Dual effects of arsenic trioxide (As2O3) on non-acute promyelocytic leukaemia myeloid cell lines: induction of apoptosis and inhibition of proliferation.
Clinical efficacy of As2O3 has been shown in patients with relapsed acute promyelocytic leukaemia (APL). There is evidence that the effects of As2O3 are not restricted to events specific for APL. As2O3 might target mechanisms involved in the pathogenesis of other malignancies. We assessed susceptibility to induction of apoptosis by As2O3 and cytostatics in 22 myeloid and non-myeloid malignant cell lines. As2O3 was used in concentrations of 0.01-10 micromol/l. Cell lines displayed different kinetics of response and different sensitivity to As2O3. The minimum concentration of As2O3 for induction of apoptosis was 0.1 micromol/l. High concentrations of As2O3 (5 micromol/l) induced apoptosis in a large proportion of cells in all cell lines tested. Low (1 micromol/l As2O3) concentrations induced apoptosis in NB-4, HL-60, U-937, CEM, HL-60, KG-1a, PBL-985, ML-2 and MV-4-11, but not in HEL, K-562, KG-1 and Jurkat up to 35 d of incubation. However, the non-apoptotic population of 1 micromol/l As2O3-treated HEL, K-562, K-562 (0.02), K-562(0.1) and Jurkat showed reduced proliferation. CEM as well as its' multidrug-resistant derivatives were sensitive to 1 micromol/l As2O3. In summary, these data demonstrate that As2O3-induced apoptosis is not restricted to cell lines with t(15;17). Apoptosis was induced in vitro by As2O3 concentrations that are achievable in vivo after infusion of well-tolerated As2O3 doses. Thus, As2O3 might be a suitable therapeutic agent for malignancies other than APL provided the adequate dose and duration of As2O3 treatment are used.
Rojewski
M T
MT
Freie Universität Berlin, Universitätsklinikum Benjamin Franklin, Medizinische Klinik III (Hämatologie, Onkologie und Transfusionsmedizin), Berlin, Germany.
Baldus
C
C
Knauf
W
W
Thiel
E
E
Schrezenmeier
H
H
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology*; D010087:Oxides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D000077237:Arsenic Trioxide