TY - JOUR
T1 - Targeting cholecystokinin-2 receptor for pancreatic cancer chemoprevention
AU - Mohammed, Altaf
AU - Janakiram, Naveena B.
AU - Suen, Chen
AU - Stratton, Nicole
AU - Lightfoot, Stanley
AU - Singh, Anil
AU - Pathuri, Gopal
AU - Ritchie, Rebekah
AU - Madka, Venkateshwar
AU - Rao, Chinthalapally V.
N1 - Publisher Copyright:
© 2019 Wiley Periodicals, Inc.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - Gastrin signaling mediated through cholecystokinin-2 receptor (CCK2R) and its downstream 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 KrasG12D mice. After dose selection using wild-type mice, six-week-old p48Cre/+-LSL-KrasG12D (22-24 per 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% (P <.004) in male mice and by 100% and 24% (P >.05) in female mice, respectively. Low and high dose YF476 inhibited the incidence of PDAC by 74% (P <.02) and 69% (P <.02) in male mice and by 45% and 33% (P >.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.
AB - Gastrin signaling mediated through cholecystokinin-2 receptor (CCK2R) and its downstream 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 KrasG12D mice. After dose selection using wild-type mice, six-week-old p48Cre/+-LSL-KrasG12D (22-24 per 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% (P <.004) in male mice and by 100% and 24% (P >.05) in female mice, respectively. Low and high dose YF476 inhibited the incidence of PDAC by 74% (P <.02) and 69% (P <.02) in male mice and by 45% and 33% (P >.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.
KW - CCK2R
KW - chemoprevention
KW - kras
KW - pancreatic cancer
UR - http://www.scopus.com/inward/record.url?scp=85071766626&partnerID=8YFLogxK
U2 - 10.1002/mc.23084
DO - 10.1002/mc.23084
M3 - Article
C2 - 31313401
AN - SCOPUS:85071766626
SN - 0899-1987
VL - 58
SP - 1908
EP - 1918
JO - Molecular Carcinogenesis
JF - Molecular Carcinogenesis
IS - 10
ER -