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, 6 (19), 17738-52

Lapatinib Promotes the Incidence of Hepatotoxicity by Increasing Chemotherapeutic Agent Accumulation in Hepatocytes

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Lapatinib Promotes the Incidence of Hepatotoxicity by Increasing Chemotherapeutic Agent Accumulation in Hepatocytes

ChunLing Dai et al. Oncotarget.

Abstract

Lapatinib has been used in combination with capecitabine or paclitaxel to treat patients with progressive HER2-overexpressing metastatic breast cancer (MBC). Unfortunately, an increased incidence of hepatotoxicity had been reported in the combinational therapy. The aim of this study was to investigate the potential mechanisms of this combinational therapy. We found that the patients receiving lapatinib and paclitaxel treatment showed a higher incidence of hepatobiliary system disorders than those receiving paclitaxel alone. Lapatinib was shown to increase the accumulation of doxorubicin in ABCB1-overexpressing hepatocellular cancer cells and normal liver tissues without altering the protein level of ABCB1. Pharmacokinetic studies revealed that lapatinib could increase the systematic exposure of paclitaxel and doxorubicin. Moreover, the in vivo experiments showed that the levels of alanine aminotransferase and serious hepatocyte injury in the group of lapatinib plus chemotherapeutic agent were significantly higher than those in the group of single chemotherapeutic agent such as paclitaxel or doxorubicin. Our study thus revealed for the first time that the higher incidence of hepatotoxicity during this combinational treatment was due to the increased drug accumulation in hepatocytes mediated by the inhibition of ABCB1 by lapatinib. Appropriate dose adjustment may be needed to optimize the combination therapy.

Keywords: ABC transporters; hepatotoxicity; lapatinib; pharmacokinetic.

Conflict of interest statement

CONFLICTS OF INTEREST

No potential conflicts of interest were disclosed.

Figures

Figure 1
Figure 1. Effect of lapatinib on the accumulations of doxorubicin and rhodamine 123
A. The expression of ABCB1 in HepG2/Adr cells was detected by Western blot. B. Lapatinib enhanced the cytotoxicity effect of doxorubicin on ABCB1-overexpressing HepG2/Adr cells. C. D. E. F. The accumulations of doxorubicin and rhodamine 123 were measured by flow cytometric analysis as described in “Materials and Methods”. The results are presented as fold change in fluorescence intensity relative to control MDR cells. ** P < 0.01 versus control group. The experiment was done at least thrice.
Figure 2
Figure 2. Effect of lapatinib on the expression of ABCB1
The protein level of ABCB1 was measured by Western blot and mRNA level was measured by qRT-PCR. A. B. Lapatinib did not alter the protein levels or mRNA levels in HepG2/Adr cells. C. Grayscale ratios of ABCB1/GAPDH were analyzed with Image J. The grayscale ratios were proportional to the ABCB1 protein levels. D. qRT-PCR was further applied to confirm unchangeable mRNA levels in HepG2/Adr cells. All experiments were repeated at least three times, and a representative set of data is shown in each panel.
Figure 3
Figure 3. Expression levels of ABCB1 and doxorubicin accumulation in normal liver tissues
The mRNA level was determined by qRT-PCR as described in “Materials and Methods”: A. the mRNA level of ABCB1 in normal liver tissues; B. Sections of human liver reacted with ABCB1 antibody, demonstrating localization in bile canaliculi and hepatocytes. C. Sections of mice liver reacted with ABCB1 antibody, demonstrating localization in bile canaliculi and hepatocytes; The magnification is 400 ×. D. The absorption spectra for doxorubicin (0.5 mg/ml) is detected by UV spectrophotometric method. E. lapatinib increased the doxorubicin accumulation in normal liver tissues. All experiments were done at least thrice.
Figure 4
Figure 4. Effect of lapatinib on pharmacokinetics of paclitaxel and doxorubicin
A. B. Effect of lapatinib on the profile of paclitaxel and doxorubicin pharmacokinetics in mice. NIH mice were p.o. administered with or without lapatinib (100 mg/kg) 1 h before i.v. administration of paclitaxel (18 mg/kg) or doxorubicin (10 mg/kg). HPLC analysis was performed as described in the “Material and Methods”. The values represent mean ± standard deviation in the triplicate determination.
Figure 5
Figure 5. The histological results in in vivo experiments
HE staining of liver tissues (Main-figure: magnification × 200; Sub-figure: magnification × 400) A. Normal liver parenchyma; B. (group of lapatinib alone) shows a similar histology to the normal group; C. (group of paclitaxel alone) shows mild liver damage: hepatocytes with hydropic changes and monocytes infiltration around the central vein; D. (group of doxorubicin alone) shows mild central venous hyperemia, Hepatic cord disorder and vacuolar degeneration; E. (group of lapatinib and paclitaxel) and F. (group of lapatinib and doxorubicin) show severe liver damage: severe inflammation with neutrophil and eosinophil in portal area, focal necrosis in lobular area, apoptotic body in periportal area. The values represent mean ± standard deviation in the triplicate determination.
Figure 6
Figure 6. Schematic illustration of the mechanism of lapatinib promoting the cytotoxic effect of chemotherapeutic agent in liver
Lapatinib can interfere with the distribution of agent and increase the plasma concentration. In hepatocytes, the chemotherapeutic agent is excreted out of the cells by ABC transporters (mainly ABCB1). Lapatinib inhibits the function of ABCB1 and elevates the concentration of chemotherapeutic agent in hepatocytes. Consequently, the hepatocytes develop into apoptosis or necrosis and the hepatic function is disordered.

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