Recent Progress in Understanding the Action of Natural Compounds at Novel Therapeutic Drug Targets for the Treatment of Liver Cancer

Abstract

Liver cancer is the third most common cause of cancer-related death following lung and stomach cancers. As a highly lethal disease, liver cancer is diagnosed frequently in less developed countries. Natural compounds extracted from herbs, animals and natural materials have been adopted by traditional Chinese medicine (TCM) practices and reported to be effective in the development of new medications for the treatment of diseases. It is important to focus on the mechanisms of action of natural compounds against hepatocellular carcinoma (HCC), particularly in terms of cell cycle regulation, apoptosis induction, autophagy mediation and cell migration and invasion. In this review, we characterize novel representative natural compounds according to their pharmacologic effects based on recently published studies. The aim of this review is to summarize and explore novel therapeutic drug targets of natural compounds, which could accelerate the discovery of new anticancer drugs.

Keywords: HCC; liver cancer; natural compound; signaling pathway; target.

Figure 1

Examples of molecular targets in tumor cells for liver cancer drug development. LHRH, luteinizing hormone releasing hormone; EGF, epidermal growth factor; TLR4, Toll-like receptor 4; MAPK, mitogen-activated protein kinase. The figure shows the following two major pathways implicated in HCC: the Raf/MEK/Erk pathway, which is the prototypical MAPK cascade (35), and the PI3K/Akt/mTOR pathway (36).

Figure 2

Cell cycle progression. (A) Example of targets of cell cycle arrest at the G2/M transition and G1/S transition in tumor cells for the development of liver cancer drugs. ATM, ataxia telangiectasia mutated; ATR, ATM and Rad3-related; Chk, human checkpoint kinase; ERK, extracellular signal-regulated kinase. (B) Example of targets of cell cycle arrest at the G1/S transition in tumor cells for the development of liver cancer drugs. pRB, retinoblastoma protein; CDK, cyclin-dependent kinase.

Figure 3

Proposed signalling pathway by which natural compounds induce apoptosis and example of targets of apoptosis in tumor cells for liver cancer drug development. FasL, Fas ligand; FADD, Fas-associated protein with death domain; TNFR1, tumor necrosis factor receptor 1; TRADD, TNFR1-associated via death domain; DISC, death-induced signalling complex; IAP, inhibitor of apoptosis protein; UPR, unfolded protein response; ER, endoplasmic reticulum; PERK, double-stranded RNA-activated protein kinase-like ER kinase; TRAF2, TNF receptor-associated factor 2; ELF2, eukaryotic initiation factor 2.

Figure 4

Proposed signalling pathway for the inhibition of migration and invasion. The effect of natural compounds likely occurs through the inhibition of FAK, a GTPase family that regulates MMP-2/-9 expression through PI3K/Ark pathways, the P38 MAPK pathway or the Ras/Raf/Erk signalling pathway to inhibit migration and invasion.