Inhibition of microtubule polymerization by 3-bromopropionylamino benzoylurea (JIMB01), a new cancericidal tubulin ligand

Biochem Pharmacol. 2003 May 15;65(10):1691-9. doi: 10.1016/s0006-2952(03)00101-1.

Abstract

3-Bromopropionylamino benzoylurea (JIMB01) is a small molecular weight compound (MW 313) that has been synthesized in our laboratory. This compound showed antiproliferative activities in a panel of thirteen human tumor cell lines with IC(50) values in the range of 0.25 to 0.51 micro M for leukemia and lymphoma cell lines and 0.33 to 9.26 micro M for solid tumor cell lines. The primary action of JIMB01 is to inhibit microtubule polymerization but not depolymerization. A 4 micro M concentration of the compound caused a complete inhibition of microtubule assembly in a cell-free reaction. An increase in the number of human hepatocarcinoma cells blocked in the M-phase was detected 12hr after exposure to JIMB01. The kinase activity of cyclin B1, which is responsible for the G(2)/M transition, was increased accordingly. Bcl-2 phosphorylation became visible, in a western blot, within 6hr in hepatocarcinoma cells treated with JIMB01 at 0.8 micro M or higher. JIMB01-induced apoptosis in liver cancer cells was confirmed by morphological methods, flow cytometry, as well as DNA gel electrophoresis, which clearly demonstrated DNA degradation in the form of a multiple-unit DNA ladder. Furthermore, in vivo experiments using nude mice showed that intraperitoneal injection of JIMB01 at 15mg/kg (with seven injections at 4-day intervals) significantly inhibited the growth of a human hepatocarcinoma (BEL-7402) by 66% in tumor volume (P=0.01), at least compatible to the inhibition by vincristine (43% inhibition), indicating good bioavailability of the compound in the circulation. Side-effects of the compound were not observed, and the body weight of the treated mice remained stable during the 4-week treatment. Since JIMB01 is a small compound, targets a specific molecule in tumor cells, and has promising activity against human hepatocarcinoma in vivo, we believe JIMB01 merits consideration for further investigation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis*
  • Carcinoma, Hepatocellular / pathology
  • Cell Cycle / drug effects
  • Cyclin B / metabolism
  • Cyclin B1
  • Disease Models, Animal
  • Drug Screening Assays, Antitumor
  • Humans
  • Liver Neoplasms / pathology
  • Liver Neoplasms / prevention & control
  • Mice
  • Mice, Nude
  • Microtubules / drug effects*
  • Microtubules / metabolism
  • Neoplasm Transplantation
  • Phosphorylation
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Tumor Cells, Cultured
  • Urea / analogs & derivatives
  • Urea / pharmacology*
  • Urea / therapeutic use
  • Xenograft Model Antitumor Assays

Substances

  • 3-bromopropionylamino benzoylurea
  • Antineoplastic Agents
  • CCNB1 protein, human
  • Ccnb1 protein, mouse
  • Cyclin B
  • Cyclin B1
  • Proto-Oncogene Proteins c-bcl-2
  • Urea