TY - JOUR
T1 - Chemopreventive effects of PBI-Se, a selenium-containing analog of PBIT, on AOM-induced aberrant crypt foci in F344 rats
AU - Janakiram, Naveena B.
AU - Mohammed, Altaf
AU - Ravillah, Durgadevi
AU - Choi, Chang In
AU - Zhang, Yuting
AU - Desai, Dhimant
AU - Amin, Shantu
AU - Rao, Chinthalapally V.
PY - 2013/8
Y1 - 2013/8
N2 - Inducible nitric oxide synthase (iNOS) is a potential target for the treatment of inflammation and cancer. Previously, we showed that the selective iNOS inhibitor S,S′-1,4-phenylenebis(1,2-ethanediyl)bis-isothiourea (PBIT) caused significant inhibition of colon carcinogenesis induced by azoxymethane (AOM), although it did not completely abrogate NO production due to the exogenous bioavailability of NO and NO generation by eNOS in tumor tissues. To create an iNOS-targeting molecule that may have additional benefits, a novel isosteric analog of PBIT, PBI-Se, was developed, in which sulfur was replaced with selenium. Chemopreventive efficacy of PBI-Se was evaluated in an AOM-induced rat colon carcinogenesis model using aberrant crypt foci (ACF) as the endpoint. At 7 weeks of age, rats (12/group) were fed the control diet (AIN 76A) and then colonic ACF were induced with two AOM treatments. Three days later, rats were fed diets containing PBI-Se (0-20 ppm) for 8 weeks, and then ACF were evaluated histopathologically. Dietary administration of 10 or 20 ppm of PBI-Se significantly suppressed AOM-induced total colonic ACF formation (32 or 41%, P<0.002-0.0003), and multi-crypt (4 or more) aberrant foci (29 or 47%, P<0.01-0.0004), respectively. The inhibition by PBI-Se was dose-dependent and was half the dose of PBIT for inhibiting total ACF in rats. Both PBIT and PBI-Se induced dose-dependent apoptosis in CaCo2 cells and caused a significant decrease in the cell cycle proteins cyclin D1 (70%, P<0.0001) and iNOS (99%, P<0.0001). Treatment with PBIT (30 and 60 μM) and PBI-Se (2 and 4 μM) significantly decreased the LPS-induced cytokine interleukin-6 level. Incorporation of selenium into the structure of PBIT provided the agent with additional novel cytotoxic and immunologic properties. Results from the in vitro and in vivo bioassays suggest that PBI-Se could be developed further for the prevention and treatment of colon cancer.
AB - Inducible nitric oxide synthase (iNOS) is a potential target for the treatment of inflammation and cancer. Previously, we showed that the selective iNOS inhibitor S,S′-1,4-phenylenebis(1,2-ethanediyl)bis-isothiourea (PBIT) caused significant inhibition of colon carcinogenesis induced by azoxymethane (AOM), although it did not completely abrogate NO production due to the exogenous bioavailability of NO and NO generation by eNOS in tumor tissues. To create an iNOS-targeting molecule that may have additional benefits, a novel isosteric analog of PBIT, PBI-Se, was developed, in which sulfur was replaced with selenium. Chemopreventive efficacy of PBI-Se was evaluated in an AOM-induced rat colon carcinogenesis model using aberrant crypt foci (ACF) as the endpoint. At 7 weeks of age, rats (12/group) were fed the control diet (AIN 76A) and then colonic ACF were induced with two AOM treatments. Three days later, rats were fed diets containing PBI-Se (0-20 ppm) for 8 weeks, and then ACF were evaluated histopathologically. Dietary administration of 10 or 20 ppm of PBI-Se significantly suppressed AOM-induced total colonic ACF formation (32 or 41%, P<0.002-0.0003), and multi-crypt (4 or more) aberrant foci (29 or 47%, P<0.01-0.0004), respectively. The inhibition by PBI-Se was dose-dependent and was half the dose of PBIT for inhibiting total ACF in rats. Both PBIT and PBI-Se induced dose-dependent apoptosis in CaCo2 cells and caused a significant decrease in the cell cycle proteins cyclin D1 (70%, P<0.0001) and iNOS (99%, P<0.0001). Treatment with PBIT (30 and 60 μM) and PBI-Se (2 and 4 μM) significantly decreased the LPS-induced cytokine interleukin-6 level. Incorporation of selenium into the structure of PBIT provided the agent with additional novel cytotoxic and immunologic properties. Results from the in vitro and in vivo bioassays suggest that PBI-Se could be developed further for the prevention and treatment of colon cancer.
KW - Aberrant crypt foci
KW - Chemoprevention
KW - Colon cancer
KW - Selenium
KW - iNOS inhibitor
UR - http://www.scopus.com/inward/record.url?scp=84879654253&partnerID=8YFLogxK
U2 - 10.3892/or.2013.2483
DO - 10.3892/or.2013.2483
M3 - Article
C2 - 23708609
AN - SCOPUS:84879654253
SN - 1021-335X
VL - 30
SP - 952
EP - 960
JO - Oncology Reports
JF - Oncology Reports
IS - 2
ER -