Abstract
We have been investigating the effects of natural polyamines and polyamine analogues on the survival and apoptosis of chondrocytes, which are cells critical for cartilage integrity. Treatment of human C-28/I2 chondrocytes with N1,N11-diethylnorspermine (DENSPM), a polyamine analogue with clinical relevance as anexperimental anticancer agent, rapidly induced spermidine/spermine N1-acetyltransferase (SSAT) and spermine oxidase (SMO), key enzymesofpolyamine catabolism and down-regulated ornithine decarboxylase, thefirst enzyme of polyamine biosynthesis, thus depleting all main polyamines within 24 h. The treatment with DENSPM did not provoke cell death and caspase activation when given alone for 24 h, but caused a caspase-3 and -9 dependent apoptosis in chondrocytes further exposed to cycloheximide (CHX). In other cellular models, enhanced polyamine catabolism or polyamine depletion has been implicated as mechanisms involvedinDENSPM-related apoptosis. However, the simultaneous additionof DENSPM and CHX rapidly increased caspase activity in C-28/I2 cells in the absence of SSAT and SMO induction or significant reduction of polyamine levels. Moreover, caspase activation induced by DENSPM plus CHX was not prevented by a N1-acetylpolyamine oxidase (PAO)/SMO inhibitor, and depletion of all polyamines obtained by specific inhibitors of polyamine biosynthesis did not reproduce DENSPM effects in the presence of CHX. DENSPM/CHX-induced apoptosis was associated with changes in the amount or activation of signalling kinases, Akt and MAPKs, and increased uptake of DENSPM. In conclusion, the results suggest that DENSPM can favour apoptosis in chondrocytes independently of its effects on polyamine metabolism and levels.
| Original language | English |
|---|---|
| Pages (from-to) | 109-116 |
| Number of pages | 8 |
| Journal | Journal of Cellular Physiology |
| Volume | 219 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Apr 2009 |
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ASJC Scopus subject areas
- Clinical Biochemistry
- Cell Biology
- Physiology
Cite this
The polyamine analogue N1,N11-diethylnorspermine can induce chondrocyte apoptosis independently of its ability to alter metabolism and levels of natural polyamines. / Stanic, Ivana; Facchini, Annalisa; Borzì, Rosa Maria; Stefanelli, Claudio; Flamigni, Flavio.
In: Journal of Cellular Physiology, Vol. 219, No. 1, 04.2009, p. 109-116.Research output: Contribution to journal › Article
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TY - JOUR
T1 - The polyamine analogue N1,N11-diethylnorspermine can induce chondrocyte apoptosis independently of its ability to alter metabolism and levels of natural polyamines
AU - Stanic, Ivana
AU - Facchini, Annalisa
AU - Borzì, Rosa Maria
AU - Stefanelli, Claudio
AU - Flamigni, Flavio
PY - 2009/4
Y1 - 2009/4
N2 - We have been investigating the effects of natural polyamines and polyamine analogues on the survival and apoptosis of chondrocytes, which are cells critical for cartilage integrity. Treatment of human C-28/I2 chondrocytes with N1,N11-diethylnorspermine (DENSPM), a polyamine analogue with clinical relevance as anexperimental anticancer agent, rapidly induced spermidine/spermine N1-acetyltransferase (SSAT) and spermine oxidase (SMO), key enzymesofpolyamine catabolism and down-regulated ornithine decarboxylase, thefirst enzyme of polyamine biosynthesis, thus depleting all main polyamines within 24 h. The treatment with DENSPM did not provoke cell death and caspase activation when given alone for 24 h, but caused a caspase-3 and -9 dependent apoptosis in chondrocytes further exposed to cycloheximide (CHX). In other cellular models, enhanced polyamine catabolism or polyamine depletion has been implicated as mechanisms involvedinDENSPM-related apoptosis. However, the simultaneous additionof DENSPM and CHX rapidly increased caspase activity in C-28/I2 cells in the absence of SSAT and SMO induction or significant reduction of polyamine levels. Moreover, caspase activation induced by DENSPM plus CHX was not prevented by a N1-acetylpolyamine oxidase (PAO)/SMO inhibitor, and depletion of all polyamines obtained by specific inhibitors of polyamine biosynthesis did not reproduce DENSPM effects in the presence of CHX. DENSPM/CHX-induced apoptosis was associated with changes in the amount or activation of signalling kinases, Akt and MAPKs, and increased uptake of DENSPM. In conclusion, the results suggest that DENSPM can favour apoptosis in chondrocytes independently of its effects on polyamine metabolism and levels.
AB - We have been investigating the effects of natural polyamines and polyamine analogues on the survival and apoptosis of chondrocytes, which are cells critical for cartilage integrity. Treatment of human C-28/I2 chondrocytes with N1,N11-diethylnorspermine (DENSPM), a polyamine analogue with clinical relevance as anexperimental anticancer agent, rapidly induced spermidine/spermine N1-acetyltransferase (SSAT) and spermine oxidase (SMO), key enzymesofpolyamine catabolism and down-regulated ornithine decarboxylase, thefirst enzyme of polyamine biosynthesis, thus depleting all main polyamines within 24 h. The treatment with DENSPM did not provoke cell death and caspase activation when given alone for 24 h, but caused a caspase-3 and -9 dependent apoptosis in chondrocytes further exposed to cycloheximide (CHX). In other cellular models, enhanced polyamine catabolism or polyamine depletion has been implicated as mechanisms involvedinDENSPM-related apoptosis. However, the simultaneous additionof DENSPM and CHX rapidly increased caspase activity in C-28/I2 cells in the absence of SSAT and SMO induction or significant reduction of polyamine levels. Moreover, caspase activation induced by DENSPM plus CHX was not prevented by a N1-acetylpolyamine oxidase (PAO)/SMO inhibitor, and depletion of all polyamines obtained by specific inhibitors of polyamine biosynthesis did not reproduce DENSPM effects in the presence of CHX. DENSPM/CHX-induced apoptosis was associated with changes in the amount or activation of signalling kinases, Akt and MAPKs, and increased uptake of DENSPM. In conclusion, the results suggest that DENSPM can favour apoptosis in chondrocytes independently of its effects on polyamine metabolism and levels.
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U2 - 10.1002/jcp.21655
DO - 10.1002/jcp.21655
M3 - Article
VL - 219
SP - 109
EP - 116
JO - Journal of cellular and comparative physiology
JF - Journal of cellular and comparative physiology
SN - 0021-9541
IS - 1
ER -