Nitric oxide donating nonsteroidal anti-inflammatory drugs induce apoptosis in human prostate cancer cell systems and human prostatic stroma via caspase-3.

Abstract

PURPOSE:

New nitric oxide (NO) donating nonsteroidal anti-inflammatory drugs (NSAIDs) have been synthesized to counteract the side effects of conventional NSAIDs. Mounting evidence suggests that NSAIDs may have a possible chemopreventative/therapeutic role in prostate cancer. NO is a powerful biological messenger with multiple cellular effects. We established the effects of 2 of these new drugs in prostate cell systems.

MATERIALS AND METHODS:

We studied the effects of NO-ibuprofen (NCX 2111) and NO-aspirin (NCX 4060) on hormone sensitive (LNCap) and insensitive (PC3) prostate cancer epithelial cell lines as well as primary cultures of prostatic stroma. Proliferation was measured using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazalium bromide) assay to examine proliferation. Subsequently flow cytometry, cell cycle analysis and TUNEL staining were used to look for apoptosis. Caspase-3 expression was also examined in treated cell types.

RESULTS:

NCX 2111 and NCX 4060 were found to be potent inhibitors of proliferation in a dose dependent fashion. The 2 drugs induced apoptosis, as seen by flow cytometry, cell cycle analysis and TUNEL staining, at doses between 10 and 100 microM. These NO-NSAIDs increased caspase-3 expression. NCX 4060 was more effective at lower concentrations (10 microM) but each compound was much more potent than conventional ibuprofen and aspirin at inducing apoptosis and inhibiting proliferation.

CONCLUSIONS:

NO-NSAIDs are potent antiproliferative pro-apoptotic compounds in prostate cell systems. This pro-apoptotic effect is mediated via caspase-3 and it is independent of the type of prostate cell used. These findings have ramifications for the use of these new drugs in prostate cancer chemoprevention or treatment.

• Authors: Justine Sarah Royle, James A Ross, Ian Ansell, Prasad Bollina, David N Tulloch, Fouad K Habib
• Journal: The Journal of urology (J Urol) Vol. 172 Issue 1 Pg. 338-44 (Jul 2004) ISSN: 0022-5347 [Print] United States
• PMID: 15201807 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(acetyloxy)benzoic acid 6-(nitrooxymethyl)-2-phenylmethyl ester
• 6-(1,1-dimethylallyl)naringenin
• Anti-Inflammatory Agents, Non-Steroidal
• Coloring Agents
• Flavanones
• N-acetyl-S-(alpha-methyl-4-(2-methylpropyl)benzeneacetyl)cysteine 4-(nitrooxy)butyl ester
• Nitrates
• Nitric Oxide Donors
• Tetrazolium Salts
• Thiazoles
• CASP3 protein, human
• Caspase 3
• Caspases
• thiazolyl blue
• Aspirin
• Ibuprofen

Topics

• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Apoptosis (drug effects)
• Aspirin (analogs & derivatives, pharmacology)
• Caspase 3
• Caspases (physiology)
• Cell Division (drug effects)
• Coloring Agents
• Dose-Response Relationship, Drug
• Flavanones (chemical synthesis, toxicity)
• Flow Cytometry
• Humans
• Ibuprofen (analogs & derivatives, pharmacology)
• In Situ Nick-End Labeling
• Male
• Nitrates (pharmacology)
• Nitric Oxide Donors (pharmacology)
• Prostatic Neoplasms (drug therapy)
• Tetrazolium Salts
• Thiazoles
• Tumor Cells, Cultured