title: Inhibitors of the arachidonic acid pathway and peroxisome proliferator-activated receptor ligands have superadditive effects on lung cancer growth inhibition.
abstract: Arachidonic acid (AA) metabolizing enzymes and peroxisome proliferator-activated receptors (PPARs) have been shown to regulate the growth of epithelial cells. We have previously reported that exposure to the 5-lipoxygenase activating protein-directed inhibitor MK886 but not the cyclooxygenase inhibitor, indomethacin, reduced growth, increased apoptosis, and up-regulated PPARalpha and gamma expression in breast cancer cell lines. In the present study, we explore approaches to maximizing the proapoptotic effects of PPARgamma on lung cancer cell lines. Non-small-cell cancer cell line A549 revealed dose-dependent PPARgamma reporter activity after treatment with MK886. The addition of indomethacin in combination with MK886 further increases reporter activity. We also show increased growth inhibition and up-regulation of apoptosis after exposure to MK886 alone, or in combination with indomethacin and the PPAR ligand, 15-deoxy-Delta12,14-prostaglandin J2 compared with single drug exposures on the adenocarcinoma cell line A549 and small-cell cancer cell lines H345, N417, and H510. Real-time PCR analyses showed increased PPAR mRNA and retinoid X receptor (RXR)alpha mRNA expression after exposure to MK886 and indomethacin in a time-dependent fashion. The results suggest that the principal proapoptotic effect of these drugs may be mediated through the known antiproliferative effects of the PPARgamma-RXR interaction. We therefore explored a three-drug approach to attempt to maximize this effect. The combination of low-dose MK886, ciglitazone, and 13-cis-retinoic acid interacted at least in a superadditive fashion to inhibit the growth of lung cancer cell lines A549 and H1299, suggesting that targeting PPARgamma and AA action is a promising approach to lung cancer growth with a favorable therapeutic index.
authors.affiliation: Intervention Section, Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Ingalill
authors.initials: I
authors.lastname: Avis
authors.forename: Alfredo
authors.initials: A
authors.lastname: Martínez
authors.forename: Jordi
authors.initials: J
authors.lastname: Tauler
authors.forename: Enrique
authors.initials: E
authors.lastname: Zudaire
authors.forename: Anatoly
authors.initials: A
authors.lastname: Mayburd
authors.forename: Raed
authors.initials: R
authors.lastname: Abu-Ghazaleh
authors.forename: Frank
authors.initials: F
authors.lastname: Ondrey
authors.forename: James L
authors.initials: JL
authors.lastname: Mulshine
mesh_terms: D000098:Acetophenones / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D015474:Isotretinoin / Q000008:administration & dosage; D008024:Ligands; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047492:Peroxisome Proliferator-Activated Receptors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000008:administration & dosage / Q000031:analogs & derivatives*; D011743:Pyrimidines / Q000008:administration & dosage; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D047490:Retinoid X Receptor alpha / Q000096:biosynthesis / Q000235:genetics; D013777:Tetrazoles / Q000008:administration & dosage; D045162:Thiazolidinediones / Q000008:administration & dosage; D002722:Chlorobenzenes
chemical_list: D000098:Acetophenones; D016718:Arachidonic Acid; D020169:Caspases; D007211:Indoles; D015474:Isotretinoin; D008024:Ligands; D047492:Peroxisome Proliferator-Activated Receptors; D015230:Prostaglandin D2; D011743:Pyrimidines; D012333:RNA, Messenger; D047490:Retinoid X Receptor alpha; D013777:Tetrazoles; D045162:Thiazolidinediones; C060893:MK-886; D002722:Chlorobenzenes; C037112:9-deoxy-delta-9-prostaglandin D2; C006253:pirinixic acid; C044660:LY 171883; C039671:ciglitazone