title: NPI-2358 is a tubulin-depolymerizing agent: in-vitro evidence for activity as a tumor vascular-disrupting agent.
abstract: 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.
authors.affiliation: Nereus Pharmaceuticals, San Diego, California 92121, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Nicholson
authors.forename: G Kenneth
authors.initials: GK
authors.lastname: Lloyd
authors.forename: Brian R
authors.initials: BR
authors.lastname: Miller
authors.forename: Michael A
authors.initials: MA
authors.lastname: Palladino
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kiso
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Saskia T C
authors.initials: ST
authors.lastname: Neuteboom
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003078:Colchicine / Q000494:pharmacology; D003911:Dextrans / Q000378:metabolism; D054659:Diketopiperazines; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects*; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000378:metabolism; D018922:HL-60 Cells; D019073:HT29 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D019169:Jurkat Cells; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D009369:Neoplasms / Q000098:blood supply; D010879:Piperazines / Q000494:pharmacology*; D013267:Stilbenes / Q000494:pharmacology; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism*; D014750:Vincristine / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D003911:Dextrans; D054659:Diketopiperazines; D007093:Imidazoles; C514351:NPI 2358; D010879:Piperazines; D013267:Stilbenes; D014404:Tubulin; C015219:fluorescein isothiocyanate dextran; D014750:Vincristine; D016650:Fluorescein-5-isothiocyanate; C058728:fosbretabulin; D003078:Colchicine