Abstract 4877: Silibinin strongly modulates the cytokine interleukin-4/6 survival signals in colon cancer stem cells.

Colorectal cancer (CRC) is the 2nd (both genders combined) leading cause of cancer-related deaths in US; statistical estimates for 2012 indicate ∼103,170 new CRC cases and 51,690 associated deaths. While removal of adenomatous polyps during screening helps in preventing CRC, only 40% of the cases are diagnosed at this stage, mostly due to under use of screening. The undetected cancer spreads to various organs and the 5-year survival drops to 11% with distant metastasis. Also, nearly 50% of CRC patients develop recurrent disease even after aggressive surgical resection and chemotherapy. Interventions that reduce incidence of adenomatous polyps and/or prevent their progression to CRC are, therefore, urgently needed. In this regard, several studies have reported the chemopreventive potential of a wide range of dietary/non-dietary agents against CRC; however, their efficacy towards cancer stem cell (CSC) generation leading to cancer initiation and tumorigenesis has not yet been well-defined. In this regard, recent studies by our group have demonstrated that silibinin, a non-toxic, chemopreventive agent, strongly decreases the percentage of sphere formation of CRC cells (a stem cell characteristic). The present study was aimed to provide an understanding of the mechanisms involved in the inhibitory effect of silibinin on the CSC population in CRC. It is evident from our earlier studies that silibinin has the potential to target the self-renewal of CSCs in CRC cell lines and that silibinin effect on CSC is mediated via blocking interleukin (IL)-4 signaling in CRC cell lines. We next examined the effect of IL-4 or IL-6 or a combination of both on the percentage of floating spheroids (colonospheres) generated in the sphere cluster assays after 1-2 weeks, and then determined how silibinin could affect the growth kinetics of these colonospheres. Results indicated that in presence of the IL-4/6 there was a significant increase in number of colonospheres generated; the IL-4/6 combination causing a further increase in the number of colonospheres compared to single agents alone. Interestingly, treatment with silibinin not only had a negative effect on the colonospheres generated in the presence of either IL-4 or IL-6, it could also significantly inhibit the booster signals of the IL-4/6 combination on the CSCs. Since the role of IL-4/6 is also implicated in increased resistance of CSC to chemotherapy agents and targeting the associated signaling presents a rational approach for the prevention and treatment of CRC, our results indicating that silibinin could significantly block the IL-4/6 survival signaling in colorectal CSC, might be of translational significance. Citation Format: Sushil Kumar, Komal Raina, Chapla Agarwal, Rajesh Agarwal. Silibinin strongly modulates the cytokine interleukin-4/6 survival signals in colon cancer stem cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4877. doi:10.1158/1538-7445.AM2013-4877