NPI-2358 is a tubulin-depolymerizing agent: in-vitro evidence for activity as a tumor vascular-disrupting agent

Anticancer Drugs. 2006 Jan;17(1):25-31. doi: 10.1097/01.cad.0000182745.01612.8a.


The diketopiperazine NPI-2358 is a synthetic analog of NPI-2350, a natural product isolated from Aspergillus sp., which depolymerizes microtubules in A549 human lung carcinoma cells. Although structurally different from the colchicine-binding site agents reported to date, NPI-2358 binds to the colchicine-binding site of tubulin. NPI-2358 has potent in-vitro anti-tumor activity against various human tumor cell lines and maintains activity against tumor cell lines with various multidrug-resistant (MDR) profiles. In addition, when evaluated in proliferating human umbilical vein endothelial cells (HUVECs), concentrations as low as 10 nmol/l NPI-2358 induced tubulin depolymerization within 30 min. Furthermore, NPI-2358 dose dependently increases HUVEC monolayer permeability--an in-vitro model of tumor vascular collapse. NPI-2358 was compared with three tubulin-depolymerizing agents with vascular-disrupting activity: colchicine, vincristine and combretastatin A-4 (CA4). Results showed that the activity of NPI-2358 in HUVECs was more potent than either colchicine or vincristine; the profile of CA4 approached that of NPI-2358. Altogether, our data show that NPI-2358 is a potent anti-tumor agent which is active in MDR tumor cell lines, and is able to rapidly induce tubulin depolymerization and monolayer permeability in HUVECs. These data warrant further evaluation of NPI-2358 as a vascular-disrupting agent in vivo. Currently, NPI-2358 is in preclinical development for the treatment of cancer.

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Cell Membrane Permeability / drug effects
  • Cell Survival / drug effects
  • Colchicine / pharmacology
  • Dextrans / metabolism
  • Diketopiperazines
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Endothelium, Vascular / drug effects*
  • Fluorescein-5-isothiocyanate / analogs & derivatives
  • Fluorescein-5-isothiocyanate / metabolism
  • HL-60 Cells
  • HT29 Cells
  • Humans
  • Imidazoles / pharmacology*
  • Inhibitory Concentration 50
  • Jurkat Cells
  • Microtubules / drug effects
  • Microtubules / metabolism
  • Neoplasms / blood supply
  • Piperazines / pharmacology*
  • Stilbenes / pharmacology
  • Time Factors
  • Tubulin / metabolism*
  • Vincristine / pharmacology


  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Dextrans
  • Diketopiperazines
  • Imidazoles
  • NPI 2358
  • Piperazines
  • Stilbenes
  • Tubulin
  • fluorescein isothiocyanate dextran
  • Vincristine
  • Fluorescein-5-isothiocyanate
  • fosbretabulin
  • Colchicine