Protuboxepin A, a marine fungal metabolite, inducing metaphase arrest and chromosomal misalignment in tumor cells

Bioorg Med Chem. 2012 Jun 15;20(12):3799-806. doi: 10.1016/j.bmc.2012.04.039. Epub 2012 Apr 27.

Abstract

Previously we reported the identification of a new oxepin-containing diketopiperazine-type marine fungal metabolite, named protuboxepin A which showed antiproliferative activity in several cancer cell lines. In this study we elucidated the mechanism by which protuboxepin A induces cancer cell growth inhibition. Here we report that protuboxepin A induced round-up morphology, M phase arrest, and an increase in the subG(1) population in tumor cells in a dose dependent manner. Our investigations revealed that protuboxepin A directly binds to α,β-tubulin and stabilizes tubulin polymerization thus disrupting microtubule dynamics. This disruption leads to chromosome misalignment and metaphase arrest which induces apoptosis in cancer. Overall, we identified protuboxepin A as a microtubule-stabilizing agent which has a distinctly different chemical structure from previously reported microtubule inhibitors. These results indicate that protuboxepin A has a potential of being a new and effective anti-cancer drug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Aquatic Organisms / microbiology
  • Aspergillus / metabolism*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chromosome Pairing / drug effects*
  • Drug Screening Assays, Antitumor
  • Humans
  • Metaphase / drug effects*
  • Microtubules / drug effects
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / pathology*
  • Oxepins / chemistry
  • Oxepins / metabolism
  • Oxepins / pharmacology*
  • Structure-Activity Relationship
  • Tubulin / metabolism

Substances

  • Antineoplastic Agents
  • Oxepins
  • Tubulin
  • protuboxepin A