Several studies have characterized the cellular and molecular mechanisms of hepatocyte injury caused by the retention of hydrophobic bile acids (BAs) in cholestatic diseases. BAs may disrupt cell membranes through their detergent action on lipid components and can promote the generation of reactive oxygen species that, in turn, oxidatively modify lipids, proteins, and nucleic acids, and eventually cause hepatocyte necrosis and apoptosis. Several pathways are involved in triggering hepatocyte apoptosis. Toxic BAs can activate hepatocyte death receptors directly and induce oxidative damage, thereby causing mitochondrial dysfunction, and induce endoplasmic reticulum stress. When these compounds are taken up and accumulate inside biliary cells, they can also cause apoptosis. Regarding extrahepatic tissues, the accumulation of BAs in the systemic circulation may contribute to endothelial injury in the kidney and lungs. In gastrointestinal cells, BAs may behave as cancer promoters through an indirect mechanism involving oxidative stress and DNA damage, as well as acting as selection agents for apoptosis-resistant cells. The accumulation of BAs may have also deleterious effects on placental and fetal cells. However, other BAs, such as ursodeoxycholic acid, have been shown to modulate BA-induced injury in hepatocytes. The major beneficial effects of treatment with ursodeoxycholic acid are protection against cytotoxicity due to more toxic BAs; the stimulation of hepatobiliary secretion; antioxidant activity, due in part to an enhancement in glutathione levels; and the inhibition of liver cell apoptosis. Other natural BAs or their derivatives, such as cholyl-N-methylglycine or cholylsarcosine, have also aroused pharmacological interest owing to their protective properties.
Reduced drug uptake is an important mechanism of chemoresistance. Down-regulation of SLC22A1 encoding the organic cation transporter-1 (OCT1) may affect the response of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CGC) to sorafenib, a cationic drug. Here we investigated whether SLC22A1 variants may contribute to sorafenib chemoresistance. Complete sequencing and selective variant identification were carried out to detect single nucleotide polymorphisms (SNPs) in SLC22A1 complementary DNA (cDNA). In HCC and CGC biopsies, in addition to previously described variants, two novel alternative spliced variants and three SNPs were identified. To study their functional consequences, these variants were mimicked by directed mutagenesis and expressed in HCC (Alexander and SK-Hep-1) and CGC (TFK1) cells. The two novel described variants, R61S fs*10 and C88A fs*16, encoded truncated proteins unable to reach the plasma membrane. Both variants abolished OCT1-mediated uptake of tetraethylammonium, a typical OCT1 substrate, and were not able to induce sorafenib sensitivity. In cells expressing functional OCT1 variants, OCT1 inhibition with quinine prevented sorafenib-induced toxicity. Expression of OCT1 variants in Xenopus laevis oocytes and determination of quinine-sensitive sorafenib uptake by high-performance liquid chromatography-dual mass spectrometry confirmed that OCT1 is able to transport sorafenib and that R61S fs*10 and C88A fs*16 abolish this ability. Screening of these SNPs in 23 HCC and 15 CGC biopsies revealed that R61S fs*10 was present in both HCC (17%) and CGC (13%), whereas C88A fs*16 was only found in HCC (17%). Considering all SLC22A1 variants, at least one inactivating SNP was found in 48% HCC and 40% CGC. Conclusion: Development of HCC and CGC is accompanied by the appearance of aberrant OCT1 variants that, together with decreased OCT1 expression, may dramatically affect the ability of sorafenib to reach active intracellular concentrations in these tumors. (HEPATOLOGY 2013;58:1065-1073 H epatocellular carcinoma (HCC) and cholangiocarcinoma (CGC) are important causes of cancer-related death worldwide. Although surgery is potentially curative for patients with localized disease, these tumors are often in an advanced stage at the time of diagnosis, when surgery is no longer the
