Chemoprevention of Colon and Small Intestinal Tumorigenesis in APCmin/+ 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 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 demonstrated reduced levels of cyclin D1 and proliferating cell nuclear antigen (PCNA) in both SHetA2 treatment groups. Western blot analysis also demonstrated SHetA2 induction of E-cadherin, Bax and caspase 3 cleavage along with reduction in Bcl-2, cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (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.

Fasting protects against the side effects of irinotecan but preserves its anti-tumor effect in Apc15lox mutant mice

“…The small molecule compound SHetA2 significantly reduced incidence and size of intestinal polyps, both in males and females. 22 In contrast, in a dietary study using the retinoidx-receptor agonist bexarotene, a greater reduction of intestinal tumors was found in male mice compared to female mice. 31 The observation that we did not find differences between genders could be attributed to the fact that we administered a flat-fixed dose to all mice, based on the bodyweight of male mice.…”

“…In this regard, the Apc Min/C mouse model is one of the most studied models of intestinal tumorigenesis in which tumor growth is suppressed by different anticancer agents. 22,23 In the present study we used fasting as a pre-conditioning method to protect against the side-effects of irinotecan. Previously, we reported that 3-days of fasting increases stress-resistance, including upregulation of the Nrf2 pathway, which is involved in the protection against oxidative stress.…”

Nrf2-Dependent Suppression of Azoxymethane/Dextran Sulfate Sodium–Induced Colon Carcinogenesis by the Cinnamon-Derived Dietary Factor Cinnamaldehyde

“…5C), and pronounced suppression of the AOM/DSS-induced inflammatory enzyme cyclooxygenase 2 (COX-2; Fig. 5D), important key factors in CRC progression, was observed in response to CA supplementation (5, 43). In addition, AOM/DSS-induced oxidative damage targeting nuclear DNA was attenuated by CA supplementation as indicated by reduced staining for 8-oxodG, an effect that was observed only in the ‘CA11’ supplementation group (Fig.…”

American ginseng significantly reduced the progression of high-fat-diet-enhanced colon carcinogenesis in Apcmice

“…Published studies suggested that ginseng not only has cancer prevention potential [4,5,11,12] , but also has anti-inflammatory effects [13,14] . Various data suggest that ginseng reduces inflammation and suppresses colitis by restoring gut homeostasis [15–17] , and this anti-inflammatory activity likely plays a critical role in cancer prevention and treatment [18–20] .…”