Polyphenol schisandrin B as an alternative treatment for colorectal cancer

Abstract

Colorectal cancer (CRC) is the third most prevalent cancer, and the second most leading cause of oncological deaths in the world. On top of that, current management of CRC includes chemotherapy and radiotherapy, and 5-FU is one of the first line chemotherapy. However, these conventional cancer therapies are often accompanied by severe side effects and significant mortality. For example, the advanced/metastatic CRC is less responsive to 5-FU, with its response rate less than 15%. Therefore, the identification of a novel but less toxic therapeutic strategy is urgently needed.

In recent decades, multiple studies suggest that polyphenols show significant efficacy on cancer development, including chemoprevention and anti-cancer ability. Schisandrin B (Sch B), a lignan extracted from the fruit Schisandra chinensis, has been reported for its anti-cancer properties in multiple cancers, including liver cancer, ovarian cancer, etc. It is also shown to improve the efficacy of chemotherapy drug, doxorubicin (DOX) in breast cancer and ovarian cancer. In these studies, Sch B was found to inhibit cancer progression by downregulating molecular pathways which are also involved in CRC, such as NF-κB and Wnt/β-catenin signaling. It is likely that Sch B can also exhibit anti-cancer effects against CRC by targeting these pathways. Therefore, the aims of this study were to evaluate the in vitro and in vivo anti-cancer effects of Sch B in CRC, and to investigate the underlying mechanisms.

In the in vitro study, Sch B exhibited inhibitory effects on cell viability in multiple CRC cell lines, and the underlying mechanism was possibly due to modulation of unfolded protein responses through upregulation of CHOP signaling, and induced ER stress. The ER stress in turn inhibited cell proliferation, induced cell cycle arrest and cell death in the CRC cells. Also, Sch B was able to inhibit migration of CRC cells. Similar anti-cancer effects were observed in subcutaneous xenograft mouse model. 2-week oral administration of Sch B reduced the tumour size significantly by 47.4%. However, Sch B’s anti-cancer mechanism in transplanted tumour was shown to differ from the cell culture model. Sch B did not affect the proliferation of the tumour cells. Also, genes associated with LXR/RXR activation were upregulated in the tumour cells, suggesting that the reduced tumour size could be due to cell death instead. In addition, Sch B increased the anti-cancer efficacy of the chemotherapy drug, 5-FU in CRC cells, even in cell lines which originally have limited sensitivity to 5-FU. Findings from the bioavailability study showed that Sch B could increase the bioavailability of bioactive 5-FU metabolite, FdUTP, suggesting that Sch B may increase efficacy of 5-FU by modulating 5-FU metabolism. This finding opened up the possibility of Sch B use as an adjuvant with 5-FU in CRC treatment.

Overall, promising anti-cancer results were obtained from our in vitro and in vivo studies, indicating a potential and effective therapeutic strategy that uses Sch B as an alternative CRC treatment.