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Silibinin Suppresses Spontaneous Tumorigenesis in APC min/+ Mouse Model by Modulating Beta-Catenin Pathway

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ABSTRACT

Purpose

Here we assessed whether silibinin, a nontoxic chemopreventive agent, inhibits spontaneous intestinal tumorigenesis in APC min/+ mouse model, a genetically predisposed animal model of human familial adenomatous polyposis (FAP).

Materials and Methods

Six-week-old APC min/+ mice were divided into four groups and orally gavaged with 0.2 ml vehicle, or 250, 500 and 750 mg silibinin/kg body weight in 0.2 ml vehicle for five days/week. After 6 weeks, polyp burden was analyzed and tissues examined for molecular alterations.

Results

Silibinin treatments decreased total number of intestinal polyps by 34% (P < 0.01), 42% (P < 0.01) and 55% (P < 0.001), respectively. Immunohistochemical analysis showed that silibinin dose-dependently decreases (P < 0.001) proliferation and induces (P < 0.001) apoptosis only in intestinal polyps without any considerable effects on normal crypt-villi in APC min/+ or wild-type mice. Further analysis of polyps showed that silibinin decreases β-catenin, cyclin D1, c-Myc and phospho-glycogen synthase kinase-3β expression. Silibinin treatment also decreased phospho-Akt, cyclooxygenase-2, inducible nitric oxide synthase, nitrotyrosine and nitrite levels in polyps, the well-known mediators of intestinal/colon carcinogenesis.

Conclusion

Together, these results establish silibinin efficacy in a well-established genetic model of FAP, APC min/+ mouse, and suggest that this natural agent modulates various molecular pathways including β-catenin in its overall chemopreventive efficacy against intestinal carcinogenesis.

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Abbreviations

APC:

Adenomatous polyposis coli

COX-2:

cyclooxygenase-2

CRC:

colorectal cancer

FAP:

familial adenomatous polyposis

GSK-3β:

glycogen synthase kinase-3β

IHC:

immunohistochemistry

iNOS:

inducible nitric oxide synthase

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ACKNOWLEDGEMENTS

This work was supported by NCI RO1 grant CA112304.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, C238- P15, Research 2, Room 3121, 12700 19th Ave., Aurora, Colorado, 80045, USA

    Subapriya Rajamanickam, Manjinder Kaur, Balaiya Velmurugan, Rana P. Singh & Rajesh Agarwal

  2. University of Colorado Cancer Center, University of Colorado Denver, Aurora, Colorado, USA

    Rajesh Agarwal

  3. Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India

    Rana P. Singh

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  1. Subapriya Rajamanickam
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  2. Manjinder Kaur
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Correspondence to Rajesh Agarwal.

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Rajamanickam, S., Kaur, M., Velmurugan, B. et al. Silibinin Suppresses Spontaneous Tumorigenesis in APC min/+ Mouse Model by Modulating Beta-Catenin Pathway. Pharm Res 26, 2558–2567 (2009). https://doi.org/10.1007/s11095-009-9968-1

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