Sorafenib Activity and Disposition in Liver Cancer Does Not Depend on Organic Cation Transporter 1

Chen, Mingqing; Neul, Claudia; Schaeffeler, Elke; Frisch, Franziska; Winter, Stefan; Schwab, Matthias; Koepsell, Hermann; Hu, Shuiying; Laufer, Stefan; Baker, Sharyn D.; Sparreboom, Alex; Nies, Anne T.

doi:10.1002/cpt.1588

Cited by 23 publications

(15 citation statements)

References 47 publications

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“…Solute carriers (SLC) play an essential role in the uptake of anticancer drugs. For instance, although a controversial study has reported the inability of organic cation transporter-1 (OCT1, SLC22A1 ) to transport sorafenib [ 8 ], others using Xenopus laevis oocytes and mammalian cells with stable expression of OCT1 have revealed that this transporter is involved in the uptake of sorafenib [ 9 , 10 ], but not regorafenib [ 10 ]. Reduced SLC22A1 expression and impaired OCT1 function, due to loss-of-function mutations and aberrantly spliced variants in HCC, have been reported ( Table 1 ) [ 9 , 10 ].…”

Section: Drug Uptake and Export (Moc-1)mentioning

confidence: 99%

Molecular Bases of Drug Resistance in Hepatocellular Carcinoma

Marin

Macı́as

Monte

et al. 2020

Cancers

140

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The poor outcome of patients with non-surgically removable advanced hepatocellular carcinoma (HCC), the most frequent type of primary liver cancer, is mainly due to the high refractoriness of this aggressive tumor to classical chemotherapy. Novel pharmacological approaches based on the use of inhibitors of tyrosine kinases (TKIs), mainly sorafenib and regorafenib, have provided only a modest prolongation of the overall survival in these HCC patients. The present review is an update of the available information regarding our understanding of the molecular bases of mechanisms of chemoresistance (MOC) with a significant impact on the response of HCC to existing pharmacological tools, which include classical chemotherapeutic agents, TKIs and novel immune-sensitizing strategies. Many of the more than one hundred genes involved in seven MOC have been identified as potential biomarkers to predict the failure of treatment, as well as druggable targets to develop novel strategies aimed at increasing the sensitivity of HCC to pharmacological treatments.

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Section: Drug Uptake and Export (Moc-1)mentioning

confidence: 99%

Molecular Bases of Drug Resistance in Hepatocellular Carcinoma

Marin

Macı́as

Monte

et al. 2020

Cancers

140

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“…A 10% dimethyl sulfoxide (DMSO) stock for sorafenib tosylate and 0.9% sodium chloride for atoravastatin and metformin were used to prepare the drug solutions. Blood samples were collected before administration and after dosing at the following time points: 0.5, 1, 2, 3, 4, 5,6,7,8,10,12,24,30,48,72, and 96 h (for sorafenib); 0.083, 0.25, 0.5, 0.75, 1, 2, 4, 6, and 12 h (for atorvastatin); and 0.083, 0.25, 0.5, 1, 1,5, 2, 4, 6, 8, 10, and 24 h (for metformin). The plasma was separated by centrifugation at 2880× g for 10 min at 4 • C and stored at −80 • C until drug analysis.…”

Section: Animal Experimentsmentioning

confidence: 99%

“…sodium hydroxide 3 67-56-1 sodium hydroxide microprills 5 1310-73-2 sorafenib 6 284461-73-0 sorafenib N-oxide 6 583840-03 rosuvastatin calcium 3 147098-20-2 ultrapure water (deionized, distilled, and filtered through Direct Q3 system) 4 7732-18-5 1 purchased from CHEMPUR (PiekaryŚląskie, Poland); 2 purchased from Santa Cruz Biotechnology, Inc. (Dallas, TX, USA); 3 purchased from Sigma-Aldrich (Saint Louis, MO, USA); 4 purchased from Merck Millipore (Burlington, MA, USA); 5 purchased from POCH S.A. (Gliwice, Poland); 6 purchased from LGC (Teddington TW11 0LY, UK).…”

