Differential Expression of Drug Uptake and Efflux Transporters in Japanese Patients with Hepatocellular Carcinoma

Abstract

Targeted chemotherapy for hepatocellular carcinoma (HCC) is impaired by intrinsic and/or acquired drug resistance. Because drugs used in HCC therapy (e.g., anthracyclines or the tyrosine kinase inhibitor sorafenib) are substrates of uptake and/or efflux transporters, variable expression of these transporters at the plasma membrane of tumor cells may contribute to drug resistance and subsequent clinical response. In this study, the variability of expression of uptake transporters [organic cation transporter (OCT) 1 and OCT3] and efflux transporters [multidrug resistance 1 (MDR1)/P-glycoprotein, multidrug resistance protein (MRP) 1, MRP2, and breast cancer resistance protein (BCRP)], selected for their implication in transporting drugs used in HCC therapy, was investigated. HCC and corresponding nontumor tissue samples were collected from 24 Japanese patients at the time of surgery.Protein expression was determined by immunohistochemistry. Expression data were correlated with clinicopathological characteristics and patients' outcome (median follow-up, 53 months). Generally, expression was highly variable among individual tumor samples. Yet median expression of OCT1, OCT3, and MDR1 in HCC was significantly lower (1.4-, 2.7-, and 2-fold, respectively) than in nontumor tissue, while expression of MRP2 persisted and BCRP showed a trend of increased levels in HCC. Patients with low BCRP expression had significantly shorter overall and recurrence-free survival times. Results suggest different expression patterns of drug transporters in HCC, which are associated only in part with clinicopathological characteristics. Detailed information on expression of drug transporters in HCC may be promising for individualization and optimization of drug therapy for liver cancer.

The lack of the organic cation transporter OCT1 at the plasma membrane of tumor cells precludes a positive response to sorafenib in patients with hepatocellular carcinoma

“…Localization of the OCT1 staining at the plasma membrane was classified as either positive or negative ( Figure 2B-2E and Figure 3B-3E). In spite of marked interindividual variability, ranging from absent to strong ( Figure 2B-2E and Figure 3B-3E), the results from the immunohistochemical analysis have confirmed previous observations on the downregulation of OCT1 in HCC when measured as the abundance of OCT1 mRNA or protein [13,17,[19][20][21]. Indeed, when the tumors were classified according to the intensity of staining approximately half of them displayed marked (defined as moderate or strong staining scores) OCT1 expression ( Figure 4A).…”

“…Using this approach OCT1 downregulation in HCC has been also confirmed [21]. The main contribution of the present study is to highlight that, in addition to reduced OCT1 expression (mRNA/protein) levels in the tumor, the reduction in functional OCT1 at the plasma membrane of tumor cells plays a key role among the multifactorial mechanisms of chemoresistance (MOC) determining the response of HCC to sorafenib.…”

“…In spite of maintained OCT1 expression, some clones developed chemoresistance to sorafenib by enhanced efflux through upregulation of the ABC protein, MRP3 [25] or activation of RAF kinases and PI3K/AKT pathway [26]. A role in MOC related to changes in the expression of ABC pumps, mainly ABCG2, has also been reported in clinical samples of HCC [21].…”

A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer

“…Sorafenib is transported into hepatocytes by organic cation transporter-1 and -3 and organic anion transporting polypeptides. 54,55 These transporters are also expressed in CRPC tumors and cell lines including PC3 and LNCaP cells. [56][57][58][59] However, no transporter has been identified for nilotinib, suggesting a passive transport across the cell membrane.…”

Avaliação da expressão imuno-histoquímica de proteínas transportadoras biliares em carcinoma hepatocelular e em colangiocarcinoma

“…(53,55,(148)(149)(150)(151) No fígado, é responsável pela excreção de ampla variedade de ânions orgânicos bivalentes relacionados ao metabolismo da bilirrubina. Sua deficiência está relacionada à síndrome de Dubin-Johnson caracterizada por uma moderada hiperbilirrubinemia conjugada crônica.…”