Expression of apoptosis-related oncoproteins and modulation of apoptosis by caffeine in human leukemic cells.
We investigated the modulation of radio- and chemoresistance by caffeine and mechanisms of resistance in human leukemic cell lines and mononuclear cells from 18 leukemic patients. Caffeine synergistically potentiated cytotoxicity and apoptosis induced by ionizing radiation or carboplatin (CPt), but attenuated induction of apoptosis by daunorubicin (DNR) in KG-1a cells. Since caffeine released irradiated as well as DNR-treated KG-1a cells from G2M cell cycle arrest and CPt-treated cells from S-phase arrest, this release does not fully explain the different effects of caffeine. Caffeine synergistically reduced the level of the apoptosis inhibitor glutathione after irradiation or CPt treatment. In contrast, treatment with DNR plus caffeine diminished glutathione levels to a lesser extent than DNR alone. We conclude that the effect of caffeine on glutathione depletion represents a mechanism of action by which caffeine can modulate apoptosis. Caffeine increased CPt cytotoxicity in K562 cells and its doxorubicin-resistant subline (K562/ADM), but little effect was seen in HL-60 cells or mononuclear cells from leukemic patients. Multivariate cluster analysis revealed an association of CPt resistance with the expression of c-Fos, c-N-Ras, and p53 oncoproteins and with proliferative activity (S-phase of cell cycle), but not with Bcl-2 expression.
Efferth
T
T
Medizinische Klinik IV, RWTH Aachen, Germany.
Fabry
U
U
Glatte
P
P
Osieka
R
R
D017209:Apoptosis / Q000187:drug effects*; D002110:Caffeine / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology; D016000:Cluster Analysis; D004396:Coloring Agents; D003630:Daunorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000096:biosynthesis; D005720:Gamma Rays; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism; D018922:HL-60 Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D007150:Immunohistochemistry; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000503:physiopathology; D007951:Leukemia, Myeloid / Q000503:physiopathology*; D015470:Leukemia, Myeloid, Acute / Q000503:physiopathology; D015473:Leukemia, Promyelocytic, Acute / Q000503:physiopathology; D008228:Lymphoma, Non-Hodgkin / Q000503:physiopathology; D015999:Multivariate Analysis; D016761:Oncogene Proteins v-fos / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D019253:Proto-Oncogene Proteins c-bcl-2; D011836:Radiation Tolerance / Q000187:drug effects; D016196:S Phase / Q000187:drug effects; D013778:Tetrazolium Salts; D013844:Thiazoles; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D018631:ras Proteins / Q000096:biosynthesis
D004396:Coloring Agents; D016761:Oncogene Proteins v-fos; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013778:Tetrazolium Salts; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D002110:Caffeine; D016190:Carboplatin; D019204:GTP-Binding Proteins; D018631:ras Proteins; C022616:thiazolyl blue; D005978:Glutathione; D003630:Daunorubicin