Bcl2-Independent Chromatin Cleavage is a Very Early Event during Induction of Apoptosis in Mouse Thymocytes after Treatment with Either Dexamethasone or Ionizing Radiation

Abstract

We have quantified the emergence of early chromatin breaks during the signal transduction phase of apoptosis in mouse thymocytes after treatment with either ionizing radiation or dexamethasone. Dexamethasone at 1 microM can induce significant levels of DNA breaks (equivalent to the amount induced directly by 7.5 Gy ionizing radiation) within 0.5 h of treatment. The execution phase of apoptosis was not observed until 4-6 h after the same treatment. The presence of the Bcl2 transgene under the control of the p56lck promoter almost completely inhibited apoptosis up to 24 h after treatment, but it had virtually no effect on the early chromatin cleavage occurring in the first 6 h. Ionizing radiation induced chromatin cleavage both directly by damaging DNA and indirectly with kinetics similar to the induction of chromatin cleavage by dexamethasone. The presence of the Bcl2 transgene had no effect on the direct or indirect radiation-induced cleavage in the first 6 h, but after the first 6 h, the Bcl2 gene inhibited further radiation-induced chromatin cleavage. These results suggest that endonucleases are activated within minutes of treatment with either dexamethasone or ionizing radiation as part of the very early signal transduction phase of apoptosis, and prior to the irreversible commitment to cell death.

Tumor Markers of Neo-Adjuvant Chemo-Radiation Response in Rectal Cancer

“…Bax can be activated by pro apoptotic stimuli or p53 and expression can be altered following radiation and is associated with resistance to chemotherapy (Miguel, Wajsenzon et al 2007), (Przemeck, Duckworth et al 2007), (Murphy, Mabruk et al 2002), (Johnson, Xiang et al 1998;Butt, Firth et al 2000), (Strobel, Swanson et al 1997), (Khanna, Wie et al 1996). This is in contrast to overexpression of bcl2 is associated with chemotherapy resistance and protects cells from radiation induced apoptosis (Hahn, Lai et al 2003), (Vrana, Grant et al 1999). 12 studies have assessed these proteins, 8 for Bcl2 expression and 4 have evaluated Bax expression as predictive markers (Qiu, Sirivongs et al 2000), (Rodel, Grabenbauer et al 2002), (Rodel, Hoffmann et al 2002), (Scott, Hale et al 1998), (Okonkwo, Musunuri et al 2001).…”