Abstract
Involvement of cancer stem cells (CSC) in initiation, progression, relapse, and therapy-resistance of colorectal cancer (CRC) warrants search for small molecules as 'adjunct-therapy' to target both colon CSC and bulk tumor population. Herein, we assessed the potential of silibinin to eradicate colon CSC together with associated molecular mechanisms. In studies examining how silibinin modulates dynamics of CSC spheroids in terms of its effect on kinetics of CSC spheroids generated in presence of mitogenic and interleukin (IL)-mediated signaling which provides an autocrine/paracrine amplification loop in CRC, silibinin strongly decreased colon CSC pool together with cell survival of bulk tumor cells. Silibinin effect on colon CSC was mediated via blocking of pro-tumorigenic signaling, notably IL-4/-6 signaling that affects CSC population. These silibinin effects were associated with decreased mRNA and protein levels of various CSC-associated transcription factors, signaling molecules and markers. Furthermore, 2D and 3D differentiation assays indicated formation of more differentiated clones by silibinin. These results highlight silibinin potential to interfere with kinetics of CSC pool by shifting CSC cell division to asymmetric type via targeting various signals associated with the survival and multiplication of colon CSC pool. Together, our findings further support clinical usefulness of silibinin in CRC intervention and therapy.
Highlights
While colon resection is the treatment of choice for patients with localized colorectal cancer (CRC) [1], depending on the stage of the malignancy, adjuvant chemo/radio-therapy may still be required [1]
We isolated different cell populations (CD44+EpCAMhigh, CD44+EpCAMlow, CD44-EpCAMhigh and CD44EpCAMlow) from human CRC cell lines SW480, HT29 and LoVo (Fig.1A) and subjected them to sphere cluster formation assay to determine which of the isolated fractions was enriched in cancer stem cells (CSC) population
Since CSC are slow dividing cells and retain BrdU for longer time periods, these results indicated that control colonospheres were highly enriched in CSC population compared to silibinin groups which showed less to negligible numbers of CSC population in colonospheres (Fig. 3A)
Summary
While colon resection is the treatment of choice for patients with localized colorectal cancer (CRC) [1], depending on the stage of the malignancy, adjuvant chemo/radio-therapy may still be required [1]. As stem cells or their progenitors are the targets of transformation into CSC which are responsible for tumorigenesis, strategies that reduce CSC number, induce either apoptosis or differentiation with a loss of self-renewal capacity of CSC, or interfere with the protumorigenic signals arising in the colon ‘niche’ that affects CSC population, represent a rational approach for CRC prevention and treatment [8, 11]. Identification and development of drugs, especially non-toxic agents, which target these ‘tumor initiating cells’ might provide opportunities to intervene at the earliest [8, 11]; such an intervention at a late stage in cancer therapy would be beneficial, as it would eradicate CSC pool, the presence of which results in cancer relapse [10]. Despite the fact that last 5 years have seen a spurt in the anti-cancer and/or anti-CSC efficacy studies with natural agents, the efficacy of these agents towards colon CSC generation leading to colon tumorigenesis has not yet been well-defined
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