Chemopreventive effects of PBI-Se, a selenium-containing analog of PBIT, on AOM-induced aberrant crypt foci in F344 rats

Naveena B. Janakiram, Altaf Mohammed, Durgadevi Ravillah, Chang In Choi, Yuting Zhang, Dhimant Desai, Shantu Amin, Chinthalapally V. Rao

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)952-960
Number of pages9
JournalOncology reports
Volume30
Issue number2
DOIs
StatePublished - Aug 1 2013

Fingerprint

Aberrant Crypt Foci
Azoxymethane
Inbred F344 Rats
Selenium
Nitric Oxide Synthase Type II
Colon
Carcinogenesis
Diet
Cell Cycle Proteins
Cyclin D1
Sulfur
Biological Assay
Colonic Neoplasms
Biological Availability
Interleukin-6
Neoplasms
Apoptosis
Cytokines
Inflammation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Janakiram, Naveena B. ; Mohammed, Altaf ; Ravillah, Durgadevi ; Choi, Chang In ; Zhang, Yuting ; Desai, Dhimant ; Amin, Shantu ; Rao, Chinthalapally V. / Chemopreventive effects of PBI-Se, a selenium-containing analog of PBIT, on AOM-induced aberrant crypt foci in F344 rats. In: Oncology reports. 2013 ; Vol. 30, No. 2. pp. 952-960.
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abstract = "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.",
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Chemopreventive effects of PBI-Se, a selenium-containing analog of PBIT, on AOM-induced aberrant crypt foci in F344 rats. / Janakiram, Naveena B.; Mohammed, Altaf; Ravillah, Durgadevi; Choi, Chang In; Zhang, Yuting; Desai, Dhimant; Amin, Shantu; Rao, Chinthalapally V.

In: Oncology reports, Vol. 30, No. 2, 01.08.2013, p. 952-960.

Research output: Contribution to journalArticle

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 - 2013/8/1

Y1 - 2013/8/1

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.

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