[Show abstract][Hide abstract] ABSTRACT: We observed AML cell lines vary in their sensitivity to induction of apoptosis by troglitazone (TG), which induces apoptosis through the generation of intracellular reactive oxygen species (ROS). TG-resistant cell lines had increased abundance of ARNT transcripts and protein. Expression of ARNT in TG-sensitive cells made these cells resistant to both TG and daunorubicin. ARNT-expressing cells had increased expression of SOD2 and Nrf2 transcripts and elevated intracellular GSH concentration. Our results indicate that ARNT expression in AML cells augments antioxidant response and confers resistance to ROS inducers. This suggests ARNT may modulate ROS signaling and drug response in AML.
No preview · Article · Oct 2013 · Leukemia research
[Show abstract][Hide abstract] ABSTRACT: We have previously shown that troglitazone (TG) induces apoptosis in acute myelogenous leukaemia (AML) cell lines. Here we show that normal bone marrow and mobilized peripheral blood progenitors are highly resistant to TG at concentrations up to 100 microM, while primary cultures of AML bone marrow show significant decline in viability at >7.5 microM TG. The combination of standard cytotoxic agents (daunorubicin, etoposide, and cytarabine) with TG is synergistic in six AML cell lines, with the strongest synergy being exhibited when cells are pretreated with TG for 24h prior to addition of the cytotoxic agent. Significant declines in IC(50) for the cytotoxic agents are seen at nanomolar concentrations of TG. The in vitro synergy between TG and the cytotoxic drugs used in AML therapy provides a basis for in vivo evaluation of these combinations.
No preview · Article · Dec 2006 · Leukemia Research