Abstract
The poly(ADP-ribose) polymerase (PARP) is involved in cell recovery from DNA damage, such as methylation of N3-adenine, that activates the base excision repair process. In the present study we demonstrated that MeOSO2(CH2)2-lexitropsin (Me-Lex), a methylating agent that almost exclusively produces N3-methyladenine, induced different modalities of cell death in human leukemic cell lines, depending on the presence of PARP inhibitor. Growth inhibition, provoked by the combination of Me-Lex and PARP inhibitor, was associated with a marked down-regulation of c-myc, increased generation of single strand breaks and apoptosis. When used as single agent, at concentrations that saturated cell repair ability, Me-Lex induced mainly cell death by necrosis. Surprisingly, addition of a PARP inhibitor enhanced apoptosis and reduced the early appearance of necrosis. Telomerase activity was completely suppressed in cells exposed to Me-Lex alone, by 24 h after treatment, whereas it did not change when Me-Lex was combined with PARP inhibitor. Thereafter, inhibition of telomerase was observed with both treatments. The results suggest new insights on different modalities of cell death induced by high levels of N3-methyladenine per se, or by the methylated base in the presence of PARP inhibitor.
| Original language | English |
|---|---|
| Pages (from-to) | 817-828 |
| Number of pages | 12 |
| Journal | Cell Death and Differentiation |
| Volume | 8 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 2001 |
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Keywords
- Apoptosis
- Drug resistance
- Methylating agents
- Necrosis
- Poly(ADP-ribose) polymerase
- Telomerase
ASJC Scopus subject areas
- Cell Biology
Cite this
Poly (ADP-ribose) polymerase inhibitor increases apoptosis and reduces necrosis induced by a DNA minor groove binding methyl sulfonate ester. / Tentori, L.; Balduzzi, A.; Portarena, I.; Levati, L.; Vernole, P.; Gold, B.; Bonmassar, E.; Graziani, G.
In: Cell Death and Differentiation, Vol. 8, No. 8, 2001, p. 817-828.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Poly (ADP-ribose) polymerase inhibitor increases apoptosis and reduces necrosis induced by a DNA minor groove binding methyl sulfonate ester
AU - Tentori, L.
AU - Balduzzi, A.
AU - Portarena, I.
AU - Levati, L.
AU - Vernole, P.
AU - Gold, B.
AU - Bonmassar, E.
AU - Graziani, G.
PY - 2001
Y1 - 2001
N2 - The poly(ADP-ribose) polymerase (PARP) is involved in cell recovery from DNA damage, such as methylation of N3-adenine, that activates the base excision repair process. In the present study we demonstrated that MeOSO2(CH2)2-lexitropsin (Me-Lex), a methylating agent that almost exclusively produces N3-methyladenine, induced different modalities of cell death in human leukemic cell lines, depending on the presence of PARP inhibitor. Growth inhibition, provoked by the combination of Me-Lex and PARP inhibitor, was associated with a marked down-regulation of c-myc, increased generation of single strand breaks and apoptosis. When used as single agent, at concentrations that saturated cell repair ability, Me-Lex induced mainly cell death by necrosis. Surprisingly, addition of a PARP inhibitor enhanced apoptosis and reduced the early appearance of necrosis. Telomerase activity was completely suppressed in cells exposed to Me-Lex alone, by 24 h after treatment, whereas it did not change when Me-Lex was combined with PARP inhibitor. Thereafter, inhibition of telomerase was observed with both treatments. The results suggest new insights on different modalities of cell death induced by high levels of N3-methyladenine per se, or by the methylated base in the presence of PARP inhibitor.
AB - The poly(ADP-ribose) polymerase (PARP) is involved in cell recovery from DNA damage, such as methylation of N3-adenine, that activates the base excision repair process. In the present study we demonstrated that MeOSO2(CH2)2-lexitropsin (Me-Lex), a methylating agent that almost exclusively produces N3-methyladenine, induced different modalities of cell death in human leukemic cell lines, depending on the presence of PARP inhibitor. Growth inhibition, provoked by the combination of Me-Lex and PARP inhibitor, was associated with a marked down-regulation of c-myc, increased generation of single strand breaks and apoptosis. When used as single agent, at concentrations that saturated cell repair ability, Me-Lex induced mainly cell death by necrosis. Surprisingly, addition of a PARP inhibitor enhanced apoptosis and reduced the early appearance of necrosis. Telomerase activity was completely suppressed in cells exposed to Me-Lex alone, by 24 h after treatment, whereas it did not change when Me-Lex was combined with PARP inhibitor. Thereafter, inhibition of telomerase was observed with both treatments. The results suggest new insights on different modalities of cell death induced by high levels of N3-methyladenine per se, or by the methylated base in the presence of PARP inhibitor.
KW - Apoptosis
KW - Drug resistance
KW - Methylating agents
KW - Necrosis
KW - Poly(ADP-ribose) polymerase
KW - Telomerase
UR - http://www.scopus.com/inward/record.url?scp=0034897316&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034897316&partnerID=8YFLogxK
U2 - 10.1038/sj.cdd.4400863
DO - 10.1038/sj.cdd.4400863
M3 - Article
C2 - 11526435
AN - SCOPUS:0034897316
VL - 8
SP - 817
EP - 828
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
SN - 1350-9047
IS - 8
ER -