Abstract A191: DHMEQ: A novel NF-kappaB inhibitor with good results in pediatric medulloblastoma cell lines.

Abstract

Abstract Medulloblastoma (MB) is the most common malignant central nervous system tumor of childhood representing 15-30% of pediatric brain tumors. The standard treatment involves surgery and chemotherapy and radiotherapy is used only for patients older than 3 years old. The risk of neurocognitive sequel, growth and endocrine systems leading the search for new therapeutic approaches. Great efforts have been made to improve treatments with high success rates and minimal toxicity, among them DHMEQ is a drug that has shown a low toxicity and high effectivity in blocking the NFkappaB, a key transcription factor that control the expression of a large number of genes related to cell proliferation, growth and apoptosis, showing antineoplasic effects in several cancer cell lines. There are no reports showing the effects of DHMEQ in MB. Cell proliferation, clonogenic capacity, wound healing assay, apoptosis (Annexin V), and combination with chemotherapeutic drugs (Cisplatin (CDDP), Temozolomide (TMZ) and Etoposide) or radiation were performed on three pediatric MB cell lines: UW402, UW473 e ONS76. Functional tests were performed using 0-20 µg/mL DHMEQ at 24, 48 and 72h. IC50 values of each drug and drug combination analyses were based in Chou-Talalay method, and simultaneous treatments of DHMEQ with CDDP (2:1 ratio), TMZ (1:200 ratio) or Etoposide (1:0,8 ratio) were performed for 48h or 72h. For gamma radiation clonogenic survival assays were used the doses of 2, 4 and 6 Gy. Statistical analysis was made by ANOVA and Pairwise Multiple Comparison de Holm-Sidak tests (SigmaStat 3.5). All experiments showed DHMEQ caused a decrease on cell proliferation, viability, migration ratio and clonogenic capacity, while increase apoptosis (P<0.05). In the drug combination assay, DHMEQ acted additively with CDDP and synergistically with TMZ and Etoposide in all cell lines. Moreover, DHMEQ enhanced significantly the radiation effects on the three cell lines studied. These results support the biological importance of the NFkappaB as a promising therapeutic target for medulloblastoma treatment, and the potencial effect radio- and chemo- sensitizing of DHMEQ on MB cells. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A191. Citation Format: Priscila Maria Manzini Ramos, Angel Mauricio Castro-Gamero, Julia Alejandra Pezuk, Carlos Alberto Scrideli, Kazuo Umezawa, Luiz Gonzaga Tone. DHMEQ: A novel NF-kappaB inhibitor with good results in pediatric medulloblastoma cell lines. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A191.