Antifibrotic effect of xanthohumol in combination with praziquantel is associated with altered redox status and reduced iron accumulation during liver fluke-associated cholangiocarcinogenesis

Wassana Jamnongkan; Malinee Thanee; Puangrat Yongvanit; Watcharin Loilome; Raynoo Thanan; Phongsaran Kimawaha; Tidarat Boonmars; Runglawan Silakit; Nisana Namwat; Anchalee Techasen

doi:10.7717/peerj.4281

Antifibrotic effect of xanthohumol in combination with praziquantel is associated with altered redox status and reduced iron accumulation during liver fluke-associated cholangiocarcinogenesis

PeerJ. 2018 Jan 22:6:e4281. doi: 10.7717/peerj.4281. eCollection 2018.

Authors

Wassana Jamnongkan^{1

2}, Malinee Thanee^{1

2}, Puangrat Yongvanit^{1

2}, Watcharin Loilome^{1

2}, Raynoo Thanan^{1

2}, Phongsaran Kimawaha^{2

3}, Tidarat Boonmars^{2

4}, Runglawan Silakit^{1

2}, Nisana Namwat^{1

2}, Anchalee Techasen^{2

3}

Affiliations

¹ Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
² Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand.
³ Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand.
⁴ Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.

Abstract

Cholangiocarcinoma (CCA) caused by infection of the liver fluke Opisthorchis viverrini, (Ov) is the major public health problem in northeast Thailand. Following Ov infection the subsequent molecular changes can be associated by reactive oxygen species (ROS) induced chronic inflammation, advanced periductal fibrosis, and cholangiocarcinogenesis. Notably, resistance to an activation of cell death in prolonged oxidative stress conditions can occur but some damaged/mutated cells could survive and enable clonal expansion. Our study used a natural product, xanthohumol (XN), which is an anti-oxidant and anti-inflammatory compound, to examine whether it could prevent Ov-associated CCA carcinogenesis. We measured the effect of XN with or without praziquantel (PZ), an anti-helminthic treatment, on DNA damage, redox status change including iron accumulation and periductal fibrosis during CCA genesis induced by administration of Ov and N-dinitrosomethylamine (NDMA) in hamsters. Animals were randomly divided into four groups: group I, Ov infection and NDMA administration (ON); group II, Ov infection and NDMA administration and PZ treatment (ONP); the latter 2 groups were similar to group I and II, but group III received additional XN (XON) and group IV received XN plus PZ (XONP). The results showed that high 8-oxodG (a marker of DNA damage) was observed throughout cholangiocarcinogenesis. Moreover, increased expression of CD44v8-10 (a cell surface in regulation of the ROS defense system), whereas decreased expression of phospho-p38^MAPK (a major ROS target), was found during the progression of the bile duct cell transformation. In addition, high accumulation of iron and expression of transferrin receptor-1 (TfR-1) in both malignant bile ducts and inflammatory cells were detected. Furthermore, fibrosis also increased with the highest level being on day 180. On the other hand, the groups of XN with or without PZ supplementations showed an effective reduction in all the markers examined, including fibrosis when compared with the ON group. In particular, the XONP group, in which a significant reduction DNA damage occurred, was also found to have iron accumulation and fibrosis compared to the other groups. Our results show that XN administered in combination with PZ could efficiently prevent CCA development and hence provide potential chemopreventive benefits in Ov-induced cholangiocarcinogenesis.

Keywords: Chemoprevention; Cholangiocarcinoma; DNA damage; Fibrosis; Iron; Oxidative stress.

Grants and funding

This study was supported by the Thailand Research Fund through the Royal Golden Jubilee Ph.D. Program (to Wassana Jamnongkan and Puangrat Yongvanit), the Thailand Research Fund and Khon Kaen University to Anchalee Techasen: TRG5880023. The Higher Education Research Promotion and National Research University Project of Thailand, Office of the Higher Education Commission, through the Center of Excellence in Specific Health Problems in Greater Mekong Sub-region cluster (SHeP-GMS), Khon Kaen University to Anchalee Techasen and a grant from the Faculty of Medicine (Grant No. IN58246), Khon Kaen University, Thailand. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.