Abstract
SJG-136 is a new pyrrolobenzodiazepine dimer inducing time-dependent cytotoxicity. HCT 116 cells were exposed to 50 nmol/L of SJG-136 for 1 hour or 1 nmol/L of SJG-136 for 24 hours to achieve similar levels of interstrand cross-links (ICL). The short exposure led to a rapid formation of ICLs (1 hour), early H2AX foci formation (4 hours), prominent S phase arrest, and greater phosphorylation of Nbs1 (on serine 343) and Chk1 (on serine 317) than a 24-hour exposure. The prolonged exposure at low concentrations of SJG-136 induced a gradual formation of ICLs (up to 24 hours) which was associated with a limited S phase arrest and delayed Nbs1 phosphorylation. Prolonged exposure was also associated with a reduced phosphorylation of p53 on serines 15 and 20, a limited and delayed phosphorylation on serine 392, and a less prominent increase in p21 levels. These data suggest that the 24-hour exposure to a low concentration of SJG-136 led to delayed and reduced DNA damage signaling compared with a higher concentration of SJG-136 for 1 hour, resulting in greater cytotoxicity and contributing to the time-dependent cytotoxic effect of SJG-136.
Original language | English |
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Pages (from-to) | 1602-9 |
Number of pages | 8 |
Journal | MOLECULAR CANCER THERAPEUTICS |
Volume | 5 |
Issue number | 6 |
DOIs | |
Publication status | Published - Jun 2006 |
Keywords
- Benzodiazepinones
- Cell Survival
- Cross-Linking Reagents
- DNA
- DNA Damage
- HCT116 Cells
- Humans
- Phosphorylation
- Protein Kinases
- Pyrroles
- S Phase
- Signal Transduction
- Time Factors