Targeting CCK2R for pancreatic cancer chemoprevention
| Autor: | Mohammed, Altaf, Janakiram, Naveena B, Suen, Chen, Stratton, Nicole, Lightfoot, Stanley, Singh, Anil, Pathuri, Gopal, Ritchie, Rebekah, Madka, Venkateshwar, Rao, Chinthalapally V |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Benzodiazepinones
Sulfonamides endocrine system diseases Phenylurea Compounds Adenocarcinoma Chemoprevention Article Receptor Cholecystokinin B Neoplasm Proteins Gene Expression Regulation Neoplastic Pancreatic Neoplasms Proto-Oncogene Proteins p21(ras) Disease Models Animal Mice Quinoxalines Animals Humans Female Carcinoma in Situ Carcinoma Pancreatic Ductal Signal Transduction |
| Zdroj: | Mol Carcinog |
| Popis: | Gastrin signaling mediated through cholecystokinin-2 receptor (CCK2R) and its down-stream molecules is altered in pancreatic cancer. CCK2R antagonists, YF476 (netazepide) and JNJ-26070109, were tested systematically for their effect on pancreatic intraepithelial neoplasia (PanIN) progression to pancreatic ductal adenocarcinoma (PDAC) in Kras(G12D) mice. After dose selection using wild-type mice, six-week-old p48(Cre/+)-LSL-Kras(G12D) (22–24/group) genetically engineered mice (GEM) were fed AIN-76A diets containing 0, 250, or 500 ppm JNJ-26070109 or YF-476 for 38 weeks. At termination, pancreata were collected, weighed, and evaluated for PanINs and PDAC. Results demonstrated that control-diet-fed mice showed 69% (males) and 33% (females) incidence of PDAC. Administration of low and high dose JNJ-26070109 inhibited the incidence of PDAC by 88% and 71% (p0.05) in female mice, respectively. Low and high dose YF476 inhibited the incidence of PDAC by 74% (p0.05) in female mice, respectively. Further, transcriptome analysis showed downregulation of Cldn1, Sstr1, Apod, Gkn1, Siglech, Cyp2c44, Bnc1, Fmo2, 623169, Kcne4, Slc27a6, Cma1, Rho GTPase activating protein 18, and Gpr85 genes in JNJ-26070109-treated mice compared with untreated mice. YF476-treated mouse pancreas showed downregulation of Riks, Zpbp, Ntf3, Lrrn4, Aass, Skint3, Kcnb1, Dgkb, Ddx60, and Aspn gene expressions compared with untreated mouse pancreas. Overall, JNJ-26070109 showed better chemopreventive efficacy than YF476. However, caution is recommended when selecting doses, as the agents appeared to exhibit gender-specific effects. |
| Databáze: | OpenAIRE |
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