Translational potential of a small-molecule silibinin in colorectal cancer: Targeting cancer stem cells and their inflammatory niche.

The inflammatory milieu of colon cancer stem cell (CSC) niche is also an important growth regulator for both CSC and progenitor cell population. Inflammatory signals, e.g., cytokines arising in CSC niche, due to inflammatory cells in microenvironment, also network with other regulatory pathways to influence the expansion of both cell types. With this background, we aimed to assess whether silibinin, a nontoxic, naturally occurring chemopreventive agent with established preclinical efficacy against growth and progression of colorectal cancer (CRC), has the potential to target colon CSC and associated inflammatory niche during CRC inhibition. Our results found that silibinin strongly decreases the percentage of colonosphere formation (a stem cell characteristic) of CRC cells, and that this effect on colon CSC is mediated via blocking IL-4/6 signaling in CRC cell lines. Silibinin also strongly decreased IL-4/6 induced activation of STAT-3 and NF-kB transcriptional activity, which is associated with decreased mRNA levels of various CSC regulatory molecules, and CSC-associated markers. In other studies, silibinin significantly reduced the booster signals of macrophages towards colon CSC, resulting in decreased colonosphere numbers under both normoxic and hypoxic conditions. Furthermore, we used a colitis-related AOM/DSS-induced colon tumorigenesis model to assess the role of inflammatory conditions on colon CSC generation and expansion, and their modulation by silibinin. Our data indicated the protective effect of oral silibinin feeding in this model in terms of an absence of large macroadenomas (>2-3 mm) in the colon. This effect was accompanied by minimal colonic inflammation (decrease in recruitment of inflammatory cells); tissue analysis indicated a decrease in the expression of proinflammatory cytokines, and associated transcription factors: STAT-3 and NF-kB in the colonic tissues from silibinin group. A decrease in transformed stem cell population (for CSC pool expansion) was also identified by dual staining for BMI-1 and CD44 in the colonic tissues. Together, these results highlight silibinin9s potential to interfere with CSC pool expansion by targeting both colon CSC and their inflammatory niche, as well as associated signals involved with the survival and multiplication of colon CSC pool. These findings further support the translational potential and clinical usefulness of silibinin in CRC intervention and therapy. (Supported by R01 CA112304.) Citation Format: Rajesh Agarwal, Chapla Agarwal. Translational potential of a small-molecule silibinin in colorectal cancer: Targeting cancer stem cells and their inflammatory niche [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; Sao Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B32.