title: In vitro sensitivity of B-cell chronic lymphocytic leukemia to cladribine and its combinations with mafosfamide and/or mitoxantrone.
abstract: 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.
authors.affiliation: Department of Cytobiochemistry, University of Lodz, 90-237 Lodz, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kobylinska
authors.forename: Jolanta
authors.initials: J
authors.lastname: Bednarek
authors.forename: Jerzy Z
authors.initials: JZ
authors.lastname: Blonski
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Hanausek
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Walaszek
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Robak
authors.forename: Zofia M
authors.initials: ZM
authors.lastname: Kilianska
mesh_terms: 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
chemical_list: 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