and the decrease in expression of Sp1 and survivin. The preliminary results of this preclinical model are in favor of combining TA with Vinc or Etop or Cis or Dox to achieve maximum therapeutic benefit while limiting the duration of treatment. Further studies are under investigation to precisely understand the underlying mechanisms and to confirm these results via in vivo assays. Addition of TA to current chemotherapy regimen for MB may reduce the dose and amount of time necessary for chemotherapy and therefore potentially reduce the toxicity and side-effects in children.