Xanthohumol inhibits STAT3 activation pathway leading to growth suppression and apoptosis induction in human cholangiocarcinoma cells

Abstract

STAT3 plays a significant role in the development of cholangiocarcinoma (CCA) associated with the liver fluke (Opisthorchis viverrini; Ov). Xanthohumol (XN), a prenylated flavonoid extracted from hops, has known anticancer activity and could potentially target STAT3. The present study determined the effect of XN on STAT3, as well as ascertained its usefulness against CCA. The CCA cell proliferation at 20 µM and 50 µM of XN was shown to inhibited, while 20 µM partially inhibited IL-6-induced STAT3 activation. At 50 µM, the inhibition was complete. The reduction in STAT3 activity at 20 and 50 µM was associated with a significant reduction of CCA cell growth and apoptosis. We also found that the administration of 50 µM XN orally in drinking water to nude mice inoculated with CCA led to a reduction in tumor growth in comparison with controls. In addition, apoptosis of cancer cells increased although there was no visible toxicity. The present study shows that XN can inhibit STAT3 activation both in vivo and in vitro due to suppression of the Akt-NFκB signaling pathway. XN should be considered as a possible therapeutic agent against CCA.

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

“…These results suggested that XN could reduce expression of CD44v8-10 via the possible mechanism of oxidative damage inhibition (reduction of phospho-p38 MAPK activation). Furthermore, it has been shown that XN could effectively suppress the growth of tumor and induced apoptosis in CCA cells and tumor inoculated mice ( Dokduang et al, 2016 ). Currently, it has been reported that the oxidative stress could induce Wnt activation ( Yoshida & Saya, 2014 ), and then triggered the transcription of CD44 ( Ishimoto et al, 2010 ).…”

“…Additionally, it reduced ROS formation ( Hartkorn et al, 2009 ) and protection against DNA damage ( Pinto et al, 2012 ). Dokduang et al (2016) reported that XN effectively suppressed the growth of tumor and induced apoptosis in CCA cells and tumor inoculated mice by which inhibiting STAT3 activation due to suppression of the Akt-NFκB signaling pathway. These data suggested that XN has a potential to become a useful new approach for the chemoprevention and/or treatment of CCA.…”

Anticancer Activity and Mechanism of Xanthohumol: A Prenylated Flavonoid From Hops (Humulus lupulus L.)

“…It has been reported that administration of Xn orally in drinking water to CCA bearing nude mice reduced tumor growth. Tumor tissues from Xn-treated mice exhibited suppressed tumor growth and increased apoptosis as demonstrated by decreased Ki67 positive cells and increased TUNEL positive cells ( Dokduang et al, 2016 ). However, it was difficult to guarantee the identity among individuals through administration of Xn orally in drinking water.…”

Xanthohumol inhibits the extracellular signal regulated kinase (ERK) signalling pathway and suppresses cell growth of lung adenocarcinoma cells

“…More detailed mechanisms of its cancer preventive action are associated with inhibition of the AKT/NFkB pathway, interruption of JAK/STAT3 and Notch1 signaling, modulation of apoptosis regulators (Bax, Bcl-2, survivin, caspases, poly(ADPribose) polimerase) and cell cycle-related factors (cyclin D1, p53, p21), and reduced expression and secretion of MMP-9 and VEGF, i.e. molecules implicated in the angiogenic switch process (Kim et al, 2013;Pilatova et al, 2010;Dokduang et al, 2016). In addition, XN is able to upregulate the E-cadherin/catenin complex in breast cancer cells and to repress the expression of the CXCR4 chemokine receptor in both breast and colon tumor cells to abolish their metastatic capability Wang et al, 2012).…”