Potentiation of cell killing by fractionated radiation and suppression of proliferative recovery in MCF-7 breast tumor cells by the Vitamin D3 analog EB 1089.
A senescence-like growth arrest succeeded by recovery of proliferative capacity was observed in MCF-7 breast tumor cells exposed to fractionated radiation, 5 x 2 Gy. Exposure to EB 1089, an analog of the steroid hormone 1alpha, 25 dihydroxycholecalciferol (1alpha, 25 dihydroxy Vitamin D(3); calcitriol), prior to irradiation promoted cell death and delayed both the development of a senescent phenotype and the recovery of proliferative capacity. EB 1089 also reduced clonogenic survival over and above that produced by fractionated radiation alone and further conferred susceptibility to apoptosis in MCF-7 cells exposed to radiation. In contrast, EB 1089 failed to enhance the response to radiation (or to promote apoptosis) in normal breast epithelial cells or BJ fibroblast cells. EB 1089 treatment and fractionated radiation additively promoted ceramide generation and suppressed expression of polo-like kinase 1. Taken together, these data indicate that EB 1089 (and 1alpha, 25 dihydroxycholecalciferol or its analogs) could selectively enhance breast tumor cell sensitivity to radiation through the promotion of cell death, in part through the generation of ceramide and the suppression of polo-like kinase.
DeMasters
Gerald A
GA
Department of Pharmacology/Toxicology and Medicine, Virginia Commonwealth University, Medical College of Virginia, P.O. Box 980230, Richmond, VA 23298, USA.
Gupta
Mona S
MS
Jones
Kara R
KR
Cabot
Myles
M
Wang
Hongtao
H
Gennings
Chris
C
Park
Misook
M
Bratland
Ase
A
Ree
Anne H
AH
Gewirtz
David A
DA
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001943:Breast Neoplasms / Q000473:pathology*; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002518:Ceramides / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000097869:Polo-Like Kinase 1
D002117:Calcitriol; D018797:Cell Cycle Proteins; D002518:Ceramides; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D000097869:Polo-Like Kinase 1; C078903:seocalcitol