4.6 Article

Oral administration of TRAIL-inducing small molecule ONC201/TIC10 prevents intestinal polyposis in the Apcmin/+ mouse model

Journal

AMERICAN JOURNAL OF CANCER RESEARCH
Volume 12, Issue 5, Pages 2118-+

Publisher

E-CENTURY PUBLISHING CORP

Keywords

Colon cancer; chemoprevention; FAP; TRAIL; ONC201; TIC10; colon polyp; min mouse

Categories

Funding

  1. NCI-PREVENT [NCI HHSN 261201500038I]
  2. NCI [CA173453]
  3. Mencoff Family University Professorship at Brown University

Ask authors/readers for more resources

The small molecule ONC201/TIC10 has shown great potential for preventing colorectal cancer (CRC). In a preclinical model representing high-risk familial adenomatous polyposis (FAP) patients, ONC201 demonstrated a strong suppressive effect on the development of intestinal tumors in male and female mice.
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 IL1 beta, IL6, TNF alpha, 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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.6
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available