02 BOOK OF ABSTRACTS .indd

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