title: Combinatorial effect of non-steroidal anti-inflammatory drugs and NF-κB inhibitors in ovarian cancer therapy.
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.
authors.affiliation: Medical Biochemistry Division, Faculty of Health Sciences, International Center for Genetic Engineering and Biotechnology, University of Cape Town, Cape Town, South Africa. luiz.zerbini@uct.ac.za
authors.forename: Luiz F
authors.initials: LF
authors.lastname: Zerbini
authors.forename: Rodrigo E
authors.initials: RE
authors.lastname: Tamura
authors.forename: Ricardo G
authors.initials: RG
authors.lastname: Correa
authors.forename: Akos
authors.initials: A
authors.lastname: Czibere
authors.forename: Jason
authors.initials: J
authors.lastname: Cordeiro
authors.forename: Manoj
authors.initials: M
authors.lastname: Bhasin
authors.forename: Fernando M
authors.initials: FM
authors.lastname: Simabuco
authors.forename: Yihong
authors.initials: Y
authors.lastname: Wang
authors.forename: Xuesong
authors.initials: X
authors.lastname: Gu
authors.forename: Linglin
authors.initials: L
authors.lastname: Li
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Jin-Rong
authors.initials: JR
authors.lastname: Zhou
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: Towia A
authors.initials: TA
authors.lastname: Libermann
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D004008:Diclofenac / Q000008:administration & dosage; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007378:Interleukins / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009687:Nuclear Proteins / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000008:administration & dosage; D013467:Sulindac / Q000008:administration & dosage / Q000031:analogs & derivatives; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000099180:Interleukin-24; D000097642:GADD45 Proteins
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018797:Cell Cycle Proteins; D004008:Diclofenac; D007378:Interleukins; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D009687:Nuclear Proteins; D012717:Sesquiterpenes; D013467:Sulindac; D000099180:Interleukin-24; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C485654:GADD45G protein, human; C103906:isohelenin; C025462:sulindac sulfide