Double blockade of cell cycle at G1-S transition and M phase by 3-iodoacetamido benzoyl ethyl ester, a new type of tubulin ligand

Jian Dong Jiang, Larry Denner, Yi He Ling, Jian Nong Li, Ashley Davis, Yue Wang, Yan Li, Julia Roboz, Long Gui Wang, Roman Perez-Soler, Marco Marcelli, George Bekesi, James F. Holland

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)6080-6088
Number of pages9
JournalCancer Research
Volume62
Issue number21
StatePublished - Nov 1 2002
Externally publishedYes

Fingerprint

Tubulin
S Phase
Cell Division
Cell Cycle
Ligands
DNA Fragmentation
Microtubules
Caspase 3
Poly(ADP-ribose) Polymerases
Caspase 9
Growth
Caspase 6
Cyclin-Dependent Kinase 2
Cyclin B
3-iodoacetamido benzoyl ethyl ester
Cyclin E
Retinoblastoma Protein
National Cancer Institute (U.S.)
Caspase 8
Vincristine

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Jiang, J. D., Denner, L., Ling, Y. H., Li, J. N., Davis, A., Wang, Y., ... Holland, J. F. (2002). Double blockade of cell cycle at G1-S transition and M phase by 3-iodoacetamido benzoyl ethyl ester, a new type of tubulin ligand. Cancer Research, 62(21), 6080-6088.

Double blockade of cell cycle at G1-S transition and M phase by 3-iodoacetamido benzoyl ethyl ester, a new type of tubulin ligand. / Jiang, Jian Dong; Denner, Larry; Ling, Yi He; Li, Jian Nong; Davis, Ashley; Wang, Yue; Li, Yan; Roboz, Julia; Wang, Long Gui; Perez-Soler, Roman; Marcelli, Marco; Bekesi, George; Holland, James F.

In: Cancer Research, Vol. 62, No. 21, 01.11.2002, p. 6080-6088.

Research output: Contribution to journalArticle

Jiang, JD, Denner, L, Ling, YH, Li, JN, Davis, A, Wang, Y, Li, Y, Roboz, J, Wang, LG, Perez-Soler, R, Marcelli, M, Bekesi, G & Holland, JF 2002, 'Double blockade of cell cycle at G1-S transition and M phase by 3-iodoacetamido benzoyl ethyl ester, a new type of tubulin ligand', Cancer Research, vol. 62, no. 21, pp. 6080-6088.
Jiang, Jian Dong ; Denner, Larry ; Ling, Yi He ; Li, Jian Nong ; Davis, Ashley ; Wang, Yue ; Li, Yan ; Roboz, Julia ; Wang, Long Gui ; Perez-Soler, Roman ; Marcelli, Marco ; Bekesi, George ; Holland, James F. / Double blockade of cell cycle at G1-S transition and M phase by 3-iodoacetamido benzoyl ethyl ester, a new type of tubulin ligand. In: Cancer Research. 2002 ; Vol. 62, No. 21. pp. 6080-6088.
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abstract = "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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AU - Ling, Yi He

AU - Li, Jian Nong

AU - Davis, Ashley

AU - Wang, Yue

AU - Li, Yan

AU - Roboz, Julia

AU - Wang, Long Gui

AU - Perez-Soler, Roman

AU - Marcelli, Marco

AU - Bekesi, George

AU - Holland, James F.

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N2 - 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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