Table 1.
Therapeutic strategies targeting cell death and tumor microenvironment.
| Target | Therapeutic Strategy | Pre-Clinical Model | Effects in Liver | References |
|---|---|---|---|---|
| Cell Death | ||||
| Apoptosis and necroptosis |
Pan caspase inhibition (Emricasan) | CCl4-cirrhotic rats: 10 g/kg/day | Reduced portal hypertension and liver fibrosis. | [147,148] |
| Caspase-8 loss | Acute liver injury in Casp8Δhepa mice | Protection from hepatocarcinogenesis. | [153] | |
| RIPK1 activity inhibition | RIPK1 D138N/D138N mice | Prevented steatohepatitis and HCC by cell death inhibition. Amelioration of liver inflammation and prevented HCC by hepatocyte cell death protection. |
[25] | |
| Caspase-3 activation (Smac mimetic BV6 and oleanolic acid) |
In vitro (HCC cell lines, MTT assay): 60 µM OA and/or 4–6 µM BV6 In vivo (Chorioallantoic membrane assay): 30 µM OA and/or 4 µM BV6 |
Induction of hepatocarcinogenic cell death.Suppressed tumor growth. | [158] | |
| Caspase-3/8/9 activation (Smac mimetic APG-1387 and TNF) |
In vitro (HCC cell lines, colony forming assay): 2 μM APC-1387 and 100 ng/mL TNFα In vivo (subcutaneous xenograft tumor model): 20 mg/kg |
Cell death induction and sensitization to natural killer cell-mediated cell killing. |
[159] | |
| Mitophagy-mediated apoptosis (Ketoconazole) | In vitro (HCC cell lines, MTT assay): 20 μM In vivo (xenograft tumor model): 20 μM |
In vitro: inhibition of cell proliferation. In vivo: inhibitory effect on tumor growth. |
[160] | |
| Inflammasome and pyroptosis |
NLRP3 inhibition (small molecule MCC950) |
NASH mouse model: 20 mg/kg | Reduced liver inflammation and fibrosis. | [161] |
| In vitro (primary hepatocytes): 50 μM | Abrogation of pyroptotic cascade in steatotic hepatocytes. | [162] | ||
| NLRP3 inhibition (pharmacological P2X7R inhibitor SGM-1019) | In vitro (primary human Kupffer Cells): 1 μM In vivo (liver fibrosis non-human primate model): 10 mL/kg |
Reduced IL-1β production. Protection against liver inflammation and fibrosis. |
[163] | |
| NLRP3 inhibition (Luteoloside) | In vitro (HCC cell lines): 50 μM In vivo (xenograft tumor and metastasis model): 2 mg/kg body |
In vitro: blockade of HCC cell migration and invasion. In vivo: inhibition of proliferation and metastasis in HCC. |
[168] | |
| NLRP3 inhibition (Anisodamine) | In vivo (xenograft tumor model): 10–200 mg/kg |
Suppressed HCC cells growth, induced apoptosis, and regulated the levels of inflammatory factors. | [169] | |
| NLRP3 activation (Alpinumisoflavone) | In vitro (HCC cell lines, proliferation, migration, and invasion assays): 0–20 μM In vivo (xenograft HCC model): 20 or 40 mg/Kg |
In vitro: suppressed cell proliferation, migration, and invasion capacity.In vivo: suppressed tumor growth. | [164] | |
| NLRP3 activation (17β estradiol/E2) |
In vitro (HCC cells): 50–100 nM | Induced pyroptotic cell death and inhibition of protective autophagy. | [165] | |
| Autophagy | Autophagy cell death (Ipatasertib GDC0068) | In vitro (HCC cells): 1–10 μM In vivo (subcutaneous xenograft tumor models): 25 mg/kg |
Suppressed sorafenib-resistant HCC cells growth by inducing autophagic cell death. | [166] |
| Autophagy cell death (SC-59) |
In vitro (HCC cells, MTT assay): 10 μM In vivo (subcutaneous xenograft tumor model): 20 mg/Kg |
Inhibition of tumor growth. | [167] | |
|
TME
reprogramming |
||||
| Stromal components and inflammation |
Tumor-infiltrated LSECs reduction (Nanoparticle-mediated delivery of miR-20) | In vitro (migration assay) In vivo (liver murine metastasis model) 16.7 lg/mL miR-20 |
Reduced activated LSEC recruitment into metastatic foci. Decreased liver metastasis progression. |
[170] |
| Blocking tumor-associated endothelium (TAEs) (Liposome-mediated delivery of anti-VEGFR2 mAb DC101) |
In vitro (MS-1 mouse endothelial cells HT-29 human colon cancer and MDA-MB-468 human breast cancer cell) In vivo (Insulinoma model Rip1Tag2 and breast cancer model MMTV-PyMT transgenic mice)protein/liposome ratio of 60 μg Fab’/μmol PL |
Reduction in blood vessel density. Inhibition of tumor growth. |
[172] | |
| Induction of aHSC necroptosis (Curcumol) | In vitro (LX2 HSC line) 30 µM In vivo (murine CCl4 fibrosis model) |
Inhibition of HSC activation. Reduction of inflammatory cell infiltration and fibrosis amelioration. |
[177] | |
| Induction of aHSC necroptosis (Gallic Acid) | In vitro (rat primary HSC): MTT assay, proliferation assay, DNA oxidative damage detection (50–75 µM) |
Induction of oxidative stress, cytotoxicity, and programmed necrosis in aHSC. | [178] | |
| Interfering collagen stabilization (βAPN: Three-aminopropionitrile fumarate) |
In vivo (mice breast adenocarcinomas engraftment): 100 mg/kg BW |
Improvement of tumor supply. Inhibition of tumor growth. |
[179] | |
| Inhibition of glycosaminoglycan (HA) synthesis (4-MU) | In vitro (MIA PaCa-2 human pancreatic cells): Proliferation assay, wound healing assay, invasion assay: 0.5 mM MU In vivo (intra-abdominal cell cancer implantation): 2 mg/g BW |
Reduced pericellular matrix containing HA. Inhibition of cell proliferation, migration, and invasion of cancer cells. Improved survival rates. |
[180] | |
| Blocking TGF-β (TGF-β–neutralizing antibody, 1D11 or Genetic overexpression sTβRII) |
In vivo (orthotopic mouse model of mammary carcinoma):1D11 (5 mg/kg) | Improvement of tumor vessel perfusion. Enhancing an intratumoral distribution of chemotherapy drugs. |
[186] | |
| Blocking circulating monocyte recruitment (CCL2 inhibitor mNOX-E36) |
CCl4-liver injury mice: 20 mg/kg | Inhibition of hepatic macrophage infiltration and reduction in steatosis development. Reduced angiogenic vessel sprouting in portal vein system and fibrosis-associated angiogenesis. |
[184,185] | |
| Blocking circulating monocyte recruitment (CCR2 antagonist RDC018) |
In vivo (orthotopic mouse model of HCC and subcutaneous tumor): 30 mg/kg/day | Suppressed liver tumor growth and postsurgical recurrence. Reduced recruitment of inflammatory monocytes and TAMs. Depletion of the crosstalk between tumor cells and macrophages and suppressed M2 macrophage polarization. |
[188] | |
| Disruption of CXCL12/CXCR4 axis (CXCR4 antagonist AMD3100) | In vitro (HCC cells, migration assay): 5 μM | Impaired in vitro migration and invasion. | [189] | |
| Disruption of CXCL12/CXCR4 axis (CXCR4 antagonist BPRCX807) | In vitro (HCC cells, wound healing assay): 10 µM In vivo (orthotopic mouse model of HCC): 15 mg/kg/day |
Inhibition of HCC cell migration and metastatic progression. Reprogramming of TME towards antitumor immune response (M1 immunostimulatory macrophages). |
[190] | |
| Immuno- suppression |
Antitumor immune surveillance (WSX1 signaling pathway) | WSX1 −/− spontaneous oncogenesis mouse model (NRAS/AKT oncogenes injection) | Tumor suppression by downregulating PD-L1 expression in tumor cells and decreasing PD-L1/PD-1 axis-induced T-cell exhaustion in tumor cells. | [191] |
| Antitumor immune surveillance (CSF-1R inhibitor PLX3397) | Orthotopic mouse model of HCC: 40 mg/kg | Suppressed infiltration of TAMs, reversed M2 polarization, and decreased PD-L1 expression in HCC. | [192] | |
Abbreviations: CCL2, chemokine (C-C motif) ligand 2; CCR2, C-C chemokine receptor type 2; CSF-1R; colony stimulating factor 1 receptor; CXCL12, C-X-C Motif Chemokine Ligand 12; CXCR4, C-X-C Motif Chemokine Receptor 4; HCC, hepatocellular carcinoma; NASH, non-alcoholic steatohepatitis; NLRP3, NLR family pyrin domain containing 3; RIPK1, receptor-interacting protein kinase 1; TAMs, tumor-associated macrophages; TME, tumor microenvironment; TNFα, tumor necrosis factor alpha.