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

• 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
• Journal Title: International Journal of Cancer
• Volume: Volume 131, Number 6
• Publisher: Wiley: 12 months | 2012-09-15, Pages 1435-1444
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1002/ijc.27344
• Subjects: Biology, Cell; Health Sciences, Oncology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Oncology; familial adenomatous polyposis; colon cancer; bromo noscapine; EM011; noscapine; ss-catenin; DEPENDENT PROTEIN-KINASE; STABILIZES BETA-CATENIN; COLON-CANCER; CELL-PROLIFERATION; MICROTUBULE DYNAMICS; UNDERGO APOPTOSIS; TUMOR-SUPPRESSOR; PERTURB MITOSIS; LIVING CELLS; APC

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.