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

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.

• Authors: Jian-Nong Li, Dan-Qing Song, Yi-He Lin, Qiong-Ying Hu, Lu Yin, George Bekesi, James F Holland, Jian-Dong Jiang
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 65 Issue 10 Pg. 1691-9 (May 15 2003) ISSN: 0006-2952 [Print] England
• PMID: 12754105 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Animals
• Antineoplastic Agents (pharmacology, 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, prevention & control)
• Mice
• Mice, Nude
• Microtubules (drug effects, metabolism)
• Neoplasm Transplantation
• Phosphorylation
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Tumor Cells, Cultured
• Urea (analogs & derivatives, pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays