GS-164, a small synthetic compound, stimulates tubulin polymerization by a similar mechanism to that of Taxol.

Abstract

PURPOSE:

During our search for new microtubule effectors as anticancer agents, we have found that a small synthetic molecule designated GS-164 interferes with the assembly of porcine microtubule proteins and has cytotoxic activity against a wide range of human tumor cell lines. In this study, we investigated mode of action of the compound in comparison with Taxol and colcemid.

METHODS:

To gain an insight into the mode of action of GS-164, we used an in vitro microtubule polymerization assay and a flow-cytometric measurement technique. Microtubule organization and the level of tubulin polymerization in HeLa cells were also examined by immunofluorescence microscopy and cytoskeletal protein analyses, respectively.

RESULTS:

GS-164 stimulated assembly of microtubule proteins in vitro in a concentration-dependent and a GTP-independent manner. Furthermore, as with Taxol, the microtubule polymerization induced by GS-164 was antagonized by podophyllotoxin, a tubulin polymerization inhibitor, and microtubules formed by GS-164 were resistant to disassembly by calcium or low temperatures. GS-164 in the micromolar range arrested the cell cycle of HeLa cells in the mitotic phase leading to cell death. GS-164 also increased the amounts of cellular microtubules in HeLa cells, resulting in the formation of microtubule bundles.

CONCLUSION:

These results indicate that GS-164 stimulates microtubule assembly by a similar mechanism to that of Taxol. A comparative conformational analysis of GS-164 and Taxol suggested that the structure of the former mimics the minimum essential sites of Taxol required to exert the Taxol-like activities described above. Although the cytotoxicity of GS-164 against human tumor cells was 1000-fold lower than that of Taxol and GS-164 was one-tenth as active as Taxol in vitro, these findings pave the way for synthesizing clinically useful anticancer agents using GS-164 as a lead compound.

• Authors: Y Shintani, T Tanaka, Y Nozaki
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 40 Issue 6 Pg. 513-20 ( 1997) ISSN: 0344-5704 [Print] Germany
• PMID: 9332466 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Biopolymers
• Bridged Bicyclo Compounds, Heterocyclic
• GS 164
• Oxazoles
• Tubulin
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Biopolymers
• Bridged Bicyclo Compounds, Heterocyclic (chemistry, pharmacology)
• Cell Cycle (drug effects)
• HeLa Cells
• Humans
• Oxazoles (chemistry, pharmacology)
• Paclitaxel (chemistry, pharmacology)
• Structure-Activity Relationship
• Swine
• Tubulin (chemistry)