Resistance to different classes of drugs is associated with impaired apoptosis in childhood acute lymphoblastic leukemia.
Resistance of leukemic cells to chemotherapeutic agents is associated with an unfavorable outcome in pediatric acute lymphoblastic leukemia (ALL). To investigate the underlying mechanisms of cellular drug resistance, the activation of various apoptotic parameters in leukemic cells from 50 children with ALL was studied after in vitro exposure with 4 important drugs in ALL therapy (prednisolone, vincristine, l-asparaginase, and daunorubicin). Exposure to each drug resulted in early induction of phosphatidylserine (PS) externalization and mitochondrial transmembrane (Deltapsim) depolarization followed by caspase-3 activation and poly(ADP-ribose) polymerase (PARP) inactivation in the majority of patients. For all 4 drugs, a significant inverse correlation was found between cellular drug resistance and (1) the percentage of cells with PS externalization (<.001 < P <.008) and (2) the percentage of cells with Deltapsim depolarization (.002 < P <.02). However, the percentage of cells with caspase-3 activation and the percentage of cells with PARP inactivation showed a significant inverse correlation with cellular resistance for prednisolone (P =.001; P =.001) and l-asparaginase (P =.01; P =.001) only. This suggests that caspase-3 activation and PARP inactivation are not essential for vincristine- and daunorubicin-induced apoptosis. In conclusion, resistance to 4 unrelated drugs is associated with defect(s) upstream or at the level of PS externalization and Deltapsim depolarization. This leads to decreased activation of apoptotic parameters in resistant cases of pediatric ALL.
Holleman
Amy
A
Erasmus MC/Sophia Children's Hospital, Pediatric Oncology/Hematology, Rm Sp2456, Dr Molewaterplein 60, PO Box 2060, 3000 CB Rotterdam, The Netherlands.
den Boer
Monique L
ML
Kazemier
Karin M
KM
Janka-Schaub
Gritta E
GE
Pieters
Rob
R
D000970:Antineoplastic Agents / Q000145:classification / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology*; D001215:Asparaginase / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002648:Child; D003630:Daunorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008563:Membrane Lipids / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010718:Phosphatidylserines / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011239:Prednisolone / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
D000970:Antineoplastic Agents; D008563:Membrane Lipids; D010718:Phosphatidylserines; D014750:Vincristine; D011239:Prednisolone; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D001215:Asparaginase; D003630:Daunorubicin