Section: Reagent Cas Numbermentioning

confidence: 99%

Pharmacokinetic Interaction between Sorafenib and Atorvastatin, and Sorafenib and Metformin in Rats

et al. 2020

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The tyrosine kinase inhibitor sorafenib is the first-line treatment for patients with hepatocellular carcinoma (HCC), in which hyperlipidemia and type 2 diabetes mellitus (T2DM) may often coexist. Protein transporters like organic cation (OCT) and multidrug and toxin extrusion (MATE) are involved in the response to sorafenib, as well as in that to the anti-diabetic drug metformin or atorvastatin, used in hyperlipidemia. Changes in the activity of these transporters may lead to pharmacokinetic interactions, which are of clinical significance. The study aimed to assess the sorafenib−metformin and sorafenib−atorvastatin interactions in rats. The rats were divided into five groups (eight animals in each) that received sorafenib and atorvastatin (ISOR+AT), sorafenib and metformin (IISOR+MET), sorafenib (IIISOR), atorvastatin (IVAT), and metformin (VMET). Atorvastatin significantly increased the maximum plasma concentration (Cmax) and the area under the plasma concentration–time curve (AUC) of sorafenib by 134.4% (p < 0.0001) and 66.6% (p < 0.0001), respectively. Sorafenib, in turn, caused a significant increase in the AUC of atorvastatin by 94.0% (p = 0.0038) and its metabolites 2−hydroxy atorvastatin (p = 0.0239) and 4−hydroxy atorvastatin (p = 0.0002) by 55.3% and 209.4%, respectively. Metformin significantly decreased the AUC of sorafenib (p = 0.0065). The AUC ratio (IISOR+MET group/IIISOR group) for sorafenib was equal to 0.6. Sorafenib did not statistically significantly influence the exposure to metformin. The pharmacokinetic interactions observed in this study may be of clinical relevance in HCC patients with coexistent hyperlipidemia or T2DM.

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“…Several studies indicated the importance of the member 22 of the solute carrier family (organic cation/anion transporter) in sorafenib resistance. SLC22A1 (OCT1) has been reported to be involved in the uptake of sorafenib, both in an animal model or human cells [53,54], even though a recent study showed opposing results [55]. Downregulation of OCT1 and OCT3 (SLC22A3) was observed in HCC [56,57] which was further associated with a poor survival in patients treated with sorafenib, independently from the clinical staging of the associated liver disease [58].…”

Section: Drug Uptake: the Slc Familymentioning

confidence: 99%

Sorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity

Cabral

Tiribelli

Sukowati

2020

Cancers

117

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Despite advances in biomedicine, the incidence and the mortality of hepatocellular carcinoma (HCC) remain high. The majority of HCC cases are diagnosed in later stages leading to the less than optimal outcome of the treatments. Molecular targeted therapy with sorafenib, a dual-target inhibitor targeting the serine-threonine kinase Raf and the tyrosine kinases VEGFR/PDGFR, is at present the main treatment for advanced-stage HCC, either in a single or combinatory regimen. However, it was observed in a large number of patients that its effectiveness is hampered by drug resistance. HCC is highly heterogeneous, within the tumor and among individuals, and this influences disease progression, classification, prognosis, and naturally cellular susceptibility to drug resistance. This review aims to provide an insight on how HCC heterogeneity influences the different primary mechanisms of chemoresistance against sorafenib including reduced drug intake, enhanced drug efflux, intracellular drug metabolism, alteration of molecular targets, activation/inactivation of signaling pathways, changes in the DNA repair machinery, and negative balance between apoptosis and survival of the cancer cells. The diverse variants, mutations, and polymorphisms in molecules and their association with drug response can be a helpful tool in treatment decision making. Accordingly, the existence of heterogeneous biomarkers in the tumor must be considered to strengthen multi-target strategies in patient-tailored treatment.

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Sorafenib Activity and Disposition in Liver Cancer Does Not Depend on Organic Cation Transporter 1

Cited by 23 publications

References 47 publications

Molecular Bases of Drug Resistance in Hepatocellular Carcinoma

Molecular Bases of Drug Resistance in Hepatocellular Carcinoma

Pharmacokinetic Interaction between Sorafenib and Atorvastatin, and Sorafenib and Metformin in Rats

Sorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity

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