title: Chemoprevention of familial adenomatous polyposis by bromo-noscapine (EM011) in the Apc(Min/+)  mouse model.
abstract: Germline mutation of the tumor suppressor gene, adenomatous polyposis coli (APC), is responsible for familial adenomatous polyposis (FAP) with nearly 100% risk for colon cancer at an early age. Although FAP is involved in only 1% of all colon cancer cases, over 80% of sporadic cancers harbor somatic mutations of APC. We show here that bromo-noscapine (EM011), a rationally designed synthetic derivative of a natural nontoxic tubulin-binding alkaloid-noscapine, that reduces the dynamics of microtubules, causes a reversible G(2) /M arrest in wild type murine embryonic fibroblasts (MEFs), but an aberrant exit from a brief mitotic block, followed by apoptosis in MEFs after APC deletion with small interfering RNA. Furthermore, both β-catenin levels and activity fell to half the original levels with a concomitant reduction of cell proliferation-inducing cyclin D1, c-Myc, and induction of cytostatic protein p21 before caspase-3 activation. Additionally, we show a statistically significant reduction in the number of newly emerging intestinal polyps (to 35% compared with untreated mice) as well as the mean size of polyps (to 42% compared with untreated mice) in EM011-treated Apc(Min/+)  mice as compared to their sham-treated control littermates. The remaining polyps in the EM011 treated group of Apc(Min/+)  mice showed evidence of elevated apoptosis as revealed by immunohistochemistry. We failed to detect any evidence of histopathological and hematological toxicities following EM011 treatment. Taken together, our data are persuasive that a clinical trial of EM011 is possible for the prevention/amelioration of polyposis in FAP patients.
authors: Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA. wang9377@gmail.com
authors: Shiwang
authors: S
authors: Li
authors: Amr M
authors: AM
authors: Ghaleb
authors: Jing
authors: J
authors: He
authors: Usha
authors: U
authors: Bughani
authors: Agnieszka B
authors: AB
authors: Bialkowska
authors: Vincent W
authors: VW
authors: Yang
authors: Harish C
authors: HC
authors: Joshi
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000517:prevention & control*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000502:physiology; D004149:Dioxoles / Q000627:therapeutic use*; D005260:Female; D017491:Genes, APC / Q000502:physiology*; D045325:HCT116 Cells; D006801:Humans; D007546:Isoquinolines / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D000073940:Transcription Factor 4; D051176:beta Catenin / Q000502:physiology
chemical_list: D016588:Anticarcinogenic Agents; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004149:Dioxoles; C510553:EM011 compound; D007546:Isoquinolines; C090743:Tcf4 protein, mouse; D000073940:Transcription Factor 4; D051176:beta Catenin