Arsenic trioxide induces apoptosis in HTLV-I infected T-cell lines and fresh adult T-cell leukemia cells through CD95 or tumor necrosis factor alpha receptor independent caspase activation.
Arsenic trioxide (As2O3) has been reported to induce apoptosis in human T-cell leukemia virus type-I (HTLV-I) infected T-cell lines and fresh adult T-cell leukemia (ATL) cells and to induce G1 phase accumulation in HTLV-I infected T-cell lines. The present study aimed to clarify the pathway of As2O3-induced apoptosis in HTLV-I infected T-cell lines, MT-1 and MT-2, and fresh ATL cells separated from peripheral blood of patients with acute or chronic type ATL. Cells were treated up to 72 h at clinically tolerable concentrations of As2O3 (1-2 micromol/l) shown to be safe in patients with acute promyelocytic leukemia (APL). Activation of caspases 3, 8, and 9, loss of mitochondrial transmembrane potential and cleavage of poly (adenosine diphosphate-ribose) polymerase (PARP) were observed during As2O3 treatment. Furthermore, prior exposure to a broad-spectrum caspase inhibitor blocked As2O3-induced apoptosis but not G1 phase accumulation. While pre-treatment with a CD95 receptor-blocking antibody (Ab) or a TNF-alpha neutralizing Ab did not show such inhibitions in these cells. In conclusion, As2O3 induces apoptosis in HTLV-I infected T-cell lines and fresh ATL cells through CD95 or TNF-alpha receptor independent caspase activation.
Ishitsuka
Kenji
K
1st Department of Internal Medicine, Fukuoka University, Japan. ken-ishi@cis.fukuoka-u.ac.jp
Ikeda
Ryuji
R
Utsunomiya
Atae
A
Uozumi
Kimiharu
K
Hanada
Shuichi
S
Suzuki
Shinsuke
S
Takeuchi
Shogo
S
Takatsuka
Yoshifusa
Y
Takeshita
Taketsugu
T
Ohno
Nobuhito
N
Arima
Terukatsu
T
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D020169:Caspases / Q000502:physiology*; D002460:Cell Line; D004789:Enzyme Activation; D016193:G1 Phase; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000473:pathology; D008564:Membrane Potentials / Q000187:drug effects; D010087:Oxides / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D013601:T-Lymphocytes / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019014:fas Receptor / Q000502:physiology*
D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D000077237:Arsenic Trioxide