title: Anticancer activity of tolfenamic acid in medulloblastoma: a preclinical study.
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 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.
authors.affiliation: MD Anderson Cancer Center Orlando, Orlando, FL, 32806, USA, don.eslin@orlandohealth.com.
authors.forename: Don
authors.initials: D
authors.lastname: Eslin
authors.forename: Chris
authors.initials: C
authors.lastname: Lee
authors.forename: Umesh T
authors.initials: UT
authors.lastname: Sankpal
authors.forename: Pius
authors.initials: P
authors.lastname: Maliakal
authors.forename: Robert M
authors.initials: RM
authors.lastname: Sutphin
authors.forename: Liz
authors.initials: L
authors.lastname: Abraham
authors.forename: Riyaz
authors.initials: R
authors.lastname: Basha
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D008527:Medulloblastoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000077022:Survivin; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D062367:ortho-Aminobenzoates / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D016329:Sp1 Transcription Factor; D000077022:Survivin; D062367:ortho-Aminobenzoates; C009500:tolfenamic acid