Lapatinib promotes the incidence of hepatotoxicity by increasing chemotherapeutic agent accumulation in hepatocytes

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.

Rapid Self-Assembly of Polymer Nanoparticles for Synergistic Codelivery of Paclitaxel and Lapatinib via Flash NanoPrecipitation

“…PTX and LAP target different mechanisms of the cell to produce an anticancer effect [70,71]. LAP inhibits the function of ABC transporters, which helps increase the intracellular concentration of PTX thereby increasing drug efficacy [24,72,73]. Similar synergistic effects were seen with chemotherapeutic agents and tyrosine kinase inhibitors [12,13].…”

The HER2 inhibitor lapatinib potentiates doxorubicin-induced cardiotoxicity through iNOS signaling

“…However, our study clearly shows that combining LAP-plus-DOX results in synergistic induction of apoptosis in hPSC-CMs. Based on previous studies showing that LAP treatment significantly increases DOX accumulation in cancer cells and hepatocytes by inhibiting transporter drug efflux 25 , 26 , it may also be possible that LAP facilitates the uptake and retention of DOX in cardiomyocytes. Therefore, LAP-plus-DOX synergistic cardiotoxicity may arise from simultaneous LAP-mediated inhibition of both DOX efflux and HER2 survival signaling, thereby exacerbating the severity of DOX-induced nitrosative stress and cardiac injury.…”

Hepatotoxic and Nephrotoxic Potential of an Anticancer Drug Paclitaxel after Prolong Exposure in Adult Female Rats

“…Moreover, cisplatin-induced nephrotoxicity and hepatotoxicity endowed with alterations in histology of kidney and liver was also found in mice (Nakashima-Kamimura et al, 2009;Sloop et al, 2019). It is established that individual chemotherapy with PTX or in combination with other conventional anticancer drugs of different inducing mechanisms may induce structural and functional impairments in some vital organs like liver and kidney resulting into disturbances of homeostasis and physiology of the subjects irrespective of age, drug doses, exposure time and sexual category (Dai et al, 2015). The results of the present study corroborate well with the findings of other clinical and preclinical investigations especially on histopathological changes in liver and kidney which ultimately disturbed the behavioural functions related to locomotory responses, exploration, anxiety, depression and cognition (data not included in this study).…”