In vitro sensitivity of B-cell chronic lymphocytic leukemia to cladribine and its combinations with mafosfamide and/or mitoxantrone.
We examined in vitro sensitivity of B-CLL cells exposed to cladribine, mafosfamide, mitoxantrone and combinations ofcladribine with mafosfamide and/or mitoxantrone. The results revealed that each applied treatment of leukemic cells, besides having a cytotoxic effect, affected the events associated with apoptosis. All drugs used alone, and cladribine combinations with mafosfamide and/or mitoxantrone induced DNA fragmentation and the changes in expression/proteolysis level of caspase-3, caspase-9 precursors, PARP-1, lamin B, Bax and Bcl-2; however, each to a different degree. The exposure of leukemic cells to both cladribine combinations induced stronger effects. Moreover, the data showed that the expression of regulatory antiapoptotic protein Bcl-2 generally decreased in drug-treated B-CLL cells, whereas proapoptotic polypeptide Bax increased, resulting in enhancement of Bax-Bcl-2 ratios in comparison with untreated cells. Drug-treatment of the studied cells induced the translocation of Bax protein from the cytosol to the cellular pellet, containing mitochondria, where this polypeptide indicated the capacity for oligomerization. These observations suggest that the examined drugs are able to induce apoptosis of B-CLL cells via the mitochondria pathway.
Kobylinska
Agnieszka
A
Department of Cytobiochemistry, University of Lodz, 90-237 Lodz, Poland.
Bednarek
Jolanta
J
Blonski
Jerzy Z
JZ
Hanausek
Malgorzata
M
Walaszek
Zbigniew
Z
Robak
Tadeusz
T
Kilianska
Zofia M
ZM
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015153:Blotting, Western; D020169:Caspases / Q000187:drug effects; D017338:Cladribine / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D053938:DNA Fragmentation / Q000187:drug effects*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D034921:Lamin Type B / Q000187:drug effects; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D008297:Male; D008928:Mitochondria / Q000187:drug effects; D008942:Mitoxantrone / Q000008:administration & dosage; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein / Q000187:drug effects
D034921:Lamin Type B; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D017338:Cladribine; C048341:mafosfamide; D003520:Cyclophosphamide; D008942:Mitoxantrone; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases