Enhanced antitumour drug delivery to cholangiocarcinoma through the apical sodium-dependent bile acid transporter (ASBT)

Lozano, Elisa; Monte, María J.; Briz, Óscar; Hernández‐Hernández, Ángel; Marin, José J.G.; Macı́as, Rocı́o I.R.

doi:10.1016/j.jconrel.2015.08.022

Cited by 35 publications

(23 citation statements)

References 29 publications

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“…We have reported that hOCT1 expression is reduced in HCC and CCA . In CCA, epigenetic abnormalities, including DNA hypermethylation, have been described .…”

Section: Discussionmentioning

confidence: 93%

Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy

et al. 2019

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Although the multi-tyrosine kinase inhibitor sorafenib is useful in the treatment of several cancers, cholangiocarcinoma (CCA) is refractory to this drug. Among other mechanisms of chemoresistance, impaired uptake through human organic cation transporter type 1 (hOCT1) (gene SLC22A1) has been suggested. Here we have investigated the events accounting for this phenotypic characteristic and have evaluated the interest of selective gene therapy strategies to overcome this limitation. Gene expression and DNA methylation of SLC22A1 were analyzed using intrahepatic (iCCA) and extrahepatic (eCCA) biopsies (Copenhagen and Salamanca cohorts; n = 132) and The Cancer Genome Atlas (TCGA)-CHOL (n = 36). Decreased hOCT1 mRNA correlated with hypermethylation status of the SLC22A1 promoter. Treatment of CCA cells with decitabine (demethylating agent) or butyrate (histone deacetylase inhibitor) restored hOCT1 expression and increased sorafenib uptake. MicroRNAs able to induce hOCT1 mRNA decay were analyzed in paired samples of TCGA-CHOL (n = 9) and Copenhagen (n = 57) cohorts. Consistent upregulation in tumor tissue was found for miR-141 and miR-330. High proportion of aberrant hOCT1 mRNA splicing in CCA was also seen. Lentiviral-mediated transduction of eCCA (EGI-1 and TFK-1) and iCCA (HuCCT1) cells with hOCT1 enhanced sorafenib uptake and cytotoxic effects. In chemically induced CCA in rats, reduced rOct1 expression was accompanied by impaired sorafenib uptake. In xenograft models of eCCA cells implanted in mouse liver, poor response to sorafenib was observed. However, tumor growth was markedly reduced by cotreatment with sorafenib and adenoviral vectors encoding hOCT1 under the control of the BIRC5 promoter, a gene highly up-regulated in CCA. Conclusion: The reason for impaired hOCT1-mediated sorafenib uptake by CCA is multifactorial. Gene therapy capable of selectively inducing hOCT1 in tumor cells can be considered a potentially useful chemosensitization strategy to improve the response of CCA to sorafenib. (Hepatology 2019;70:1246-1261).

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“…We have reported that hOCT1 expression is reduced in HCC and CCA . In CCA, epigenetic abnormalities, including DNA hypermethylation, have been described .…”

Section: Discussionmentioning

confidence: 93%

Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy

et al. 2019

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“…Targeted anti-fibrotic therapy is also under investigation 183 . In addition, the expression in tumour cells of the specific uptake transporter for bile acids, the apical sodium-dependent bile acid transporter (ASBT), has suggested the possibility of using cytostatic bile acid derivatives, such as the ursodeoxycholic acid-cisplatin conjugate BAMET-UD2, in targeted chemotherapy for CCA 270 . In 2015, the rationale for immunotherapy with checkpoint-molecule-specific monoclonal antibodies in patients bearing iCCA without defects in HLA class I antigen expression has been provided 271 but, so far, no clinical trial has been performed.…”

Section: Biliary Stentingmentioning

confidence: 99%

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

Bañales

Cardinale

Carpino

et al. 2016

Nat Rev Gastroenterol Hepatol

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“…Both in vitro and in vivo assays have demonstrated better antitumoural effect of Bamet-UD2 than cisplatin alone, with less exposure of extrahepatic tissues together with non-detectable toxicity at therapeutic dose. 208,209 Gene therapy has also been envisaged as a potential tool to overcome drug resistance. One explored rational has been to use vectors that express a drug transporter or a tumour suppressor protein under the control of a specific promoter that is upregulated in the target tumour cell.…”

Section: Novel Chemosensitization Strategiesmentioning

confidence: 99%

Signalling networks in cholangiocarcinoma: Molecular pathogenesis, targeted therapies and drug resistance

Fouassier

Marzioni

Afonso

et al. 2019

Liver International

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Cholangiocarcinoma (CCA) is a deadly disease. While surgery may attain cure in a minor fraction of cases, therapeutic options in either the adjuvant or advanced setting are limited. The possibility of advancing the efficacy of therapeutic approaches to CCA relies on understanding its molecular pathogenesis and developing rational therapies aimed at interfering with oncogenic signalling networks that drive and sustain cholangiocarcinogenesis. These efforts are complicated by the intricate biology of CCA, which integrates not only the driving force of tumour cell‐intrinsic alterations at the genetic and epigenetic level but also pro‐tumorigenic cues conveyed to CCA cells by different cell types present in the rich tumour stroma. Herein, we review our current understanding of the mechanistic bases underpinning the activation of major oncogenic pathways causative of CCA pathogenesis. We subsequently discuss how this knowledge is being exploited to implement rationale‐based and genotype‐matched therapeutic approaches that predictably will radically transform CCA clinical management in the next decade. We conclude by highlighting the mechanisms of therapeutic resistance in CCA and reviewing innovative approaches to combat resistance at the preclinical and clinical level.

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Enhanced antitumour drug delivery to cholangiocarcinoma through the apical sodium-dependent bile acid transporter (ASBT)

Cited by 35 publications

References 29 publications

Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy

Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

Signalling networks in cholangiocarcinoma: Molecular pathogenesis, targeted therapies and drug resistance

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