Naslov
S-dimethylarsino-glutathione (SGLU1), an organic arsenic derivative as effective but less toxic than inorganic arsenic trioxide, has different mode of action

Autori
Golemović, Mirna ; Oršolić, Nada ; Zingaro, R ; Gao, MZ ; Cheng, X ; 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
Ostalo

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Arsenic; Leukemia; Experimental Therapeutics

Sažetak
Arsenic trioxide (ATO) induces high rate of clinical remissions in relapsed acute promyelocytic leukemia (APL) patients. Clinical trials of ATO, an inorganic compound, in other diseases are underway ; however, toxicity is a problem. Organic arsenic derivatives have a potential to combine clinical activity that is similar or greater than ATO with significantly lower toxicity. S-dimethylarsino-glutathione (SGLU1), an organic arsenic derivative, is being developed as a new therapy for cancer (ASH 2003 abstract). Because of important differences in their chemical structures, inorganic and organic derivatives possibly utilize different mechanisms to exert their anti-cancer activity. We have compared mechanisms of action of SGLU1 and ATO. ATO exerts its anti-leukemic activity via several mechanisms, including induction of apoptosis, alteration in the production of intracellular reactive oxygen species resulting in the modulation of cellular glutathione redox system (a major factor in cellular defense against toxic compounds), cell differentiation/maturation, and, particularly in APL cells (most sensitive to ATO), degradation of the PML/RARa gene product, the protein that drives the growth of APL cells. It is not clear whether ATO has an effect on cell cycle regulation. SGLU1 is more potent in induction of apoptosis than ATO. Our results show that it induces apoptosis by activating the mitochondrial apoptotic pathway, as it alters mitochondrial membrane potential and cleaves caspase 9, but also by alternate, extrinsic, pathway as it cleaves caspase 8. This results in the induction of caspase 3 activity, cleavage of PARP and binding of annexin V to the cells. SGLU1 induced apoptosis is not followed by changes in protein levels of bcl-2, bcl-xl and bax, similar to ATO. Pretreatment of leukemic cells with BSO (resulting in glutathione depletion) renders them more sensitive to ATO and SGLU1 ; while pretreated with DTT renders the cells less sensitive. This suggests that SGLU1, like ATO, modulates the glutathione redox system in leukemic cells. SGLU1 does not induce cell differentiation/maturation like ATO, as judged by the lack of induction of CD11b maturation marker on the surface of leukemic cells, as well as by negative nitroblue tetrazolium differentiation test. Activity of SGLU1 does not depend on the expression of PML/RAR gene (which renders cells more sensitive to ATO) since SGLU1 is equally potent against leukemic cells with or without PML/RAR gene expression (experiments done using U937/PR9 cell line that expresses PML/RAR in Zn2+ inducible manner). Flow cytometry evaluation of cell cycle revealed SGLU1 to cause G2/M cell cycle arrest, in contrast to ATO that had no effect ; this finding was confirmed by BrdU incorporation method. The results of our studies may help to understand the mechanism of action of SGLU1 as it enters the clinical arena in very near future.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

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