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Published on: October 6, 2014
Oral administration of TRAIL-inducing small molecule ONC201/TIC10 prevents intestinal polyposis in the Apc min/+
Venkateshwar Madka1, Arielle De La Cruz2,3,4, Gopal Pathuri1
1Center for Cancer Prevention and Drug Development, Hem-Onc Section, Department of Medicine, Stephenson Cancer Center, University of Oklahoma Health Sciences Center Oklahoma City, OK, USA.
Abstract:
Colorectal cancer (CRC) incidence is rising globally. Hence, preventing this disease is a high priority. With this aim, we determined the CRC prevention potential of the TRAIL-inducing small molecule ONC201/TIC10 using a preclinical model representing high-risk familial adenomatous polyposis (FAP) patients, Apc min/+ mice. Prior to the efficacy study, optimal and non-toxic doses of ONC201 were determined by testing five different doses of ONC201 (0-100 mg/kg body weight (BW); twice weekly by oral gavage) in C57BL/6J mice (n=6/group) for 6 weeks. BW gain, organ weights and histopathology, blood profiling, and the plasma liver enzyme profile suggested no toxicities of ONC201 at doses up to 100 mg/kg BW. For efficacy determination, beginning at six weeks of age, groups of Apc min/+ male and female mice (n≥20) treated with colon carcinogen azoxymethane (AOM) (AOM-Apc min/+) were administered ONC201 (0, 25, and 50 mg/kg BW) as above up to 20 weeks of age. At termination, efficacy was determined by comparing the incidence and multiplicity of intestinal tumors between vehicle- and drug-treated groups. ONC201 showed a strong suppressive effect against the development of both large and small intestinal tumors in male and female mice. Apc min/+ mice treated with ONC201 (50 mg/kg BW) showed >50% less colonic tumor incidence (P<0.0002) than controls. Colonic tumor multiplicity was also significantly reduced by 68% in male mice (0.44 ± 0.11 in treated vs. 1.4 ± 0.14 in controls; P<0.0001) and by 75% in female mice (0.30 ± 0.10 in treated vs. 1.19 ± 0.19 in controls; P<0.0003) with ONC201 treatment (50 mg/kg BW). Small intestinal polyps were reduced by 68% in male mice (11.40 ± 1.19 in treated vs. 36.08 ± 2.62 in controls; P<0.0001) and female mice (9.65 ± 1.15 in treated vs. 29.24 ± 2.51 in controls; P<0.0001). Molecular analysis of the tumors suggested an increase in TRAIL, DR5, cleaved caspases 3/7/8, Fas-associated death domain protein (FADD), and p21 (WAF1) in response to drug treatment. Serum analysis indicated a decrease in pro-inflammatory serum biomarkers, such as IL1β, IL6, TNFα, G-CSF, and GM-CSF, in the ONC201-treated mice compared with controls. Our data demonstrated excellent chemopreventive potential of orally administered ONC201 against intestinal tumorigenesis in the AOM-Apc min/+ mouse model.
Insights
The small molecule ONC201 demonstrates significant potential for preventing colorectal cancer (CRC) by reducing intestinal tumors in a preclinical model. This TRAIL-inducing compound proved non-toxic and effective in reducing tumor incidence and multiplicity.
Area of Science:
- Oncology
- Gastroenterology
- Pharmacology
Background:
- Colorectal cancer (CRC) incidence is increasing globally, necessitating effective prevention strategies.
- Familial adenomatous polyposis (FAP) represents a high-risk group for CRC development.
- The TRAIL-inducing small molecule ONC201 (also known as TIC10) is being investigated for its therapeutic potential.
Purpose of the Study:
- To evaluate the chemopreventive efficacy of ONC201 in a preclinical model of familial adenomatous polyposis (FAP).
- To determine the optimal and non-toxic dosage range of ONC201 for oral administration.
- To assess the molecular mechanisms underlying ONC201's anti-tumorigenic effects.
Main Methods:
- Toxicity studies were conducted in C57BL/6J mice to establish safe ONC201 dosage (0-100 mg/kg BW).
- The chemopreventive efficacy was tested in azoxymethane (AOM)-treated Apcmin/+ mice, a model for FAP.
- Mice received ONC201 (0, 25, 50 mg/kg BW) via oral gavage, and tumor incidence and multiplicity were assessed.
Main Results:
- ONC201 administration up to 100 mg/kg BW showed no toxicity in mice.
- ONC201 significantly suppressed both large and small intestinal tumor development in AOM-Apcmin/+ mice.
- Treatment with ONC201 (50 mg/kg BW) reduced colonic tumor incidence by over 50% and multiplicity by 68-75%.
- Small intestinal polyp reduction was observed at 68% in both male and female mice.
- Molecular analysis revealed increased TRAIL, DR5, cleaved caspases, FADD, and p21 (WAF1) in tumors.
- Pro-inflammatory serum biomarkers (IL1β, IL6, TNFα, G-CSF, GM-CSF) were decreased following ONC201 treatment.
Conclusions:
- Orally administered ONC201 exhibits excellent chemopreventive potential against intestinal tumorigenesis.
- ONC201 effectively reduces tumor incidence and multiplicity in a relevant preclinical model of FAP.
- The compound's mechanism involves TRAIL pathway activation and modulation of inflammatory responses.
