title: Stilbene 5c, a microtubule poison with vascular disrupting properties that induces multiple modes of growth arrest and cell death.
abstract: The stilbene derivative, cis-3,4',5-trimethoxy-3'-aminostilbene (stilbene 5c), is a potentially potent antitumor agent that acts via binding to the colchicine-binding site in tubulin. The current studies were designed to investigate the effectiveness of stilbene 5c against the HCT-116 human colon cancer cell line and B16/F10 melanoma cells as well as human endothelial cell tube formation and tumor perfusion. Stilbene 5c produced a time-dependent decrease in cell viability in both cell lines and the capacity of the cells to proliferate was not restored upon removal of the drug. Treatment with stilbene 5c also promoted both senescence and autophagy in both cell lines. TUNEL and annexin 5 staining indicated that apoptosis also occurs in stilbene 5c-treated HCT-116 cells, but not in B16/F10 melanoma cells. DAPI staining revealed morphological changes in the cell nuclei (binucleated and micronucleated cells) indicative of mitotic catastrophe in HCT-116 cells but not in the B16/F10 melanoma cells. p53-null HCT-116 cells demonstrated a similar growth arrest/cell death response to stilbene as p53-wild type HCT-116 cells. Stilbene 5c also completely inhibited human endothelial cell tube formation on Matrigel, consistent with potential anti-angiogenic actions. Using a new method developed for monitoring the pharmacodynamic effects of stilbene 5c in vivo, we found that a single injection of stilbene 5c reduced tumor perfusion by 65% at 4h, returning to baseline by 24h, while subsequent daily injections of stilbene 5c produced progressively larger reductions and smaller rebounds. This work indicates that stilbene 5c could potentially be effective against melanoma and colon cancer through the promotion of multiple modes of growth arrest and cell death coupled with anti-angiogenic and antivascular actions.
authors.affiliation: Departments of Pharmacology and Toxicology and Medicine and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Alotaibi
authors.forename: B
authors.initials: B
authors.lastname: Asnake
authors.forename: Xu
authors.initials: X
authors.lastname: Di
authors.forename: M J
authors.initials: MJ
authors.lastname: Beckman
authors.forename: D
authors.initials: D
authors.lastname: Durrant
authors.forename: D
authors.initials: D
authors.lastname: Simoni
authors.forename: R
authors.initials: R
authors.lastname: Baruchello
authors.forename: R M
authors.initials: RM
authors.lastname: Lee
authors.forename: E L
authors.initials: EL
authors.lastname: Schwartz
authors.forename: D A
authors.initials: DA
authors.lastname: Gewirtz
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000473:pathology; D006801:Humans; D008545:Melanoma / Q000473:pathology; D008870:Microtubules / Q000187:drug effects*; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D013267:Stilbenes; C529077:cis-3,4',5-trimethoxy-3'-aminostilbene
keywords: Angiogenic; Autophagy; Microtubules; Senescence; Vascular disrupting