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Triarylethylenes and related derivatives as novel<br />
antileukemic agents<br />
E. Levy 1 , Z. Rappaport 2 , D. Arad 3 , O. Shpilberg 4 , I. Levy 1 , I. Nathan 1<br />
1<br />
Institute of Hematology, Soroka University Medical Center and Ben-Gurion University<br />
of the Negev, Beer Sheva, Israel; 2 The Hebrew University of Jerusalem, Department of<br />
Organic Chemistry, Israel; 3 NLC Pharma; 4 Institute of Hematology, Medical Center Rabin,<br />
Campus Belinson, Petach Tikva, Israel<br />
In our search for novel derivatives whose structure consists of an arylethylene<br />
moiety which can serve as anticancer agents, we found two groups of compounds<br />
that have an antitumoral effect that is stronger than that of the known derivatives,<br />
namely, substituted 9- arylideneanthrones and members of the triarylvinylic systems.<br />
Newly synthesized compounds based on a structure-function relationship and drugs<br />
commonly used in clinics were studied for their antitumoral efficacy and mode of<br />
action. Leukemia cell lines and primary cells obtained from chronic lymphoblastic<br />
leukemia (CLL) and acute myeloid leukemia (AML) patients were used in the study.<br />
Various substituted derivatives displayed marked antitumoral activity and exhibited<br />
a high degree of selectivity for leukemic cells and low toxicity against normal blood<br />
cells and hematopoietic progenitors. Both groups of compounds studied were found<br />
to act through different signaling pathways which have not yet been fully elucidated.<br />
However, both pathways involve the production of reactive oxygen species (ROS)<br />
that leads to cell death cell with apoptotic characteristics. Specific translocation of<br />
protein kinase C-ε (PKC-ε) from the cytosol to the plasma membrane was observed,<br />
indicating that PKC-ε is activated and takes place prior to ROS formation. PKC<br />
activation is an important step in cell death induced by members of the triarylvinylic<br />
systems. In order to identify the enzyme/system responsible for the formation of<br />
18l5<br />
ROS, we used various inhibitors of candidate enzymes. It was found that MK886,<br />
an inhibitor of lipoxygenase, was able to inhibit apoptosis induction by members<br />
of the triarylvinylic systems but not that of the substituted 9- arylideneanthrones<br />
group. The mitochondrial uncoupler CiCCP inhibited the activity of substituted<br />
9- arylideneanthrones, suggesting that the mitochondria is involved in this process.<br />
Studies with isolated rat liver mitochondria showed protection against Ca 2+ induced<br />
swelling, which indicated that these compounds have an effect on mitochondrial<br />
permeability transition. The results from ex-vivo experiments with cells obtained<br />
from CLL and AML patients showed that they were sensitive to the action of<br />
these two groups of compounds. On the basis of these results, we conducted a<br />
phase I-II clinical trial to evaluate the potential therapeutic effect of triarylvinylic<br />
systems in advanced and refractory CLL and AML patients. The findings from these<br />
studies suggest that the derivatives of these compounds are potential agents for<br />
the treatment of cancer and for the identification of cellular targets responsible for<br />
cancer eradication.