title: Pachymic acid inhibits cell growth and modulates arachidonic acid metabolism in nonsmall cell lung cancer A549 cells.
abstract: Aberrant arachidonic acid (AA) metabolism has been involved in inflammation and carcinogenesis. The key enzymes in AA metabolism such as cytosolic phospholipase A2 (cPLA(2)) and cyclooxygenase-2 (COX-2) have been implicated in the development and progression of many human cancers, including lung cancer. Hence, the blockade of these enzymes may suppress promotion and survival of human cancer cells. We and others have shown that a natural triterpenoid, pachymic acid (PA), can exhibit antiinflammatory and anticancer properties; however, its potential mechanism has not been fully clarified. In this study, we examined the effect of PA on the proliferation of human nonsmall cell lung cancer A549 cells. Furthermore, we investigated the influences of nontoxic levels of PA on AA metabolism. Additionally, the cellular events and signal transduction pathways influenced by PA were also examined. Our results showed that PA (1) inhibited anchorage-dependent and -independent A549 growth in a concentration-dependent manner, (2) induced apoptosis and disrupted mitochondrial membrane potential in A549 cells, and at nonlethal levels, (3) decreased IL-1 beta-induced activation of cPLA(2) and COX-2, (4) suppressed IL-1 beta-induced activation of mitogen-activated protein kinases (MAPKs), and (5) inhibited IL-1 beta-stimulated nuclear factor kappa B (NF-kappaB) signaling pathways. We speculate that inhibition of AA metabolism by PA is mediated in part by its inhibition of MAPKs and NF-kappaB signaling pathways. Our study reveals that, apart from its cytotoxic effect, PA has the chemopreventive potential by reducing production of eicosanoids from AA metabolism.
authors.affiliation: Department of Pharmacy, National University of Singapore, Singapore, Republic of Singapore.
authors.forename: Hui
authors.initials: H
authors.lastname: Ling
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Jia
authors.forename: Yaochun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Gapter
authors.forename: Yin-shan
authors.initials: YS
authors.lastname: Lim
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
authors.forename: Ka-yun
authors.initials: KY
authors.lastname: Ng
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D016718:Arachidonic Acid / Q000378:metabolism*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014315:Triterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D053583:Interleukin-1beta; D016328:NF-kappa B; D012333:RNA, Messenger; D014315:Triterpenes; D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; D020928:Mitogen-Activated Protein Kinases; D010741:Phospholipases A; C102487:pachymic acid