Recent functional studies have suggested that, in addition to simple diffusion, carrier-mediated transport may play an important role in foetal unconjugated bilirubin (UCB) uptake by the placenta. We have investigated the role of organic anion-transporting polypeptides (OATPs) in UCB transport by the placenta-maternal liver tandem. RNA was obtained from human liver (hL), human placenta (hPl) at term, and purified (> 80%) cytokeratin-7-positive mononucleated human trophoblast cells (hTCs). By analytical reverse transcription (RT)-PCR, agarose gel electrophoresis separation and sequencing, the mRNA of OATP-A ( SLC21A3 ) and OATP-8 ( SLC21A8 ) was identified in hL, hPl and hTCs, whereas that of OATP-C ( SLC21A6 ) was detectable only in hL. Real-time quantitative RT-PCR revealed that in hL the abundance of mRNA was OATP-8 > OATP-C >> OATP-A, whereas in hPl and hTCs this was OATP-8 >> OATP-A >> OATP-C. Expression levels for these OATPs were hL >> hTCs > hPl. Injection of mRNA of OATP-A, OATP-C or OATP-8 or RNA from hL, hPl or hTCs into Xenopus laevis oocytes conferred on them the ability to take up [(3)H]17 beta-D-glucuronosyl oestradiol ([(3)H]E(2)17 beta G) and [(3)H]UCB, although in the case of OATP-A mRNA, the induced uptake of [(3)H]UCB was very low. Cis -inhibition of [(3)H]E(2)17 beta G and [(3)H]UCB uptake by both unlabelled E(2)17 beta G and UCB was found in all cases. The affinity and efficiency of [(3)H]UCB transport was OATP-C > OATP-8. Kinetic parameters for [(3)H]UCB uptake induced by RNA from hTCs resembled most closely those of OATP-8. In conclusion, our results suggest that OATP-8 may play a major role in the carrier-mediated uptake of foetal UCB by the placental trophoblast, whereas both OATP-8 and OATP-C may substantially contribute to UCB uptake by adult hepatocytes.
The intrauterine environment is a major contributor to increased rates of metabolic disease in adults. Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that affects 0.5%-2% of pregnant women and is characterized by increased bile acid levels in the maternal serum. The influence of ICP on the metabolic health of offspring is unknown. We analyzed the Northern Finland birth cohort 1985-1986 database and found that 16-year-old children of mothers with ICP had altered lipid profiles. Males had increased BMI, and females exhibited increased waist and hip girth compared with the offspring of uncomplicated pregnancies. We further investigated the effect of maternal cholestasis on the metabolism of adult offspring in the mouse. Females from cholestatic mothers developed a severe obese, diabetic phenotype with hepatosteatosis following a Western diet, whereas matched mice not exposed to cholestasis in utero did not. Female littermates were susceptible to metabolic disease before dietary challenge. Human and mouse studies showed an accumulation of lipids in the fetoplacental unit and increased transplacental cholesterol transport in cholestatic pregnancy. We believe this is the first report showing that cholestatic pregnancy in the absence of altered maternal BMI or diabetes can program metabolic disease in the offspring.
