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The anti-apoptotic property of NS-398 at high dose can be mediated in part through NF-kappaB activation, hsp70
Sandra Moalic-Juge1, Bertrand Liagre, Raphaël Duval
1Laboratoire de Biochimie, UPRES EA 1085, Faculté de Pharmacie, 2 rue du Docteur Marcland, 87025 Limoges Cedex, France.
Abstract:
Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to produce an anti-proliferative and pro-apoptotic effect on different types of cancer cell lines. Previously, we demonstrated that high dose of NS-398 (100 microM), a selective cyclooxygenase-2 inhibitor, induced a cell cycle slowing or arrest and, in contrast to low dose (10 microM), a marked decrease in apoptosis in human 1547 osteosarcoma cells. In this study, we investigated particularly the effect of 100 microM NS-398 on p53 and p21 expression, caspase activities and nuclear factor-kappaB (NF-kappaB). We found a correlation between p53, p21 mRNA expression and NF-kappaB activation and, we observed an induction of heat shock protein 70 expression with a large decrease in caspase-3 activity after 100 microM NS-398 treatment. Moreover, the inhibition of apoptosis was correlated with an increase in bcl-2/bax ratio. Our new findings confirm the novel anti-apoptotic property of NS-398 at 100 microM, as we previously found, which contrasts to the described NS-398 pro-apoptotic effect on other cancer cell lines.
Insights
High-dose NS-398, a cyclooxygenase-2 inhibitor, surprisingly inhibits apoptosis in osteosarcoma cells by affecting p53, p21, and NF-kappaB pathways. This contrasts with its known pro-apoptotic effects in other cancer types.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Non-steroidal anti-inflammatory drugs (NSAIDs) exhibit anti-cancer properties, including anti-proliferation and pro-apoptosis.
- Selective cyclooxygenase-2 (COX-2) inhibitors like NS-398 have shown varied effects on cancer cell lines.
- Previous studies indicated high-dose NS-398 (100 µM) induced cell cycle arrest but decreased apoptosis in human 1547 osteosarcoma cells, contrary to low-dose effects.
Purpose of the Study:
- To investigate the molecular mechanisms behind the anti-apoptotic effect of high-dose NS-398 in human osteosarcoma cells.
- To examine the impact of 100 µM NS-398 on key apoptosis-related factors including p53, p21, caspase activities, and nuclear factor-kappaB (NF-kappaB).
Main Methods:
- Human 1547 osteosarcoma cells were treated with 100 µM NS-398.
- Analysis of p53 and p21 mRNA expression.
- Measurement of caspase activities (specifically caspase-3).
- Assessment of nuclear factor-kappaB (NF-kappaB) activation.
- Evaluation of heat shock protein 70 (HSP70) expression.
- Determination of the bcl-2/bax protein ratio.
Main Results:
- A correlation was observed between p53 and p21 mRNA expression and NF-kappaB activation.
- Treatment with 100 µM NS-398 induced heat shock protein 70 (HSP70) expression.
- A significant decrease in caspase-3 activity was noted.
- The inhibition of apoptosis was associated with an increased bcl-2/bax ratio.
Conclusions:
- High-dose NS-398 (100 µM) exhibits a novel anti-apoptotic effect in human 1547 osteosarcoma cells.
- This anti-apoptotic effect is linked to the modulation of p53, p21, NF-kappaB, HSP70, and the bcl-2/bax ratio.
- These findings contrast with the established pro-apoptotic effects of NS-398 in other cancer cell lines, highlighting cell-type-specific responses.