Radiosensitization of HL-60 human leukaemia cells by bryostatin-1 in the absence of increased DNA fragmentation or apoptotic cell death.
Ionizing radiation produced a dose-dependent reduction in the proliferative capacity of HL-60 human promyelocytic leukaemia cells. A small percentage of the cell population demonstrated morphological evidence of apoptosis at 24h following radiation doses of > or = 5 Gy (i.e. 8% at 5 Gy and 16% at 10 Gy respectively) and produced a laddered oligonucleosomal pattern of DNA fragments by static-field gel electrophoresis. The antiproliferative effects of 1 and 2.5 Gy ionizing radiation were significantly enhanced by preincubating cells with bryostatin-1 at a concentration (10 nM) and time frame (24h) associated with down-regulation of total cellular protein kinase C (PKC) activity. Potentiation by bryostatin-1 of the radiation effect on proliferation was not associated with a concomitant increase in internucleosomal DNA fragmentation, in the fraction of cells exhibiting apoptotic morphology, or in the extent of radiation-induced single- or double-strand breaks in bulk DNA. Staurosporine, a potent but nonspecific inhibitor of PKC, was ineffective in altering the radiosensitivity of HL-60 cells or the degree of DNA fragmentation induced by ionizing radiation. These findings indicate that bryostatin 1 increases the sensitivity of human myeloid leukaemic cells to low radiation doses without enhancing DNA fragmentation or apoptosis, and that this capacity may involve factors other than, or in addition to, down-modulation of PKC activity.
Watson
N C
NC
Department of Medicine, Medical College of Virginia, Richmond 23298-0230, USA.
Jarvis
W D
WD
Orr
M S
MS
Grant
S
S
Gewirtz
D A
DA
D017209:Apoptosis / Q000187:drug effects*; D054713:Bryostatins; D002455:Cell Division / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004307:Dose-Response Relationship, Radiation; D018922:HL-60 Cells / Q000187:drug effects* / Q000528:radiation effects; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D018942:Macrolides; D011838:Radiation-Sensitizing Agents
D054713:Bryostatins; D007783:Lactones; D018942:Macrolides; D011838:Radiation-Sensitizing Agents; C046785:bryostatin 1