Anti-Hepatocellular Carcinoma Biomolecules: Molecular Targets Insights

Abstract

This report explores the available curative molecules directed against hepatocellular carcinoma (HCC). Limited efficiency as well as other drawbacks of existing molecules led to the search for promising potential alternatives. Understanding of the cell signaling mechanisms propelling carcinogenesis and driven by cell proliferation, invasion, and angiogenesis can offer valuable information for the investigation of efficient treatment strategies. The complexity of the mechanisms behind carcinogenesis inspires researchers to explore the ability of various biomolecules to target specific pathways. Natural components occurring mainly in food and medicinal plants, are considered an essential resource for discovering new and promising therapeutic molecules. Novel biomolecules normally have an advantage in terms of biosafety. They are also widely diverse and often possess potent antioxidant, anti-inflammatory, and anti-cancer properties. Based on quantitative structure-activity relationship studies, biomolecules can be used as templates for chemical modifications that improve efficiency, safety, and bioavailability. In this review, we focus on anti-HCC biomolecules that have their molecular targets partially or completely characterized as well as having anti-cancer molecular mechanisms that are fairly described.

Keywords: cancer; drug; hepatocellular carcinoma; molecular target; phytochemicals; signaling pathway.

Figure 1

Chemical structure of Sorafenib.

Figure 2

Dysregulation of Signaling through Raf-1 in tumor cells (left panel), endothelial cells, and/or pericytes (right panel) that could result in tumor growth and/or angiogenesis by an autocrine mechanism in HCC, and the effect of sorafenib (Sf), The white arrows indicate the effect on intra-cellular signal molecules or pathways. The dotted arrows indicate the effect on cell membrane receptors (Modified from [12]).

Figure 3

Representation of Sorafenib in complex with B-Raf. (A) Ribbon representation of b-Raf in complex with Sorafenib (yellow sticks). The 3-D structure used (pdb code 1UWH) was uploaded from the protein data bank (https://www.rcsb.org/structure/1UWH). (B) zoom from A showing interacting residues (blue sticks) with Sorafenib in the active site of b-Raf. Figure was constructed using the BIOVIA Discovery Studio software (BIOVIA, Dassault Systèmes, [BIOVIA Discovery Studio], [v17.2.0.16349], San Diego: Dassault Systèmes, [2017]).

Figure 4

Molecular targeted therapies in HCC. Tyrosine kinase and mTOR inhibitors in preclinical studies or clinical trials for HCC. Some monoclonal antibodies directed against tyrosine kinase receptors are also indicated (Modified from [47]).

Figure 5

Chemical structure of PHA665752 (A) and SU11274 (B) compounds.

Figure 6

The mechanism of HZC in the HCC treatment model through the PTEN/PI3K/Akt pathway. HZC could inhibit activation of the PI3K/Akt signaling pathway by enhancing PTEN transcription, and then induce apoptosis of HepG2 cells via regulating the expression of apoptosis-related proteins (Modified from [63]).

Figure 7

Activation of STAT3 in cancer cells. (A) Inhibition of cancer signaling activates STAT3 pathways. (B) Novel activators of STAT3 secreted by cancer cells, mesenchymal stem cells, cancer‒associated fibroblast cells, or macrophages. (C) Activators of STAT3 promote cancer growth through immunosuppression. STAT3 target genes IL-6, IL-10, and VEGF are regulated by STAT3. These tumor-associated factors activate STAT3 in the immune system (Modified from [72]).

Figure 8

Several miRNAs act synergistically to promote HCC through the modulation of multiple cell phenotypes (Modified from [77]).

Figure 9

Chlorogenic Acid (A); Gigantol (B); Resveratrol (C); Gallic Acid (D); Decursin (E); Oleocanthal (F); and Sesamol (G).

Figure 10

Chemical structure of quercetin.

Figure 11

Working model on how quercetin blocks tumor necrosis factor-α (TNFα)‒mediated inflammation (Modified from [98]).

Figure 12

(A) Chemical structure of Nutlin‒3. (B) Nutlin‒3 inhibits binding of p53 and p73 to MDM2 when combined with DOX and increases p53 and p73 activity in human HCC cell lines (Modified from [109]).

Figure 13

Chemical structure of evodiamine (A) and caffeine (B).

Figure 14

Chemical structure of Crocin.

Figure 15

Chemical structure of Capsaicin.