Combinatorial effect of non-steroidal anti-inflammatory drugs and NF-kappaB inhibitors in ovarian cancer therapy

Zerbini, Luiz F; Tamura, Rodrigo E; Correa, Ricardo G; Czibere, Akos; Cordeiro, Jason; Bhasin, Manoj; Simabuco, Fernando M; Wang, Yihong; Gu, Xuesong; Li, Linglin

Combinatorial effect of non-steroidal anti-inflammatory drugs and NF-kappaB inhibitors in ovarian cancer therapy

Journal Article

2011

Journal Title

PLoS One

Link to Journal

http://journals.plos.org/plosone

Publisher

Public Library of Science

Publisher

University of Cape Town

Department

Division of Medical Biochemistry

Faculty

Faculty of Health Sciences

License

http://creativecommons.org/licenses/by/4.0

Abstract

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 α and γ and JNK activation. The NF-κB family of transcription factors has been implicated in ovarian cancer development. We previously established NF-κB/IκB signaling as an essential step for cell survival in cancer cells and hypothesized that targeting NF-κB could potentiate NSAID-mediated apoptosis induction in ovarian cancer cells. Indeed, combining NSAID treatment with NF-κB inhibitors led to enhanced apoptosis induction. Our results indicate that inhibition of NF-κB in combination with activation of mda -7/IL-24 expression may lead to a new combinatorial therapy for ovarian cancer.