Gifu International I titute of Biotechnology, Yagi Memorial Park, Mitake, Japan.
We showed that arsenic inhibited the cell growth of four B-cell leukaemia cell lines of 11 various cell lines in vitro. In two of these four lines, KOCL44 and LyH7, apoptosis was identified by morphological and nucleosomal DNA fragmentation studies. Three of the four B-cell lines that were growth inhibited were acute infantile leukaemia with t(11;19)(q23 13) tra locatio involving the MLL gene that encodes the tra criptional factor Drosophila trithorax. The arsenic-induced apoptosis in KOCL44 and LyH7 cells was found to be linked to ca ases by Western blot and enzymological analyses. The amount of Bcl-2 was reduced during apoptosis in LyH7 as judged by Western blot analysis. We concluded that combined activation of the ca ases and down-regulation of Bcl-2 could determine the fate of B-cell leukaemic cells in re o e to arsenic.
Blood 1998 Jun 1;91(11):4300-10
Combined arsenic and retinoic acid treatment enhances differentiation and apoptosis in arsenic-resistant 4 cells.
Gia i M, Koken MH, Chelbi-Alix MK, Benoit G, Lanotte M, Chen Z, de The H.
Centre National de la Recherche Scientifique Unite Propre de Recherche 9051, Laboratoire a ocie au Comite de Paris de la Ligue Contre le Cancer, UIH, Universite Paris VII, Service de Biochimie B, Hopital St Louis, Paris, France.
In the acute promyelocytic leukemia (APL) cell line 4, as well as in APL patients\' cells, arsenic trioxide (As2O3) leads to incomplete cell maturation, induction of apoptosis, as well as to the degradation of the oncogenic PML/RARalpha fusion protein. We have isolated an arsenic-resistant 4 subline ( 4-AsR), which fails to undergo apoptosis, but maintai the partial differentiation re o e to this drug. When grown in the presence of As2O3, 4-AsR cells degrade PML/RARalpha, slightly differentiate, and become more se itive to serum deprivation-induced apoptosis. Similarly, in RA-resistant 4-R1 cells, RA induced a significant PML/RARalpha degradation and yet failed to induce cell maturation. Thus, As2O3- or retinoic acid (RA)-induced PML/RARalpha degradation may be a prerequisite, but is not sufficient for the full differentiative/apoptotic re o e to these drugs. Strikingly, RA-triggered differentiation and apoptosis were greatly accelerated in As2O3-treated 4-AsR cells. The synergism between these two agents in this setting could provide an experimental basis for combined or sequential RA/As2O3 therapies.
Blood 1997 Jul 15;90(2):562-70
Comparative activity of melarsoprol and arsenic trioxide in chronic B-cell leukemia lines.
Konig A, Wrazel L, Warrell RP Jr, Rivi R, Pandolfi , Jakubowski A, Gabrilove JL.
Sloan-Kettering I titute, the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Inorganic arsenic trioxide (As2O3) was recently shown to induce apoptosis in 4 promyelo