Animal-derived natural products for hepatocellular carcinoma therapy: current evidence and future perspectives

Abstract

Hepatocellular carcinoma (HCC) has a high morbidity and mortality rate, and the survival rate of HCC patients remains low. Animal medicines have been used as potential therapeutic tools throughout the long history due to their different structures of biologically active substances with high affinity to the human body. Here, we focus on the effects and the mechanism of action of animal-derived natural products against HCC, which were searched in databases encompassing Web of Science, PubMed, Embase, Science Direct, Springer Link, and EBSCO. A total of 24 natural products from 12 animals were summarized. Our study found that these natural products have potent anti-hepatocellular carcinoma effects. The mechanism of action involving apoptosis induction, autophagy induction, anti-proliferation, anti-migration, and anti-drug resistance via phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), Ras/extracellular signal regulated kinases (ERK)/mitogen-activated protein kinase (MAPK), Wnt/β-catenin, and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways. Huachansu injection and sodium cantharidate have been used in clinical applications with good efficacy. We review the potential of animal-derived natural products and their derivatives in the treatment of HCC to date and summarize their application prospect and toxic side effects, hoping to provide a reference for drug development for HCC.

Keywords: animal medicines; animal-derived natural products; anti-hepatocellular carcinoma; mechanisms; natural products.

FIGURE 1

We show the process of inclusion and exclusion of literature in the systematic review. Screening of literature after retrieval, including a total of 43 eligible articles according to the criteria.

FIGURE 2

Chemical structures of animal-derived natural products. Classification of animal-derived natural products according to species.

FIGURE 3

The anti-hepatocellular carcinoma mechanism of animal-derived natural products. The anti-hepatocellular carcinoma activity of each animal-derived natural product is mainly achieved by inducing apoptosis in HCC, blocking the cell cycle, inhibiting invasion and migration, and inducing autophagy. ACC, acetyl-CoA carboxylase; ACLY, ATP citrate lyase; Akt, protein kinase B; AURKA, aurora kinase A; BAX, Bcl2 associated X; BCL-2, Bcl2 apoptosis regulator; CDC, cell division cycle; CDK, cyclin-dependent kinase; CHK1, checkpoint kinase 1; EGFR, epidermal growth factor receptor; eIF4E, eukaryotic translation initiation factor 4E; EMT, epithelial-mesenchymal transition; EPHB4, ephrin type-B receptor 4; ERK, extracellular signal regulated kinases; ERK1/2, extracellular signal-regulated kinase 1/2; FAM46C, terminal nucleotidyltransferase 5C; FAK, focal adhesion kinase; FASN, fatty acid synthase; GRB2, growth factor receptor-bound protein 2; GSK3β, glycogen synthase kinase-3 beta; IL-8, interleukin-8; JAK2, Janus kinase2; JNK, c-Jun N-terminal kinase; Lc3, light chain-3; MAPK, mitogen-activated protein kinase; MDR, multidrug resistance; MEK, mitogen-activated protein kinase 1; MEKK4, MAPK kinase kinasekinase4; MKK3, mitogen-activated protein kinase3; MMPs, matrix metalloproteinase; mTOR, mammalian target of rapamycin; NOXA, phorbol-12-myristate-13-acetate-induced protein 1; NF-κB, nuclear factor-κB; p, phosphorylation; PARP, poly ADP-ribose polymerase; PI3K, phosphoinositide 3-kinase; PKC, anti-humanprotein kinase C; PP, serine/threonine phosphatases; PUMA, Bcl2 binding component 3; p21, cyclin-dependent kinase inhibitor 1; SCD1, Stearoyl-CoA desaturase-1; SPHK1, sphingosine kinase 1; SRE, sterol regulatory elements; SREBF1, sterol regulatory element-binding protein 1; STAT3, signal transducer and activator of transcription 3; TIMP-1/2, tissue inhibitor of metalloproteinase-1/2; UNC5B, netrin receptor UNC5B; uPA, urokinase-type plasminogen activator; VEGF, vascular endothelial growth factor; WEE1, wee1-like protein kinase; ΔΦm, mitochondrial membrane potential.