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Author Notes:

Correspondence should be addressed to Harish C. Joshi or Shiwang Li, Department ofCell Biology, Emory University School of Medicine, 455 WhiteheadBiomedical Research Building, 615 Michael Street, Atlanta, GA30322, E-mail: joshi@cellbio.emory.edu or wang9377@gmail.com.

We thank Rekha Pai, Bing Yu, Mandayam O. Nandan, the membersof the Joshi and the other members of the Yang and Joshi laboratories for ex-perimental assistance.

We wish to thank Dr. Meenakshi Gupta, pathologist for evaluating animal tissue sections in a blinded manner.

No potential conflicts of interest were disclosed.

Subjects:

Research Funding:

Grant support: NIH grants CA-095317-01A2 (H.C. Joshi), DK52230, DK64399, and CA84197 (V.W. Yang).

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

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

Journal Title:

International Journal of Cancer

Volume:

Volume 131, Number 6

Publisher:

, Pages 1435-1444

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2011 UICC.

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