Phenylarsine oxide (PAO) more intensely induces apoptosis in acute promyelocytic leukemia and As2O3-resistant APL cell lines than As2O3 by activating the mitochondrial pathway.
We studied the cytotoxic effect of an organic arsenical compound, phenylarsine oxide (PAO) on an acute promyelocytic leukemia (APL) cell line (NB4) and an As2O3-resistant NB4 subline (NB4/As). Cell growth was inhibited by 50% (IC50) upon 2-day treatment with As2O3 or PAO at 0.54 and 0.06 microM, respectively in NB4 cells (P = 0.025), and 2.80 and 0.08 microM, respectively in NB4/As (P = 0.030). 0.1 microM PAO increased the proportion of hypodiploid cells (50.3%) by a greater degree than the same dose of As2O3 (3.8%) in NB4 cells. In NB4 cells, 0.1 microM PAO reduced the mitochondrial transmembrane potential (20.5% in a PI(negative)-Rhodamine123(low) fraction) by a greater degree than 1 microM As2O3 (7.1%). Western blotting showed that 0.1 microM PAO downregulated the expression of both Bcl-2 and Bcl-X(L) proteins, whereas I microM As2O3 downregulated only Bcl-2 expression. These results suggest that the cytotoxic effect of PAO on an APL cell line and As2O3-resistant subline is significantly higher than that of As2O3. PAO-induced apoptosis seems to be related to the activation of the mitochondrial pathway and downregulation of both Bcl-2 and Bcl-X(L). PAO is a considerable agent for relapsed/refractory APL and for purging APL cells following stem cell transplantation.
Sahara
Naohi
N
Internal Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Japan. sahara@hama-med.ac.jp
Takeshita
Akihiro
A
Kobayashi
Miki
M
Shigeno
Kazuyuki
K
Nakamura
Satoki
S
Shinjo
Kaori
K
Naito
Kensuke
K
Maekawa
Masato
M
Horii
Toshinobu
T
Ohnishi
Kazunori
K
Kitamura
Kunio
K
Naoe
Tomoki
T
Hayash
Hideharu
H
Ohno
Ryuzo
R
D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000473:pathology*; D008564:Membrane Potentials; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051020:bcl-X Protein
D001152:Arsenicals; C494811:BCL2L1 protein, human; D010087:Oxides; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C029341:oxophenylarsine; D019938:Cyclin D1; D000077237:Arsenic Trioxide