title: Thalidomide induces phosphorylation of histone H2AX and increases rate of apoptosis caused by fludarabine in malignant lymphocytes of chronic lymphocytic leukemia in short-term cell cultures.
abstract: In this study we attempted to assess interactions of thalidomide with fludarabine in terms of their effect on DNA damage and apoptosis of chronic lymphocytic leukemia (CLL) cells. The experiments were done in ex vivo short-term cell cultures of peripheral blood cells from newly diagnosed untreated patients. We analyzed phosphorylation of histone H2AX on Ser139 (gammaH2AX), reporter of DNA damage, and expression of activated caspase-3, as a marker of apoptosis. Modest increase in expression of gammaH2AX caused by thalidomide was observed in samples of some analyzed patients. The increase in expression of gammaH2AX was also seen in leukemic TK6 cells treated with thalidomide. While treatment of CLL cells with thalidomide alone had no significant effect on apoptosis the treatment with thalidomide+fludarabine had greater than the additive effect on frequency of apoptotic cells. The data suggest that oxidative DNA damage likely induced by thalidomide sensitizes CLL cells to undergo apoptosis in response to fludarabine.
authors.affiliation: Department of Haematooncology and Bone Marrow Transplantation Medical University of Lublin, Staszica 11, 20-081 Lublin, Poland. monika.podhorecka@am.lublin.pl
authors.forename: Monika
authors.initials: M
authors.lastname: Podhorecka
authors.forename: H Dorota
authors.initials: HD
authors.lastname: Halicka
authors.forename: Piotr
authors.initials: P
authors.lastname: Klimek
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Kowal
authors.forename: Anna
authors.initials: A
authors.lastname: Dmoszynska
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D018929:Cell Culture Techniques; D004357:Drug Synergism; D005455:Fluorescent Antibody Technique; D006657:Histones / Q000378:metabolism*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology*; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D013792:Thalidomide / Q000008:administration & dosage; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: C468783:H2AX protein, human; D006657:Histones; D013792:Thalidomide; D053148:Caspase 3; D014740:Vidarabine; C024352:fludarabine