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

  • Authors:
    • Naveena B. Janakiram
    • Altaf Mohammed
    • Durgadevi Ravillah
    • Chang In Choi
    • Yuting Zhang
    • Dhimant Desai
    • Shantu Amin
    • Chinthalapally V. Rao
  • View Affiliations

  • Published online on: May 23, 2013     https://doi.org/10.3892/or.2013.2483
  • Pages: 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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August 2013
Volume 30 Issue 2

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Janakiram NB, Mohammed A, Ravillah D, Choi CI, Zhang Y, Desai D, Amin S and Rao CV: Chemopreventive effects of PBI-Se, a selenium-containing analog of PBIT, on AOM-induced aberrant crypt foci in F344 rats. Oncol Rep 30: 952-960, 2013
APA
Janakiram, N.B., Mohammed, A., Ravillah, D., Choi, C.I., Zhang, Y., Desai, D. ... Rao, C.V. (2013). Chemopreventive effects of PBI-Se, a selenium-containing analog of PBIT, on AOM-induced aberrant crypt foci in F344 rats. Oncology Reports, 30, 952-960. https://doi.org/10.3892/or.2013.2483
MLA
Janakiram, N. B., Mohammed, A., Ravillah, D., Choi, C. I., Zhang, Y., Desai, D., Amin, S., Rao, C. V."Chemopreventive effects of PBI-Se, a selenium-containing analog of PBIT, on AOM-induced aberrant crypt foci in F344 rats". Oncology Reports 30.2 (2013): 952-960.
Chicago
Janakiram, N. B., Mohammed, A., Ravillah, D., Choi, C. I., Zhang, Y., Desai, D., Amin, S., Rao, C. V."Chemopreventive effects of PBI-Se, a selenium-containing analog of PBIT, on AOM-induced aberrant crypt foci in F344 rats". Oncology Reports 30, no. 2 (2013): 952-960. https://doi.org/10.3892/or.2013.2483