Models for Understanding Resistance to Chemotherapy in Liver Cancer

Abstract

The lack of response to pharmacological treatment constitutes a substantial limitation in the handling of patients with primary liver cancers (PLCs). The existence of active mechanisms of chemoresistance (MOCs) in hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma hampers the usefulness of chemotherapy. A better understanding of MOCs is needed to develop strategies able to overcome drug refractoriness in PLCs. With this aim, several experimental models are commonly used. These include in vitro cell-free assays using subcellular systems; studies with primary cell cultures; cancer cell lines or heterologous expression systems; multicellular models, such as spheroids and organoids; and a variety of in vivo models in rodents, such as subcutaneous and orthotopic tumor xenografts or chemically or genetically induced liver carcinogenesis. Novel methods to perform programmed genomic edition and more efficient techniques to isolate circulating microvesicles offer new opportunities for establishing useful experimental tools for understanding the resistance to chemotherapy in PLCs. In the present review, using three criteria for information organization: (1) level of research; (2) type of MOC; and (3) type of PLC, we have summarized the advantages and limitations of the armamentarium available in the field of pharmacological investigation of PLC chemoresistance.

Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg

“… 1 Systemic therapies are used for patients diagnosed at more advanced stages. HCC is very resistant to conventional chemotherapies, 4 but targeted agents such as the multikinase inhibitors sorafenib, lenvatinib, regorafenib and cabozantinib, as well as monoclonal antibodies like ramucirumab (which targets vascular endothelial growth factor [VEGF] receptor 2), confer some survival benefit. 1 , 3 , 5 , 6 Immunotherapy is also being actively tested in HCC, and immune checkpoint inhibitors (ICIs), which are antibodies that block the programmed cell death protein 1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway, or the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathway, have shown clinical activity.…”

Cinnamic Acid Derivatives and Their Biological Efficacy

“…Most anticancer agents used to treat hepatocellular carcinoma suffer from drug resistance [46]. In order to overcome drug resistance, Ling et al developed β-carboline and N-hydroxycinnamamide compounds (55a-p) ( Figure 14) [30].…”

“…The presence of an electrondonating group such as the R group such as methoxyl (55g-j) or more than one methoxyl groups (5m-p) enhanced inhibitory potency compared to compounds with a hydrogen (55a,b) or methyl (55c,d) [30]. Most anticancer agents used to treat hepatocellular carcinoma suffer from drug resistance [46]. In order to overcome drug resistance, Ling et al developed β-carboline and N-hydroxycinnamamide compounds (55a-p) ( Figure 14) [30].…”

“…Mancilla-Montelongo et al evaluated the in vitro anthelmintic (AH) activity of cinnamic acid (1) and its six derivatives (p-coumaric acid (46), caffeic acid (47), trans-ferulic acid (64), trans-sinapic acid (65), 3,4-dimethoxycinnamic acid (66) and chlorogenic acid (51) (Figure 18) against the larvae and eggs of a gastrointestinal nematode, Haemonchus contortus. Only ferulic acid and chlorogenic acid showed notable AH activity >74% and >39% egg inhibition, respectively, at 300 µg/mL.…”

“…Lee et al reported the ability of hydroxycinnamic acids (cinnamic acid (1), p-coumaric acid (46), caffeic acid (47) and chlorogenic acid (33) on reducing furan and trapping α-dicarbonyl compounds, which are possible human carcinogens. [79].…”