Chemoprevention of colon and small intestinal tumorigenesis in APC min/+ mice by SHetA2 (NSC721689) without toxicity

Doris Mangiaracina Benbrook, Suresh Guruswamy, Yuhong Wang, Zhongjie Sun, Altaf Mohammed, Yuting Zhang, Qian Li, Chinthalapally V. Rao

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 APCmin/+ 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 APCmin/+ 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 APCmin/+ model. SHetA2 modulation of biomarkers in colon polyps identifies potential pharmacodynamic endpoints for SHetA2 clinical trials.

Original languageEnglish (US)
Pages (from-to)908-916
Number of pages9
JournalCancer Prevention Research
Volume6
Issue number9
DOIs
StatePublished - Sep 1 2013

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Chemoprevention
Colon
Carcinogenesis
Intestinal Polyps
Polyps
(((4-nitrophenyl)amino)(2,2,4,4-tetramethyl thiochroman-6-yl)amino) methane-1-thione
Western Blotting
Cyclin D1
Proliferating Cell Nuclear Antigen
Cadherins
Heterografts
Caspase 3
Vascular Endothelial Growth Factor A
Oral Administration
Weight Loss
Colorectal Neoplasms
Biomarkers
Magnetic Resonance Imaging
Clinical Trials
Apoptosis

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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Chemoprevention of colon and small intestinal tumorigenesis in APC min/+ mice by SHetA2 (NSC721689) without toxicity. / Benbrook, Doris Mangiaracina; Guruswamy, Suresh; Wang, Yuhong; Sun, Zhongjie; Mohammed, Altaf; Zhang, Yuting; Li, Qian; Rao, Chinthalapally V.

In: Cancer Prevention Research, Vol. 6, No. 9, 01.09.2013, p. 908-916.

Research output: Contribution to journalArticle

Benbrook, Doris Mangiaracina ; Guruswamy, Suresh ; Wang, Yuhong ; Sun, Zhongjie ; Mohammed, Altaf ; Zhang, Yuting ; Li, Qian ; Rao, Chinthalapally V. / Chemoprevention of colon and small intestinal tumorigenesis in APC min/+ mice by SHetA2 (NSC721689) without toxicity. In: Cancer Prevention Research. 2013 ; Vol. 6, No. 9. pp. 908-916.
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AU - Rao, Chinthalapally V.

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