Molecular bases for targeting bile acid-cisplatin derivatives Bamet-R2 [cis-diammine-chloro-cholylglycinate-platinum(II)]and Bamet-UD2 [cis-diammine-bisursodeoxycholate-platinum(II)] toward liver cells were investigated. Carriers for bile acids [human Na ϩ -taurocholate cotransporting polypeptide (NTCP)], organic anions [organic anion transporting polypeptide (OATP)], and organic cations [organic cation transporter (OCT)] were expressed in Xenopus laevis oocytes (XO) and Chinese hamster ovary (CHO) cells. Drug uptake was measured by flameless atomic absorption of platinum. Rat Oatp1-or rat Ntcp-transfected CHO cells were able to take up Bamets, but not cisplatin, severalfold more efficiently than wild-type cells. This uptake was enhanced by butyrate-induced expression of both carriers. Uptake of both Bamets by Ntcp-transfected CHO cells was stimulated by extracellular sodium. The amount of Bamets, but not cisplatin, taken up by XO was enhanced when expressing OATP-A, OATP-C, NTCP, OCT1, or OCT2, a nonhepatic OCT isoform used for comparative purposes. Bamet uptake by XO was inhibited by known substrates of these carriers (glycocholate for NTCP and OATP-C, ouabain for OATP-A, and quinine for OCT1 and OCT2). Drug uptake versus substrate concentration revealed saturation kinetics (K m was in the 8 -58 M range), with the following order of efficiency of transport (V max / K m ) for Bamet-R2: OATP-C Ͼ OCT2 Ͼ OATP-A Ͼ NTCP Ͼ OCT1; and the following order of efficiency of transport for Bamet-UD2: OATP-C Ͼ OCT2 Ͼ OATP-A Ͼ OCT1 Ͼ NTCP. Increasing the generation of cationic forms of Bamets by incubation in the absence of chloride increased drug uptake by OATP-A, OCT1, and OCT2 but reduced that achieved by NTCP and OATP-C. These results suggest a role for carriers of organic anions and cations in Bamet-R2 and Bamet-UD2 uptake, which may determine their ability to accumulate in liver tumor cells and/or be taken up and efficiently excreted by hepatocytes.
Although surgical resection is the standard curative therapy for gastric cancer, these tumors are often diagnosed at an advanced stage, when surgery is not recommended. Alternative treatments such as radiotherapy and chemotherapy achieve only very modest results. There is therefore an urgent need to advance in this field of oncologic gastroenterology. The poor response of gastric cancer to chemotherapy is usually due to a combination of mechanisms of chemoresistance (MOC), which may include a reduction in drug uptake (MOC-1a), enhanced drug efflux (MOC-1b), a reduced proportion of active agents in tumor cells due to a reduction in pro-drug activation or an enhancement in drug inactivation (MOC-2), changes in the expression/function of the molecular targets of anticancer drugs (MOC-3), an enhanced ability of cancer cells to repair anticancer drug-induced DNA damage (MOC-4), and decreased expression/function of pro-apoptotic factors or up-regulation of anti-apoptotic genes (MOC-5). Two major goals of modern pharmacology aimed at overcoming this situation are the prediction of a lack of response to chemotherapy and the identification of the underlying mechanisms accounting for primary or acquired refractoriness to anticancer drugs. These are important issues if we are to select the best pharmacological regime for each patient and develop novel strategies to overcome chemoresistance. The present review reports updated information regarding the mechanisms of chemoresistance (from MOC-1 to MOC-5) in gastric cancer, the advances made in the prediction of the failure of chemotherapeutic treatment, and novel strategies based on gene therapy currently being developed to treat these tumors.
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death in industrialized countries. Chemoprevention is a promising approach, but studies demonstrating their usefulness in large populations are still needed. Among several compounds with chemopreventive ability, cyclooxygenase inhibitors have received particular attention. However, these agents are not without side effects, which must be weighed against their beneficial actions. Early diagnosis is critical in the management of CRC patients, because, in early stages, surgery is curative in >90% of cases. If diagnosis occurs at stages II and III, which is often the case, neoadjuvant chemotherapy and radiotherapy before surgery are, in a few cases, recommended. Because of the high risk of recurrence in advanced cancers, chemotherapy is maintained after tumor resection. Chemotherapy is also indicated when the patient has metastases and in advanced cancer located in the rectum. In the last decade, the use of anticancer drugs in monotherapy or in combined regimens has markedly increased the survival of patients with CRC at stages III and IV. Although the rate of success is higher than in other gastrointestinal tumors, adverse effects and development of chemoresistance are important limitations to pharmacological therapy. Genetic profiling regarding mechanisms of chemoresistance are needed to carry out individualized prediction of the lack of effectiveness of pharmacological regimens. This would minimize side effects and prevent the selection of aggressive, cross-resistant clones, as well as avoiding undesirable delays in the use of the most efficient therapeutic approaches to treat these patients.
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