Mechanisms of Anticancer Drug Resistance in Hepatoblastoma

Abstract

The most frequent liver tumor in children is hepatoblastoma (HB), which derives from embryonic parenchymal liver cells or hepatoblasts. Hepatocellular carcinoma (HCC), which rarely affects young people, causes one fourth of deaths due to cancer in adults. In contrast, HB usually has better prognosis, but this is still poor in 20% of cases. Although more responsive to chemotherapy than HCC, the failure of pharmacological treatment used before and/or after surgical resection is an important limitation in the management of patients with HB. To advance in the implementation of personalized medicine it is important to select the best combination among available anti-HB drugs, such as platinum derivatives, anthracyclines, etoposide, tyrosine-kinase inhibitors, Vinca alkaloids, 5-fluorouracil, monoclonal antibodies, irinotecan and nitrogen mustards. This requires predicting the sensitivity to these drugs of each tumor at each time because, it should be kept in mind, that cancer chemoresistance is a dynamic process of Darwinian nature. For this goal it is necessary to improve our understanding of the mechanisms of chemoresistance involved in the refractoriness of HB against the pharmacological challenge and how they evolve during treatment. In this review we have summarized the current knowledge on the multifactorial and complex factors responsible for the lack of response of HB to chemotherapy.

Redox-Mediated Mechanism of Chemoresistance in Cancer Cells

“…Chemoresistance arises after long-time exposures to anticancer drugs [81,82]. The difference between temporary treatment and continuous treatment leads to different levels of ROS homeostasis in cancer cells.…”

“…The EMT process allows metastatic tumor cells to migrate to organs. Altered intracellular ROS levels may lead to the promotion of EMT in cancer cell lines that are resistant to anti-cancer drugs [81,108]. Several proteins function in the development of chemoresistance in metastatic advanced carcinomas [151,152].…”

Dna Methylation as a Key Epigenetics Player for Hepatoblastoma Stratification

“…Most drugs based on the mechanisms of anticancer resistance in HB will act on pathways such as p53, tyrosine kinase, cell cycle control, and transcriptional and translational events. A specific gene,CYP3A4, upregulated in Set-3, is related to five drugs used in the treatment of HBs 44 , particularly etoposide (a drug used in neoadjuvant chemotherapy), which causes demethylation in liver cells 45,46 , and Sorafenib, a kinase inhibitor mainly oxidized by CYP3A4 , with the collaboration ofCYP1A1 and CYP1B1 47 . Vincristine, Cyclophosphamide and Isofosfamide are also metabolized by CYP3A4 [48][49][50][51] .…”

Neurokinin-1 Receptor Antagonists against Hepatoblastoma

“…In HB patients, the high-risk group is characterized by a marked chemoresistance and poor outcome [75]. Multidrug resistance often occurs after four cycles of chemotherapy [12].…”