Cholangiocarcinoma (CCA), a primary carcinoma of the intrahepatic bile duct, is generally a rare cancer. However, it has been frequently reported among oriental populations who are endemically infected with the liver flukes, Opisthorchis viverrini (OV) (Waraasawapati et al. 2021) or Clonochis sinensis, in parts of the Greater Mekong Sub-region countries (Shin et al. 2010; Sirica et al. 2019). Northeast Thailand has the highest risk of all, with an annual incidence rate of 90 per 100,000 person-years in males and 38.3 per 100,000 person-years in females (Sriamporn et al. 2004). In Northeast Thailand, OV infection is acquired by eating popular simple dishes; marinated chopped raw fish or a short-pickled fish, preparations from freshwater fish which contains the infective stage of OV in tissue (Prueksapanich et al. 2018). Moreover, people in northeastern Thailand are also exposed to a carcinogen (i.e., nitrosamine) in favorite fermented fish (Mitacek et al. 1999). Thus, traditional eating habits on a daily basis result in a local population repeatedly exposed to both OV infection and nitrosamine-contaminated food from early in life.
Synergistic effects of nitrosamines and OV infection induce CCA in Syrian golden hamsters, under conditions whereby the administration of chemical carcinogen or fluke infection alone do not cause cancer (Thamavit et al. 1987). In this carcinogenesis model, chronic inflammation in response to chronic infestation by liver flukes results in release of cytokines and growth factors leading to biliary cell proliferation (Sripa et al. 2018; van Tong et al. 2017; Yongvanit et al. 2012). At the same time, nitrosamines act as xenobiotics and stimulate hyperplasia of oval cells (hepatic stem/progenitor cells) and develop atypical ductular proliferation. The proliferation of oval cells by liver cell injury is suspected to be early progenitor cells for hepatocytes and bile duct cells origin to cause cholangiofibrosis, cholangiofibroma, hepatocellular and/or cholangiocellular carcinomas (cholangiocarcinoma, CCA) (Chen et al. 2019; Lee et al. 1997). Based on case series, epidemiological data, and experimental animal models, the international Agency for Research on Cancer have classified OV and C. sinensis as class 1 carcinogen in humans (IARC 2012).
Oncogenesis of CCA in fluke-associated tumors is initiated by oxidation/nitration of DNA damage (Banales et al. 2020; Yongvanit et al. 2012). Upregulation of inflammation-associated transcription factors, e.g. nuclear factor kappa (NF-κB) and activator protein 1 (AP-1), as well as their downstream targets such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), have been identified both in animal models (Prakobwong et al. 2010) and clinical samples (Pinlaor et al. 2005). Upregulation of NF-κB (Dolcet et al. 2005), forkhead box m1 (FOXM1) (Wierstra 2013) and high mobility group box 1 (HMGB1) (Vijayakumar et al. 2019) are involved in inflammation-associated carcinogenesis and targeted for cancer therapy. Hence, discovery of agents that exert anti-inflammatory and anti-infection effects and that can attenuate cholangiofibrosis could lead to alternative treatments for CCA.
Compounds derived from herbs have been extensively studied and proposed as alternative treatments for several cancers. Curcumin, a yellow pigment derived from the rhizome of Curcuma longa, is one of the most-studied natural compounds for cancer treatment. It exerts several health-beneficial properties particularly anti-inflammatory, anti-infection and also anti-fibrosis activities (Razavi et al. 2021). Curcumin is a promising agent for prevention and treatment of cancers in animal models including O. viverrini-associated CCA (Pinlaor et al. 2009; Prakobwong et al. 2011b), and clinical trials of curcumin has been introduced for many cancer types (Mansouri et al. 2020; Shehzad et al. 2010). However, curcumin has several unfavorable properties, especially poor water solubility, low bioavailability and it is prone to degradation (Liu et al. 2016), limiting its activity in clinical trials (Anand et al. 2007; Baker 2017). Efforts have therefore been made to overcome these unfavorable properties (Mahran et al. 2017; Rafiee et al. 2019; Zhang et al. 2019).
One of the approaches is incorporation of curcumin into nanocarrier systems such as lipid-based nanocarriers, polymer-based nanocarriers, hydrogels, dendrimers and so on (Ipar et al. 2019; Rafiee et al. 2019; Zhang et al. 2019). Incorporation of curcumin into a mucoadhesive polymeric nanocarrier to deliver this payload into the gastrointestinal tract has been particularly promising (Suwannateep et al. 2011). Polymeric nanocurcumin has recently been improved by covering particles with xanthan and arabic gums—so-called curcumin-loaded nanocomplexes (CNCs) (Pinlaor S et al. 2021). CNCs have very low toxicity for biliary epithelial cells and exhibit anti-CCA activity against CCA cell lines (Pinlaor S et al. 2021). Similarly, CNCs have very low acute and chronic toxicity in animal models (Jantawong et al. 2021). However, attenuation of progression of CCA by CNCs in vivo has not yet been demonstrated.
The objective of this study was to assess the effect of a five-month regimen of treatment with CNCs against CCA induced in a hamster model by O. viverrini infection. In this model, there is poor prognosis due to multi-site metastasis. Assessment of animal survival, number of tumors, histopathological changes, biochemical parameters, and the expression of inflammatory/oncogenic transcription factors were all investigated to assess the attenuation efficacy of CNCs on tumor development. This preclinical study should be a basis for translation to eventual clinical use.