Combinatorial Effect of Non-Steroidal Anti-inflammatory Drugs and NF-κB Inhibitors in Ovarian Cancer Therapy

Authors

Luiz F. Zerbini, University of Cape Town
Rodrigo E. Tamura, University of Cape Town
Ricardo G. Correa, Sanford-Burnham Institute for Medical Research
Akos Czibere, Heinrich Heine-University
Jason Coideiro, Beth Israel Deaconess Medical Center and Harvard Medical School
Manoj Bhasin, Beth Israel Deaconess Medical Center and Harvard Medical School
Fernando M. Simabuco, Beth Israel Deaconess Medical Center and Harvard Medical School
Yihong Wang, Beth Israel Deaconess Medical Center and Harvard Medical School
Xuesong Gu, Beth Israel Deaconess Medical Center and Harvard Medical School
Linglin Li, Beth Israel Deaconess Medical Center and Harvard Medical School
Devanand Sarkar, Virginia Commonwealth UniversityFollow
Jin-Rong Zhou, Beth Israel Deaconess Medical Center and Harvard Medical School
Paul B. Fisher, Virginia Commonwealth UniversityFollow
Towia A. Libermann, Beth Israel Deaconess Medical Center and Harvard Medical School

Document Type

Article

Original Publication Date

2011

Journal/Book/Conference Title

PLOS ONE

Volume

6

DOI of Original Publication

10.1371/journal.pone.0024285

Comments

Originally Published at http://dx.doi.org/10.1371/journal.pone.0024285

Date of Submission

November 2014

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.

Rights

Copyright: © 2011 Zerbini et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Is Part Of

VCU Human and Molecular Genetics Publications