Abstract
Introduction: The tumor microenvironment is involved in acquiring tumor malignancies of colorectal liver metastasis (CRLM). We have reported that TU-100 (Daikenchuto) suppresses hepatic stellate cell (HSC) activation in obstructive jaundice. In this study, we report new findings as the direct and indirect inhibitory effects of TU-100 on cancer cell growth through the suppression of HSC activation.Materials and Methods: The HSCs (LX2) were cultured in colon cancer cells (HCT116 and HT29)-conditioned medium (CM) with or without TU-100 treatment (90, 270, 900 μg/ml). Activated HSCs (aHSCs) were detected by α-SMA and IL-6 mRNA expressions and cytokine arrays of HSC’s culture supernatants. Cancer cell growth was analyzed for proliferation and migration ability, compared with TU-100 treatment. To investigate the direct anti-tumor effect of TU-100, cancer cells were cultured in the presence of aHSC-CM and TU-100 (90, 270, 900) or aHSC-CM alone, and assessed autophagosomes, conversion to LC3-II protein, and Beclin-1 mRNA expression.Results: Colon cancer-CM significantly increased α-SMA and IL-6 mRNA expressions of aHSC. α-SMA and IL-6 mRNA expressions of aHSC, and IL-6 secretions from aHSCs were significantly decreased with TU-100 (270, 900) treatment, compared to colon cancer-CM alone. Compared with normal culture medium, aHSC-CM led to a significantly increased cell number and modified HSC-CM (TU-100; 270, 900) significantly suppressed cancer cell growth and migration. TU-100 (900) treatment induced autophagy and significantly promoted the autophagic cell death.Conclusions: TU-100 inhibited colon cancer cell malignant potential by both suppressing HSC activation and inducing directly autophagy of cancer cells.
Highlights
The tumor microenvironment is involved in acquiring tumor malignancies of colorectal liver metastasis (CRLM)
Colon cancer-conditioned medium (CM) significantly increased α-smooth muscle actin (α-SMA) and IL-6 messenger RNA (mRNA) expressions of Activated HSCs (aHSCs). α-SMA and IL-6 mRNA expressions of aHSC, and IL-6 secretions from aHSCs were significantly decreased with TU-100 (270, 900) treatment, compared to colon cancer-CM alone
Since previous studies have reported that interleukin-6 (IL-6) was a precancerous cytokine, which can promote the migration of cancer cells [30], this study tried to check the role of IL-6 in the interaction between hepatic stellate cells (HSCs) and cancer cells
Summary
The tumor microenvironment is involved in acquiring tumor malignancies of colorectal liver metastasis (CRLM). We have reported that TU100 (Daikenchuto) suppresses hepatic stellate cell (HSC) activation in obstructive jaundice. We report new findings as the direct and indirect inhibitory effects of TU-100 on cancer cell growth through the suppression of HSC activation. Herbal medicine is considered an effective resource and important in pharmacological research and drug development [6]. Many of these compounds have been used to treat a variety of diseases in clinical, even in CRC [7]. It has been reported that TU-100 has antiinflammatory by decreasing expression of inflammatory cytokines and anti-cancer effects by inducing programmed cell death in animal model [16,17,18,19,20,21], its mechanism is not fully known
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