Chemoprevention of Familial Adenomatous Polyposis by Bromo-noscapine (EM011) in the ApcMin/+ Mouse Model

• Type of Material: Article
• Authors: Shiwang Li, Emory University; Amr M. Ghaleb, Emory University; Jing He, Emory University; Usha Bughani, Emory University; Agnieszka B. Bialkowska, Emory University; Vincent W. Yang, Emory University; Harish C Joshi, Emory University
• Language: English
• Date: 2012-09-15
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 UICC.
• Final Published Version (URL): http://dx.doi.org/10.1002/ijc.27344
• Title of Journal or Parent Work: International Journal of Cancer
• ISSN: 0020-7136
• Volume: 131
• Issue: 6
• Start Page: 1435
• End Page: 1444
• Grant/Funding Information: Grant support: NIH grants CA-095317-01A2 (H.C. Joshi), DK52230, DK64399, and CA84197 (V.W. Yang).
• Keywords: PERTURB MITOSIS; STABILIZES BETA-CATENIN; noscapine; EM011; familial adenomatous polyposis; COLON-CANCER; TUMOR-SUPPRESSOR; MICROTUBULE DYNAMICS; ss-catenin; Life Sciences & Biomedicine; DEPENDENT PROTEIN-KINASE; Oncology; CELL-PROLIFERATION; colon cancer; Science & Technology; APC; UNDERGO APOPTOSIS; bromo noscapine; LIVING CELLS
• Research Categories: Health Sciences, Oncology; Biology, Cell

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 G2/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 ApcMin/+ mice as compared to their sham-treated control littermates. The remaining polyps in the EM011 treated group of ApcMin/+ 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.