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

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-p38MAPK (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.

Curative effect of xanthohumol supplementation during liver fluke-associated cholangiocarcinogenesis: Potential involvement of autophagy

“…CCA carcinogenesis was induced in Syrian golden hamsters by an infection of Ov metacercariae combined with NDMA treatment. 24 The treatment protocol with XH in this experimental model has been reported previously. 24 Animal experiments were approved by the Animal Ethics Committee of the Faculty of Medicine, Khon Kaen University (AEKKU 23/2555), Thailand.…”

“… 24 The treatment protocol with XH in this experimental model has been reported previously. 24 Animal experiments were approved by the Animal Ethics Committee of the Faculty of Medicine, Khon Kaen University (AEKKU 23/2555), Thailand. Syrian golden hamsters ranging from 6 to 8 weeks of age were divided into four groups (eight/group): (i) untreated; (ii) treated with XH; (iii) ON (Ov with NDMA administration); and (iv) XHON (Ov infection and NDMA administration and XH treatment).…”

“… 23 Recently, it has been reported that XH suppresses inflammation and fibrosis resulting in a slow progression of CCA development in this experimental model. 24 XH has been shown to induce apoptosis in CCA cells and to inhibit the growth of CCA xenograft via suppression of the Akt—NF—kB signaling pathway and inhibition of STAT3 expression. 25 , 26 These data indicate that XH is a promising chemotherapeutics for CCA treatment.…”

Integrating modern approaches to pathogenetic concepts of malignant transformation of endometriosis

“…We hypothesized that endometriotic cells would acquire (epi)genetic modifications required for survival among the harshest and poorest environments. The cells selected for oxidative resistance enable clonal expansion/differentiation and could survive (66). Indeed, endometriosis is considered to be monoclonal in origin and neoplastic in nature (67).…”

Current and Novel Therapies Against Helminthic Infections: The Potential of Antioxidants Combined with Drugs

“…Following administration of the combined regime, there was no CCA development; the most severe pathological changes observed in these groups were only bile duct hyperplasia. XTH may repress CCA development via antioxidant activity through protection of cholangiocytes from oxidative stress [165].…”