Naslov
Different mechanism of anti-leukemic action of arsenic trioxide, an inorganic compound, and S-dimethylarsino-thiosuccinic acid, equally effective but less toxic organic arsenic derivative

Autori
Cheng, X ; Golemović, Mirna ; Oršolić, Nada ; Zingaro, R ; Gao, MZ ; Johansen, M ; Giles, F ; Cortes, J ; Freireich, EJ ; Kantarjian, H ; Verstovšek, Srđan

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Blood, 45th ASH Meeting Abstracts / - , 2003

Skup
45th ASH meeting

Mjesto i datum
San Diego (CA), Sjedinjene Američke Države, 06.12.2003. - 09.12.2003

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Arsenic; Leukemia; Experimental Therapeutics

Sažetak
Newly synthesized organic arsenic derivative S-dimethylarsino-thiosuccinic acid (MER1) has been found to have comparable in vitro antileukemic activity to arsenic trioxide (ATO). MER1, however, was significantly less toxic than ATO in in vitro and in vivo testing (Blood, 110(11), 2002 ; abstract 4614). We have evaluated, and compared to ATO, the activity of MER1 on several cellular mechanisms, reported as targets of ATO. To evaluate the effect of MER1 on PML/RAR (acute promyelocytic leukemia (APL) specific protein) expressing cells, we used the model of U937/PR9 cell line that expresses PML/RAR a in Zn2+ inducible manner. Treatment with MER1 affected equally U937/PR9 cells regardless whether PML/RAR was expressed or not ; ATO, however, killed only cells with expressed protein. NB4 (APL) cell line was used in 2 different tests (CD11b expression by flow cytometry and nitroblue tetrazolium immunohistochemistry staining) to evaluate the effect of MER1 on differentiation/maturation ; unlike ATO, MER1 had no effect. MER1 was able to cause apoptosis in NB4 and HL60 leukemic cells in time- and dose-dependent manner ; this activity was more abundant than in the case of ATO. MER1 caused dissipation of mitochondrial transmembrane potential, cleavage of caspase 9, caspase 3 activation, PARP cleavage, and compromise in cell membrane integrity. However, MER1 treatment also resulted in caspase 8 cleavage, suggesting that MER1 affects both intrinsic and extrinsic apoptotic pathway. MER1 induced apoptosis was not followed by changes in protein levels of bcl-2, bcl-xl and bax, similar to ATO. Flow cytometry evaluation of cell cycle disturbance revealed MER1 to cause G2/M cell cycle arrest, in contrast to ATO that had no effect ; this finding was confirmed by BrdU incorporation method. While further experimentation is needed to fully understand how MER1 kills leukemic cells, our findings do support the hypothesis that organic arsenic derivatives may have a different mode of action than ATO in exerting their anti-leukemia activity.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

POVEZANOST RADA