title: Naproxen induces cell-cycle arrest and apoptosis in human urinary bladder cancer cell lines and chemically induced cancers by targeting PI3K.
abstract: Naproxen [(S)-6-methoxy-α-methyl-2-naphthaleneacetic acid] is a potent nonsteroidal anti-inflammatory drug that inhibits both COX-1 and COX-2 and is widely used as an over-the-counter medication. Naproxen exhibits analgesic, antipyretic, and anti-inflammatory activities. Naproxen, as well as other nonsteroidal anti-inflammatory drug, has been reported to be effective in the prevention of urinary bladder cancer in rodents. However, potential targets other than the COX isozymes have not been reported. We examined potential additional targets in urinary bladder cancer cells and in rat bladder cancers. Computer kinase profiling results suggested that phosphoinositide 3-kinase (PI3K) is a potential target for naproxen. In vitro kinase assay data revealed that naproxen interacts with PI3K and inhibits its kinase activity. Pull-down binding assay data confirmed that PI3K directly binds with naproxen in vitro and ex vivo. Western blot data showed that naproxen decreased phosphorylation of Akt, and subsequently decreased Akt signaling in UM-UC-5 and UM-UC-14 urinary bladder cancer cells. Furthermore, naproxen suppressed anchorage-independent cell growth and decreased cell viability by targeting PI3K in both cell lines. Naproxen caused an accumulation of cells at the G1 phase mediated through cyclin-dependent kinase 4, cyclin D1, and p21. Moreover, naproxen induced significant apoptosis, accompanied with increased levels of cleaved caspase-3, caspase-7, and PARP in both cell types. Naproxen-induced cell death was mainly because of apoptosis in which a prominent downregulation of Bcl-2 and upregulation of Bax were involved. Naproxen also caused apoptosis and inhibited Akt phosphorylation in rat urinary bladder cancers induced by N-butyl-N-(4-hydroxybutyl)-nitrosamine.
authors: The Hormel Institute University of Minnesota, 801 16th Avenue NE, Austin, MN 55912. ambode@hi.umn.edu.
authors: Mi-Sung
authors: MS
authors: Kim
authors: Jong-Eun
authors: JE
authors: Kim
authors: Do Young
authors: DY
authors: Lim
authors: Zunnan
authors: Z
authors: Huang
authors: Hanyong
authors: H
authors: Chen
authors: Alyssa
authors: A
authors: Langfald
authors: Ronald A
authors: RA
authors: Lubet
authors: Clinton J
authors: CJ
authors: Grubbs
authors: Zigang
authors: Z
authors: Dong
authors: Ann M
authors: AM
authors: Bode
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D009288:Naproxen / Q000494:pharmacology*; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D011916:Rats, Inbred F344; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000473:pathology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000081082:Phosphoinositide-3 Kinase Inhibitors; D009288:Naproxen