Anticancer activity of tolfenamic acid in medulloblastoma: a preclinical study
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RESEARCH ARTICLE
Anticancer activity of tolfenamic acid in medulloblastoma: a preclinical study Don Eslin & Chris Lee & Umesh T. Sankpal & Pius Maliakal & Robert M. Sutphin & Liz Abraham & Riyaz Basha
Received: 13 March 2013 / Accepted: 1 May 2013 # International Society of Oncology and BioMarkers (ISOBM) 2013
Abstract Medulloblastoma (MB) is the most common malignancy in children arising in the brain. Morbidities associated with intensive therapy are serious concerns in treating MB. Our aim was to identify novel targets and agents with less toxicity for treating MB. Specificity protein 1 (Sp1) transcription factor regulates several genes involved in cell proliferation and cell survival including survivin, an inhibitor of apoptosis protein. We previously showed that tolfenamic acid (TA), a nonsteroidal anti-inflammatory drug, inhibits neuroblastoma cell growth by targeting Sp1. We investigated the anticancer activity of TA using human MB cell lines and a mouse xenograft model. DAOY and D283 cells were treated with vehicle (dimethyl sulfoxide) or TA (5–50 μg/ml), and cell viability was measured at 1–3 days posttreatment. TA inhibited MB cell growth in a time- and dose-dependent manner. MB cells were treated with vehicle or TA (10 μg/ml), and the effect on cell apoptosis was measured. Apoptosis was analyzed by flow cytometry (annexin V staining), and caspase 3/7 activity was determined using Caspase-Glo kit. The expression of Sp1, cleaved poly(ADP-ribose) polymerase (c-PARP), and survivin
Part of this research work was presented at the 4th International Conference on Drug Therapy and Discovery (ICDDT), Dubai, UAE in February 2012. Electronic supplementary material The online version of this article (doi:10.1007/s13277-013-0836-6) contains supplementary material, which is available to authorized users. D. Eslin : C. Lee : U. T. Sankpal : P. Maliakal : R. M. Sutphin : L. Abraham : R. Basha (*) MD Anderson Cancer Center Orlando, Orlando, FL 32806, USA e-mail: [email protected] D. Eslin (*) : R. M. Sutphin Arnold Palmer Hospital for Children, Orlando, FL 32806, USA e-mail: [email protected]
was determined by Western blot analysis. TA inhibited the expression of Sp1 and survivin and upregulated c-PARP. Athymic nude mice were subcutaneously injected with D283 cells and treated with TA (50 mg/kg, three times per week) for 4 weeks. TA caused a decrease of ~40 % in tumor weight and volume. The tumor growth inhibition was accompanied by a decrease in Sp1 and survivin expression in tumor tissue. These preclinical data demonstrate that TA acts as an anticancer agent in MB potentially targeting Sp1 and survivin. Keywords Pediatric brain tumors . Medulloblastoma . NSAID . Survivin . Transcription factors . Sp1
Introduction Medulloblastoma (MB) is a highly malignant brain tumor arising primarily in the cerebellum and accounts for approximately 20 % of all brain tumors in children [1, 2]. Current therapies for MB include surgery, standard chemotherapy drugs, and radiation. Despite these treatment options,
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