Farnesoid X receptor (FXR) has been recently reported to enhance chemoresistance through bile acid-independent mechanisms. Thus, FXR transfection plus activation with GW4064 resulted in reduced sensitivity to cisplatin-induced toxicity. This is interesting because primary tumors of the liver, an organ where FXR is expressed, exhibit marked refractoriness to pharmacological treatment. Here we have determined whether FXR is upregulated in hepatocellular carcinoma (HCC), cholangiocarcinoma (CGC) and hepatoblastoma (HPB) and whether this is related with the expression of genes involved in mechanisms of chemoresistance. Using RT-QPCR and Taqman low density arrays we have analyzed biopsies from healthy livers or surgically removed tumors from naive patients and cell lines derived from HCC (SK-HEP-1, Alexander and Huh7), CGC (TFK1) and HPB (HepG2), before and after exposure to cisplatin at IC50 for 72 h. In liver tumors FXR expression was not enhanced but significantly decreased (healthy liver > HCC > HPB ≈ CGC). Except for CGC, this was not accompanied by changes in the proportions of FXR isoforms. Changes in 36 genes involved in drug uptake/efflux and metabolism, expression/function of molecular targets, and survival/apoptosis balance were found. Changes affecting SLC22A1, CYP2A1 and BIRC5 were shared by HCC, CGC and HPB. Similarity in gene expression profiles between cell lines and parent tumors was found. Pharmacological challenge with cisplatin induced changes that increased this resemblance. This was not dependent upon FXR expression. Thus, although FXR may play a role in inducing chemoresistance under certain circumstances, its upregulation does not seem to be involved in the multidrug resistance phenotype characteristic of HCC, CGC and HPB.

Sulfated progesterone metabolite (P4-S) levels are raised in normal pregnancy and elevated further in intrahepatic cholestasis of pregnancy (ICP), a bile acid-liver disorder of pregnancy. ICP can be complicated by preterm labor and intrauterine death. The impact of P4-S on bile acid uptake was studied using two experimental models of hepatic uptake of bile acids, namely cultured primary human hepatocytes (PHH) and Na ؉ -taurocholate co-transporting polypeptide (NTCP)-expressing Xenopus laevis oocytes. Two P4-S compounds, allopregnanolone-sulfate (PM4-S) and epiallopregnanolone-sulfate (PM5-S), reduced [ 3 H]taurocholate (TC) uptake in a dose-dependent manner in PHH, with both Na ؉ -dependent and -independent bile acid uptake systems significantly inhibited. PM5-S-mediated inhibition of TC uptake could be reversed by increasing the TC concentration against a fixed PM5-S dose indicating competitive inhibition. Experiments using NTCP-expressing Xenopus oocytes confirmed that PM4-S/PM5-S are capable of competitively inhibiting NTCPmediated uptake of [ 3 H]TC. Total serum PM4-S ؉ PM5-S levels were measured in non-pregnant and third trimester pregnant women using liquid chromatography-electrospray tandem mass spectrometry and were increased in pregnant women, at levels capable of inhibiting TC uptake. In conclusion, pregnancy levels of P4-S can inhibit Na ؉ -dependent and -independent influx of taurocholate in PHH and cause competitive inhibition of NTCP-mediated uptake of taurocholate in Xenopus oocytes.Normal pregnancy is characterized by altered bile acid homeostasis, and two recent studies have reported asymptomatic hypercholanemia of pregnancy in 10 -40% of pregnant women (1, 2). Approximately 25% of women with asymptomatic hypercholanemia of pregnancy subsequently develop intrahepatic cholestasis of pregnancy (ICP), 4 a liver disorder that presents with pruritus, raised serum bile acids, and liver transaminases (3). In pregnancies complicated by maternal serum bile acid levels of Ͼ40 M, there are increased rates of spontaneous preterm labor, fetal asphyxial events, and meconium-stained amniotic fluid (3). ICP may also be complicated by third trimester intrauterine death (3, 4).ICP has a complex etiology with genetic and endocrine components. Parous sisters have a 12-fold increased risk (5), and in ϳ10% of ICP cases, mutations have been identified in genes that encode biliary transporters (6 -9) and the primary bile acid sensor farnesoid X receptor (NR1H4) (10). Furthermore, the V444A polymorphism in the ABCB11 gene is a population risk factor for ICP (8), and ICP patients homozygous for the polymorphism have been shown to have increased bile acid levels when compared with controls (11).Cholestatic metabolites of estrogen and progesterone influence bile acid metabolism and transport. A subgroup of women with a history of ICP who take the oral contraceptive pill or exogenous estrogens develop pruritus and hepatic impairment (4). In addition, administration of oral micronized natural progesterone for prophylaxis of...

Primary malignancies of the liver and the gastrointestinal tract constitute one of the main health problems worldwide. Together, these types of tumour are the first cause of death due to cancer, followed by lung and breast cancer respectively. One important limitation in the treatment of these tumours is that, with a few exceptions, they exhibit marked resistance to currently available drugs. Moreover, most of them develop chemoresistance during treatment. The mechanisms responsible for drug refractoriness in gastrointestinal tumours include a reduction in drug uptake; enhanced drug export; intracellular inactivation of the effective agent; alteration of the molecular target; an increase in the activity of the target route to be inhibited or the appearance or stimulation of alternative routes; enhanced repair of drug-induced modifications in the target molecules, and the activation/inhibition of intracellular signalling pathways, which leads to a negative balance between the apoptosis/survival of tumour cells. A better understanding of these mechanisms is needed in order to develop accurate tests to predict the lack of response to chemotherapy and novel approaches aimed at overcoming resistance to anticancer agents. The purpose of the present review is to offer an updated overview of the molecular mechanisms of resistance to cytostatic drugs in the most frequent types of primary malignant tumour affecting the liver and gastrointestinal tract.