Depolarization of mitochondria and activation of caspases are common features of arsenic(III)-induced apoptosis in myelogenic and lymphatic cell lines.
The clinical efficacy of arsenic(III) oxide (As(2)O(3)) has been shown in patients with relapsed acute promyelocytic leukemia (APL). To identify potential common primary targets of action of As(2)O(3) in myelogenic and lymphatic cell lines, we analyzed As(2)O(3) effects on caspases and on the mitochondrial membrane potential (Psi(M)) under uniform conditions. As(2)O(3) induced breakdown of Psi(M) and activated caspases in cell lines with different sensitivities for As(2)O(3), including cell lines resistant to mitoxantron or camptothecin but sensitive to As(2)O(3). Caspase inhibitors could not prevent breakdown of Psi(M) in lymphoid cell lines, whereas activation of caspases and apoptosis could be inhibited. Activation of caspases seems to be a downstream effect occurring after breakdown of Psi(M). We could show that all of these effects are independent of MDR-1 expression. There was no difference in the mode of action of As(2)O(3) in cell lines sensitive or resistant to camptothecin, mitoxantrone, or doxorubicin. As(2)O(3) deserves further evaluation as an adjunct or alternative to other cytostatic drugs.
Rojewski
Markus T
MT
Freie Universität Berlin, Universitätsklinikum Benjamin Franklin, Medizinische Klinik III, Hämatologie, Onkologie und Transfusionsmedizin, D-12203 Berlin, Germany. markus.rojewskI@medizin.uni-ulm..de
Körper
Sixten
S
Thiel
Eckhard
E
Schrezenmeier
Hubert
H
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology* / Q000627:therapeutic use; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D005456:Fluorescent Dyes; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D010087:Oxides / Q000494:pharmacology* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D001152:Arsenicals; D061945:Caspase Inhibitors; D005456:Fluorescent Dyes; D010087:Oxides; D020169:Caspases; D000077237:Arsenic Trioxide