Differential in vitro effects of targeted therapeutics in primary human liver cancer: importance for combined liver cancer

Differential in vitro effects of targeted therapeutics in primary human liver cancer: importance for combined liver cancer

The incidence of primary liver tumors, hepatocellular carcinoma (HCC), intrahepatic cholangiocellular carcinoma (ICC), and combined HCC/ICC (cHCC/CC) is increasing. For ICC, targeted therapy exists only for a small subpopulation of patients, while for HCC, Sorafenib and Lenvatinib are in use. Diagno...

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Published in:BMC cancer Vol. 22; no. 1; pp. 1 - 1193
Main Authors: Malik, Ihtzaz Ahmed, Rajput, Mansi, Werner, Rieke, Fey, Dorothea, Salehzadeh, Niloofar, von Arnim, Christine A. F, Wilting, Jörg
Format: Journal Article
Language:English
Published: London BioMed Central Ltd 19-11-2022
BioMed Central
BMC
Subjects:
1-Phosphatidylinositol 3-kinase
AKT pathway
AKT protein
Cancer therapies
Care and treatment
Cell culture
Cell growth
Cell proliferation
Cholangiocellular carcinoma
Combined liver cancer
Diagnosis
Dosage
Drugs
Extracellular signal-regulated kinase
Hepatectomy
Hepatocellular carcinoma
Kinase inhibitors
Kinases
Liver cancer
Medical prognosis
Molecular targeted therapy
Patient outcomes
Patients
Proteins
Rapamycin
TOR protein
Tumors
Variance analysis
Wortmannin
Germany
United States > US
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Summary:The incidence of primary liver tumors, hepatocellular carcinoma (HCC), intrahepatic cholangiocellular carcinoma (ICC), and combined HCC/ICC (cHCC/CC) is increasing. For ICC, targeted therapy exists only for a small subpopulation of patients, while for HCC, Sorafenib and Lenvatinib are in use. Diagnosis of cHCC/CC is a great challenge and its incidence is underestimated, bearing the risk of unintended non-treatment of ICC. Here, we investigated effects of targeted inhibitors on human ICC cell lines (HUH28, RBE, SSP25), in comparison to extrahepatic (E)CC lines (EGI1, CCC5, TFK1), and HCC/hepatoblastoma cell lines (HEP3B, HUH7, HEPG2). Cells were challenged with: AKT inhibitor MK-2206; multikinase inhibitors Sorafenib, Lenvatinib and Dasatinib; PI3-kinase inhibitors BKM-120, Wortmannin, LY294002, and CAL-101; and mTOR inhibitor Rapamycin. Dosage of the substances was based on the large number of published data of recent years. Proliferation was analyzed daily for four days. All cell lines were highly responsive to MK-2206. Thereby, MK-2206 reduced expression of phospho(p)-AKT in all ICC, ECC, and HCC lines, which mostly corresponded to reduction of p-mTOR, whereas p-ERK1/2 was upregulated in many cases. Lenvatinib showed inhibitory effects on the two HCC cell lines, but not on HEPG2, ICCs and ECCs. Sorafenib inhibited proliferation of all cells, except the ECC line CCC5. However, at reduced dosage, we observed increased cell numbers in some ICC experiments. Dasatinib was highly effective especially in ICC cell lines. Inhibitory effects were observed with all four PI3-kinase inhibitors. However, cell type-specific differences were also evident here. Rapamycin was most effective in the two HCC cell lines. Our studies show that the nine inhibitors differentially target ICC, ECC, and HCC/hepatoblastoma lines. Caution should be taken with Lenvatinib and Sorafenib administration in patients with cHCC/CC as the drugs may have no effects on, or might even stimulate, ICC.
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ISSN:1471-2407
1471-2407
DOI:10.1186/s12885-022-10247-6