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
Center 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.
Department of Pathology and Laboratory Medicine, Warren Alpert Medical School RI, USA.
Am J Cancer Res. 2022 May 15;12(5):2118-2131. eCollection 2022.
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, 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 (=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 male and female mice (≥20) treated with colon carcinogen azoxymethane (AOM) (AOM- ) 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. mice treated with ONC201 (50 mg/kg BW) showed >50% less colonic tumor incidence (<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; <0.0001) and by 75% in female mice (0.30 ± 0.10 in treated vs. 1.19 ± 0.19 in controls; <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; <0.0001) and female mice (9.65 ± 1.15 in treated vs. 29.24 ± 2.51 in controls; <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- mouse model.
全球范围内，结直肠癌（CRC）的发病率正在上升。因此，预防这种疾病是当务之急。出于这一目的，我们使用一种代表高危家族性腺瘤性息肉病（FAP）患者的临床前模型——小鼠，来确定诱导TRAIL的小分子ONC201/TIC10预防结直肠癌的潜力。在进行疗效研究之前，通过在C57BL/6J小鼠（每组=6只）中测试五种不同剂量的ONC201（0 - 100毫克/千克体重（BW）；每周两次经口灌胃），持续6周，来确定ONC201的最佳无毒剂量。体重增加、器官重量和组织病理学、血液分析以及血浆肝酶谱表明，剂量高达100毫克/千克BW时，ONC201没有毒性。为了确定疗效，从六周龄开始，给用结肠致癌物氧化偶氮甲烷（AOM）处理过的（AOM - ）雄性和雌性小鼠（每组≥20只）按照上述方法给予ONC201（0、25和50毫克/千克BW），直至20周龄。在实验结束时，通过比较载体处理组和药物处理组之间肠道肿瘤的发生率和多发性来确定疗效。ONC201对雄性和雌性小鼠大肠和小肠肿瘤的发生均显示出强大的抑制作用。用ONC201（50毫克/千克BW）处理的小鼠结肠肿瘤发生率比对照组低>50%（<0.0002）。在用ONC201（50毫克/千克BW）处理的雄性小鼠中，结肠肿瘤多发性也显著降低了68%（处理组为0.44±0.11，对照组为1.4±0.14；<0.0001），在雌性小鼠中降低了75%（处理组为0.30±0.10，对照组为1.19±0.19；<0.0003）。对肿瘤的分子分析表明，药物处理后TRAIL、DR5、裂解的半胱天冬酶3/7/8、Fas相关死亡结构域蛋白（FADD）和p21（WAF1）增加。血清分析表明，与对照组相比，用ONC201处理的小鼠中促炎血清生物标志物如IL1β、IL6、TNFα、G - CSF和GM - CSF减少。我们的数据证明，口服ONC201在AOM - 小鼠模型中对肠道肿瘤发生具有出色的化学预防潜力。
