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

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) p...

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Published in:American journal of cancer research 2022-05, Vol.12 (5), p.2118-2131
Main Authors: Madka, Venkateshwar, De La Cruz, Arielle, Pathuri, Gopal, Panneerselvam, Janani, Zhang, Yuting, Stratton, Nicole, Hacking, Sean, Finnberg, Niklas K, Safran, Howard P, Sei, Shizuko, Glaze, Elizabeth R, Shoemaker, Robert, Fox, Jennifer T, Raufi, Alexander G, El-Deiry, Wafik S, Rao, Chinthalapally V
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Language:English
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Summary: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
ISSN:2156-6976