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Double Blockade of Cell Cycle at G₁-S Transition and M Phase by 3-Iodoacetamido Benzoyl Ethyl Ester, a New Type of Tubulin Ligand¹

Division of Medical Oncology, Mount Sinai School of Medicine-New York University, New York, New York 10029 [J-D. J., Y. W., Y. L., J. R., L-G. W., G. B., J. F. H.]; Department of Cell Biology, Texas Biotechnology Corp., Houston, Texas 77030 [L. D.]; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10164 [Y-H. L., P-S. R.]; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of China [J-D. J., J-N. L.]; Cytoskeleton, Inc. Denver, Colorado 80206 [A. D.]; and VA Medical Center, Baylor College of Medicine, Houston, Texas 77030 [M. M.]

3-Iodoacetamido benzoyl ethyl ester (3-IAABE) is a new compound synthesized in our laboratory. The primary action of 3-IAABE is to inhibit microtubule assembly by interacting with -SH groups on tubulin. In contrast to other known microtubule disrupters, 3-IAABE caused a double blockade in the cell cycle at G₁-S transition and in M phase. The blockade was determined by cell cycle analysis and chromosome distribution. Kinase activities of cyclin E and cyclin-dependent kinase 2 responsible for the G₁-S transition were increased, as were the activities of mitotic cyclin B and cdc2. 3-IAABE treatment also increased p53 expression and dephosphorylated (or activated) retinoblastoma protein. Investigation of the signal transduction pathway showed that 3-IAABE induced bcl-2 phosphorylation, followed by activation of caspase-9, -3, and -6, but not caspase-8. DNA fragmentation factor and poly(ADP-ribose) polymerase, the downstream substrates of caspase-3 and -6, were cleaved after 3 h of exposure to 3-IAABE, followed by DNA fragmentation. Pretreatment of the cells with inhibitors of caspase-9, -3, or -6, respectively, inhibited the cleavage of DNA fragmentation factor and poly(ADP-ribose) polymerase and thus inhibited the onset of apoptosis. 3-IAABE showed antitumor activities in the panel of 60 National Cancer Institute human tumor cell lines with total growth inhibition in the range of 0.22–4.3 µM for solid tumor lines and 0.025–0.22 µM for leukemia/lymphoma cell lines. The 3-IAABU total growth inhibition of phytohemagglutinin-stimulated healthy human lymphocytes was 450-fold greater than that of leukemic cells. 3-IAABE significantly inhibited the growth of human hepatocarcinoma (BEL-7402) in nude mice by 72% in tumor volume, more strongly than did vincristine (43% inhibition). Besides being a novel lead for the design of new anticancer tubulin ligands, the activity of 3-IAABE in the cell cycle may also help us to understand the molecular pharmacology of microtubule-active drugs.

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