Cancer stem cells (CSC) are now recognized as the main cause for initiation, promotion and progression of most of the cancers, including colorectal cancer (CRC). Despite this fact, efficacy of chemopreventive agents towards CSC generation leading to cancer initiation and tumorigenesis has not yet been well- defined. Our completed and published studies show strong preventive and therapeutic efficacy of silibinin against CRC xenografts in nude mice, AOM-induced colon tumorigenesis in A/J mice and spontaneous tumorigenesis in APCmin/+ models, together with strong anti-proliferative, pro-apoptotic and anti-inflammatory effects. Also, silibinin strongly decreases the expression of NOTCH survival signaling molecules and b- catenin together with an inhibition in b-catenin transcriptional activity, which are important regulators of CSC renewal;as well as decreases the expression of CD44, an important colon CSC marker. Another important observation we made is that silibinin significantly decreases colonosphere formation (a stem cell characteristic) by CRC cells, thereby highlighting its potential to target colon CSC. Present continuation application builds upon these highly novel observations, where we propose to examine and establish silibinin efficacy on colon CSC generation, expansion, self-renewal and differentiation in the context of CRC chemoprevention. The central hypothesis proposed is that silibinin targets CSC generation and expansion by modulating signaling pathways as well as pro-inflammatory milieu that regulate CSC 'self renewal'and 'differentiation'capabilities, leading to its strong efficacy against CRC initiation, promotion and recurrence.
Specific aims are: I) to examine and establish silibinin efficacy on colon CSC generation and expansion, and associated signaling pathways;II) to examine and establish silibinin efficacy on self-renewal and differentiation potential of colon CSC;and III) to examine and define silibinin efficacy on the inflammatory milieu of the colon CSC 'niche'. We believe that the present proposal would have profound impact as 'first of its kind study'with a goal to prevent CRC by targeting 'cancer stem cells'. We rationalized our approach based upon the fact that stem cells are the long lived population in colon and are the preferential target for initial oncogenic mutations, and therefore, CSC are identified as the real driving force behind CRC initiation, promotion and progression. We strongly believe that present proposal will provide a new direction to 'cancer chemoprevention research'by laying greater focus on the role of CSC in prevention and recurrence of disease. Human Health Relevance: Since silibinin consumption is safe in humans and its bioavailability has already been established in CRC patients, the outcomes of the studies in present proposal would have significant clinical impact on the rationalized use of silibinin in human CRC control.

Public Health Relevance

Cancer stem cells (CSC) are now recognized as the main cause for most of the cancers, including colorectal cancer (CRC). Despite this fact, efficacy of chemopreventive agents towards CSC generation leading to cancer initiation and tumorigenesis has not yet been well-defined. In our completed and published studies, we observed a strong chemopreventive efficacy of silibinin against CRC in various pre- clinical models. Present continuation application proposes to examine and establish silibinin efficacy on colon CSC generation, expansion, self-renewal and differentiation in the context of CRC chemoprevention. The central hypothesis proposed is that silibinin targets CSC by modulating signaling pathways as well as pro-inflammatory milieu that regulate CSC 'self renewal'and 'differentiation'capabilities, leading to its strong efficacy against CRC initiation, promotion and recurrence. We strongly believe that present proposal will provide a new direction to 'cancer chemoprevention research'by laying greater focus on the role of CSC in prevention and recurrence of disease. Since silibinin consumption is safe in humans and its bioavailability has already been established in CRC patients, the outcomes of the studies in present proposal would have significant clinical impact on the rationalized use of silibinin in human CRC control.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA112304-08
Application #
8384884
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Malone, Winfred F
Project Start
2005-03-01
Project End
2015-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
8
Fiscal Year
2013
Total Cost
$269,324
Indirect Cost
$93,295
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Kumar, Sushil; Kumar, Dileep; Raina, Komal et al. (2014) Functional modification of adipocytes by grape seed extract impairs their pro-tumorigenic signaling on colon cancer stem cells and the daughter cancer cells. Oncotarget 5:10151-69
Derry, Molly M; Raina, Komal; Agarwal, Rajesh et al. (2014) Characterization of azoxymethane-induced colon tumor metastasis to lung in a mouse model relevant to human sporadic colorectal cancer and evaluation of grape seed extract efficacy. Exp Toxicol Pathol 66:235-42
Derry, Molly M; Somasagara, Ranganatha R; Raina, Komal et al. (2014) Target identification of grape seed extract in colorectal cancer using drug affinity responsive target stability (DARTS) technique: role of endoplasmic reticulum stress response proteins. Curr Cancer Drug Targets 14:323-36
Kumar, Sushil; Raina, Komal; Agarwal, Chapla et al. (2014) Silibinin strongly inhibits the growth kinetics of colon cancer stem cell-enriched spheroids by modulating interleukin 4/6-mediated survival signals. Oncotarget 5:4972-89
Agarwal, R; Kale, R K; Rao, C V et al. (2013) Introduction to Special Issue on Molecular Basis for Cancer Prevention with Bioactive Food Components in Nutrition and Cancer--an International Journal. Nutr Cancer 65 Suppl 1:1-2
Agarwal, Chapla; Wadhwa, Ritambhara; Deep, Gagan et al. (2013) Anti-cancer efficacy of silybin derivatives -- a structure-activity relationship. PLoS One 8:e60074
Deep, Gagan; Agarwal, Rajesh (2013) Targeting tumor microenvironment with silibinin: promise and potential for a translational cancer chemopreventive strategy. Curr Cancer Drug Targets 13:486-99
Kaur, Manjinder; Deep, Gagan; Jain, Anil K et al. (2013) Bitter melon juice activates cellular energy sensor AMP-activated protein kinase causing apoptotic death of human pancreatic carcinoma cells. Carcinogenesis 34:1585-92
Forster, Genevieve M; Raina, Komal; Kumar, Ajay et al. (2013) Rice varietal differences in bioactive bran components for inhibition of colorectal cancer cell growth. Food Chem 141:1545-52
Raina, Komal; Agarwal, Rajesh (2013) Promise and potential of silibinin in colorectal cancer management: what patterns can be seen? Future Oncol 9:759-61

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