Abstract
Despite high cure rates in pediatric patients with acute leukemia, development of resistance limits the efficacy of antileukemic therapy. Tris(1,10-phenanthroline)tris(thiocyanato-κN)lanthanum(III) (KP772) is an experimental antineoplastic agent to which multidrug-resistant cell models have shown hypersensitivity. Antiproliferative and apoptotic activities of KP772 were tested in leukemia, lymphoma and solid tumor cell lines as well as primary leukemia cells (isolated from the bone marrow of a child with acute myeloid leukemia (AML). The ability to overcome drug resistances was investigated in doxorubicin- and vincristine-resistant cell lines. Real-time PCR was used to gain insight into the mechanism of apoptosis induction. KP772 inhibited proliferation and induced apoptosis in various leukemia and lymphoma cell lines in a concentration-dependent manner (LC50 = 1–2.5 µM). Primary AML cells were also sensitive to KP772, whereas daunorubicin showed no significant effect. KP772 induces apoptosis independently of Bcl-2, Smac, and the CD95 receptor and is also effective in caspase 3-deficient MCF7 cells, indicating that apoptosis is partly triggered independently of caspase 3. mRNA expression profiling revealed an upregulation of the BH3-only Bcl-2 protein Harakiri in the course of KP772-induced apoptosis. Remarkably, KP772 overcame drug resistance to doxorubicin and vincristine in vitro, and the apoptotic effect in resistant cells was even superior to that in non-resistant parental cells. In combination with vincristine, doxorubicin and cytarabine, synergistic effects were observed in BJAB cells. The cytotoxic potency in vitro/ex vivo and the remarkable ability to overcome multidrug resistance propose KP772 as a promising candidate drug for antileukemic therapy, especially of drug-refractory malignancies.Graphic abstract
Highlights
IntroductionGreat efforts were made to improve the outcome of patients with acute leukemia
In recent decades, great efforts were made to improve the outcome of patients with acute leukemia
Inhibition appeared at a concentration of 0.6 μM, was 40% at 0.8 μM, and the effect increased to 70% inhibition at 1.2 μM in BJAB cells (Fig. 2)
Summary
Great efforts were made to improve the outcome of patients with acute leukemia. Most children suffering from acute leukemia can be cured by standardized combination chemotherapies. The development of drug resistances limits the efficiency of therapy. Apoptosis is a form of programmed cell death, which is essential in various biological settings, such as different levels of embryonic development, tissue homeostasis, development of the nervous system and the immune system, and in chemically induced cell death [1]. Two main pathways lead to apoptosis, the extrinsic (death receptormediated) and the intrinsic (mitochondrial) pathway. Defects in apoptotic pathways are involved in tumorigenesis, and inactivation of apoptotic signaling is central in the development of drug resistance [1]
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