title: Chemoprevention of colon and small intestinal tumorigenesis in APC(min/+) mice by SHetA2 (NSC721689) without toxicity.
abstract: The occurrence of intestinal polyps in people at high risk for developing colorectal cancer provides an opportunity to test the efficacy of chemoprevention agents. In this situation of treating otherwise healthy people, the potential for toxicity must be minimal. The small-molecule flexible heteroarotinoid (Flex-Het), called SHetA2, has chemoprevention activity in organotypic cultures in vitro and lack of toxicity at doses capable of inhibiting xenograft tumor growth in vivo. The objective of this study was to evaluate SHetA2 chemoprevention activity and toxicity in the APC(min/+) murine model. Oral administration of SHetA2 at 30 and 60 mg/kg five days per week for 12 weeks significantly reduced development of intestinal polyps by 40% to 60% depending on the dose and sex of the treatment group. Immunohistochemical and Western blot analysis of polyps showed reduced levels of cyclin D1 and proliferating cell nuclear antigen in both SHetA2 treatment groups. Western blot analysis also showed SHetA2 induction of E-cadherin, Bax, and caspase-3 cleavage along with reduction in Bcl-2, COX-2, and VEGF, consistent with SHetA2 regulation of apoptosis, inflammation, and angiogenesis. Neither dose caused weight loss nor gross toxicity in APC(min/+) or wild-type littermates. Magnetic resonance imaging (MRI) of cardiac function showed no evidence of SHetA2 toxicity. SHetA2 did not alter left ventricular wall thickness. In summary, SHetA2 exerts chemoprevention activity without overt or cardiac toxicity in the APC(min/+) model. SHetA2 modulation of biomarkers in colon polyps identifies potential pharmacodynamic endpoints for SHetA2 clinical trials.
authors.affiliation: Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Room 1374, Oklahoma City, OK 73104, USA. Doris-Benbrook@ouhsc.edu
authors.forename: Doris Mangiaracina
authors.initials: DM
authors.lastname: Benbrook
authors.forename: Suresh
authors.initials: S
authors.lastname: Guruswamy
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhongjie
authors.initials: Z
authors.lastname: Sun
authors.forename: Altaf
authors.initials: A
authors.lastname: Mohammed
authors.forename: Yuting
authors.initials: Y
authors.lastname: Zhang
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Chinthalapally V
authors.initials: CV
authors.lastname: Rao
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000284:Administration, Oral; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000473:pathology; D002839:Chromans / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000517:prevention & control*; D005260:Female; D006331:Heart Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D007249:Inflammation / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D007414:Intestinal Neoplasms / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D007417:Intestinal Polyps / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D007421:Intestine, Small / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D013871:Thiones / Q000627:therapeutic use*
chemical_list: C476105:(((4-nitrophenyl)amino)(2,2,4,4-tetramethyl thiochroman-6-yl)amino) methane-1-thione; D025601:Adenomatous Polyposis Coli Protein; D015415:Biomarkers; D002839:Chromans; D013871:Thiones