Different ways to induce apoptosis by fenretinide and all-trans-retinoic acid in human B lymphoma cells.
All-trans-retinoic acid (ATRA) and its synthetic analog fenretinide (4HPR) are potent anticancer drugs. Only a few reports are available about the effects of retinoids on B lymphoma cells. In our study, non-Hodgkin lymphoma cells (HT58) were treated with ATRA and 4HPR. Both agents induced cell death time- and dose-dependently. Reactive oxygen species (ROS) production was elevated in 4HPR-treated cells, but not in ATRA-treated cells. The depolarization of the mitochondrial membrane occured earlier after ATRA than after 4HPR treament. Z-VAD-fmk, the general caspase inhibitor, decreased the DNA fragmentation in ATRA-treated cells, but simultaneously increased necrosis. However, z-VAD-fmk did not influence the DNA fragmentation in 4HPR-treated cells. Endonuclease G was released from the mitochondria during 4HPR treatment, which could be an inducer for caspase-independent DNA fragmentation. Our results suggest that natural (ATRA) and synthetic (4HPR) retinoids induce different apoptotic pathways in B lymphoma cells, which is particularly relevant for their potential use in leukemia treatment.
Barna
Gábor
G
First Department of Pathology and Experimental Cancer Research, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
Sebestyén
Anna
A
Weischede
Silke
S
Peták
István
I
Mihalik
Rudolf
R
Formelli
Franca
F
Kopper
László
L
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D061945:Caspase Inhibitors; D004305:Dose-Response Relationship, Drug; D004706:Endodeoxyribonucleases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D017313:Fenretinide; D014212:Tretinoin; D004706:Endodeoxyribonucleases; C052391:endonuclease G