Arsenic trioxide-induced apoptosis and differentiation are associated respectively with mitochondrial transmembrane potential collapse and retinoic acid signaling pathways in acute promyelocytic leukemia
X. Cai et al., Arsenic trioxide-induced apoptosis and differentiation are associated respectively with mitochondrial transmembrane potential collapse and retinoic acid signaling pathways in acute promyelocytic leukemia, LEUKEMIA, 14(2), 2000, pp. 262-270
Recent studies showed that arsenic trioxide (As2O3) could induce apoptosis
and partial differentiation of leukemic promyelocytes. Here, we addressed t
he possible mechanisms underlying these two different effects. 1.0 mu M As2
O3-induced apoptosis was associated with condensation of the mitochondrial
matrix, disruption of mitochondrial transmembrane potentials (Delta psi m)
and activation of caspase-3 in acute promyelocytic leukemia (APL) cells reg
ardless of their sensitivity to all-trans retinoic acid (ATRA). All these e
ffects were inhibited by dithiothreitol (DTT) and enhanced by buthionine su
lfoximine (BSO). Furthermore, BSO could also render HL60 and U937 cells, wh
ich had the higher cellular catalase activity, sensitive to As2O3-induced a
poptosis. Surprisingly, 1.0 mu M As2O3 did not induce the Delta psi m colla
pse and apoptosis, while 0.1 mu M As2O3 induced partial differentiation of
fresh BM cells from a de novo APL patient. In this study, we also showed th
at 0.2 mM DTT did not block low-dose As2O3-induced NB4 cell differentiation
, and 0.1 similar to 0.5 mu M As2O3 did not induce differentiation of ATRA-
resistant NB4-derived sublines, which were confirmed by cytomorphology, exp
ression of CD11b, CD33 and CD14 as well as NET reduction. Another interesti
ng finding was that 0.1 similar to 0.5 mu M As2O3 could also induce differe
ntiation-related changes in ATRA-sensitive HL60 cells. However, the differe
ntiation-inducing effect could not be seen in ATRA-resistant HL60 sublines
with RAR alpha mutation. Moreover, low-dose As2O3 and ATRA yielded similar
gene expression profiles in APL cells. These results encouraged us to hypot
hesize that As2O3 induces APL cell differentiation through direct or indire
ct activation of retinoic acid receptor-related signaling pathway(s), while
Delta psi m collapse is the common mechanism of As2O3-induced apoptosis.