[1] Regarding chemotherapy, HCC and CGC are among the tumors with the highest refractoriness. Although some drugs, such as doxorubicin, can achieve a partial effect in some cases, no relevant survival benefit has been obtained.[2] Chemoresistance is often present before the treatment, but it can be further enhanced in response to the pharmacological challenge.[3] Mechanisms of chemoresistance (MOCs) have been classified based on their role in drug uptake (MOC-1a) or efflux (MOC-1b), intracellular

drug metabolism (MOC-2), changes in the expression/function of molecular targets (MOC-3), changes in LDK378 solubility dmso the DNA repair machinery (MOC-4), reduced activation of apoptosis (MOC-5a), and enhanced expression/activity of antiapoptotic proteins (MOC-5b).[4] MOCs may involve changes in the expression levels of specific proteins and the presence of genetic variants affecting their function.[5] One of the most promising strategies to overcome chemoresistance of primary liver cancer is the development of

tyrosine kinase inhibitors (TKIs), such as sorafenib. This drug has been approved for the treatment of HCC, although the beneficial effect, regarding the inhibition of tumor progression and the enhancement of overall survival, is rather modest.[6] Sorafenib has been reported to be effective in vitro against cells derived from CGC,[7, 8] although its efficacy in 上海皓元 CGC patients is low.[9]

The mechanism of action of sorafenib Everolimus depends on its access to the intracellular targets, which may be affected by changes in the expression and activity of transporters accounting for its uptake. The organic cation transporter-1 (OCT1, gene symbol SLC22A1), located at the basolateral membrane of healthy hepatocytes, is one of these transporters. OCT1 mediates the uptake of endogenous and exogenous organic cations,[10] including drugs such as metformin,[11] platinum derivatives,[12] anthracyclines,[10] and TKIs.[13] The response to drugs whose hepatic uptake depends on this transporter, such as metformin, is affected by changes in OCT1 expression and by the appearance of less functional variants.[14] In HCC and CGC, a decreased expression of OCT1 has been found.[3, 15] Moreover, a relationship between the presence of inactivating mutations in the SLC22A1 gene and a lower response to imatinib in patients with chronic myeloid leukemia has been reported.[16] In the present study we investigated the expression of aberrant OCT1 variants in HCC and CGC and evaluated in vitro their potential impact on the sensitivity of these tumors to sorafenib. Tumor samples from 23 HCC and 15 CGC (see patient and tumor information in Supporting Table 1) were obtained with written consent of patients from surgically removed tumors. None of these patients had received chemotherapy prior to the resection.