Combination of 13 cis-retinoic acid and tolfenamic acid induces apoptosis and effectively inhibits high-risk neuroblastoma cell proliferation

• Published in: International journal of developmental neuroscience 2015-11, Vol.46 (1), p.92-99
• Main Authors: Shelake, Sagar, Eslin, Don, Sutphin, Robert M., Sankpal, Umesh T., Wadwani, Anmol, Kenyon, Laura E., Tabor-Simecka, Leslie, Bowman, W. Paul, Vishwanatha, Jamboor K., Basha, Riyaz
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Annexin A5 - metabolism; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Antineoplastic Combined Chemotherapy Protocols; Apoptosis - drug effects; Caspases - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemotherapy; Dose-Response Relationship, Drug; Flow Cytometry; Humans; Infants; Isotretinoin - pharmacology; Neuroblastoma; Neuroblastoma - pathology; ortho-Aminobenzoates - pharmacology; Retinoic acid; Sympathetic nervous system; Teratogens - pharmacology; Time Factors; Tolfenamic acid
• ISSN: 0736-5748; 1873-474X
• DOI: 10.1016/j.ijdevneu.2015.07.012

•Studied novel strategy to improve therapeutic efficacy in a childhood nervous system cancer.•Targeting Sp1 enhances response to retinoic acid in neuroblastoma (NB) cells.•Retinoic acid and tolfenamic acid combination effectively induces apoptosis in NB cells. Chemotherapeutic regimens used for the treatment of Neuroblastoma (NB) cause long-term side effects in pediatric patients. NB arises in immature sympathetic nerve cells and primarily affects infants and children. A high rate of relapse in high-risk neuroblastoma (HRNB) necessitates the development of alternative strategies for effective treatment. This study investigated the efficacy of a small molecule, tolfenamic acid (TA), for enhancing the anti-proliferative effect of 13 cis-retinoic acid (RA) in HRNB cell lines. LA1-55n and SH-SY5Y cells were treated with TA (30μM) or RA (20μM) or both (optimized doses, derived from dose curves) for 48h and tested the effect on cell viability, apoptosis and selected molecular markers (Sp1, survivin, AKT and ERK1/2). Cell viability and caspase activity were measured using the CellTiter-Glo and Caspase-Glo kits. The apoptotic cell population was determined by flow cytometry with Annexin-V staining. The expression of Sp1, survivin, AKT, ERK1/2 and c-PARP was evaluated by Western blots. The combination therapy of TA and RA resulted in significant inhibition of cell viability (p