Combinatorial Effect of Non-Steroidal Anti-inflammatory Drugs and NF-[kappa]B Inhibitors in Ovarian Cancer Therapy

• Published in: PloS one 2011-09, Vol.6 (9), p.e24285
• Main Authors: Zerbini, Luiz F, Tamura, Rodrigo E, Correa, Ricardo G, Czibere, Akos, Cordeiro, Jason, Bhasin, Manoj, Simabuco, Fernando M, Wang, Yihong, Gu, Xuesong, Li, Linglin, Sarkar, Devanand, Zhou, Jin-Rong, Fisher, Paul B, Libermann, Towia A
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Apoptosis; Cancer prevention; Development and progression; Epidemiology; Genes; Health aspects; Interleukins; Nonsteroidal anti-inflammatory agents; Ovarian cancer; RNA; Stomach cancer; Sulfides
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0024285

Several epidemiological studies have correlated the use of non-steroidal anti-inflammatory drugs (NSAID) with reduced risk of ovarian cancer, the most lethal gynecological cancer, diagnosed usually in late stages of the disease. We have previously established that the pro-apoptotic cytokine melanoma differentiation associated gene-7/Interleukin-24 (mda-7/IL-24) is a crucial mediator of NSAID-induced apoptosis in prostate, breast, renal and stomach cancer cells. In this report we evaluated various structurally different NSAIDs for their efficacies to induce apoptosis and mda-7/IL-24 expression in ovarian cancer cells. While several NSAIDs induced apoptosis, Sulindac Sulfide and Diclofenac most potently induced apoptosis and reduced tumor growth. A combination of these agents results in a synergistic effect. Furthermore, mda-7/IL-24 induction by NSAIDs is essential for programmed cell death, since inhibition of mda-7/IL-24 by small interfering RNA abrogates apoptosis. mda-7/IL-24 activation leads to upregulation of growth arrest and DNA damage inducible (GADD) 45 [alpha] and [gamma] and JNK activation. The NF-[kappa]B family of transcription factors has been implicated in ovarian cancer development. We previously established NF-[kappa]B/I[kappa]B signaling as an essential step for cell survival in cancer cells and hypothesized that targeting NF-[kappa]B could potentiate NSAID-mediated apoptosis induction in ovarian cancer cells. Indeed, combining NSAID treatment with NF-[kappa]B inhibitors led to enhanced apoptosis induction. Our results indicate that inhibition of NF-[kappa]B in combination with activation of mda-7/IL-24 expression may lead to a new combinatorial therapy for ovarian cancer.