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Table 2 Pharmacological effects of artemisinin and its derivatives on hepatic diseases in vitro

From: Anti-malarial drug: the emerging role of artemisinin and its derivatives in liver disease treatment

Hepatic disease

Cell lines

Drug

Dosage

Variations

Refs.

Effects on cell cycle

 HCC

HepG2 cells, PLC/PRF/5 cells, Hep3B cells

DHA

20–40 μM

↓cyclin B, CDC25C; ↑P21, G2/M phase

[50]

 

HepG2 cells, Hep3B cells

ART, DHA

0–50  μM

↓E2F1, CDK2

, CDK3, cyclin D1, cyclin E;

↑G1 phase, Kip1/p27, Cip/p21

[51]

Liver fibrosis

HSCs

DHA

15–50 μM

↓cyclin A, CDK2;

↑S phase, p53, p21

[52]

Effects on cell proliferation

 HCC

HepG2215 cells

DHA

50–200  μM

↓cell proliferation

[55]

 

HepG2215 cells

DHA

5–20  μM

↓cell proliferation, colony formation

[56]

 

HepG2 cells

DHA

0–200  μM ol/L

↓cell proliferation;

↑ROS, [Ca2+]

[58]

 

HCCLM6 cells

DHA

1–100  μM

↓cell proliferation, E2F1, BCL, PCNA, MKI67, CCNE2

[59]

 

HCCLM3 cells, MHCC97H cells

ART

0–100  μM

↓cell growth, colony formation; cell cycle arrest

[60]

 CCA

HUCCT-1 cells, FRH201 cells

DHA

20  μM ol/L

↓cell proliferation

[57]

 Liver fibrosis

HSCs

ART

125–225  μM ol/L

↓cell proliferation

[63]

 

LX-2 cells

ART

0–50 ug/ml

↓cell proliferation

[64]

Effects on cell apoptosis

 Liver fibrosis

LX-2 cells

ART

12.5–50 ug/ml

↓Bcl-2;

↑Bax/Bcl-2

[64]

 

HSCs

ART

150–200  μM ol/L

↑p53

[63]

 HCC

SMMC-7721 cells

Artemisinin

100–200  μM ol/L

↑apoptotic rate

[65]

 

HepG2 cells

ART and DHA

0–50  μM

↓Bcl-2, PARP;

↑Bax, caspase-3, p53, MDM2

[51]

 

HepG2 cells

ART

0.5–8 mg/L

↓p-STAT3; ↑Fas

[69]

 

HepG2, cells

DHA

0–200  μM ol/L

↓Bcl-2;

↑GADD153, Bax,

[58]

 

HepG2 cells

DHA

0–100 μM

↑cleaved PARP, caspase-3

[71]

 

SK-Hep-1 cells

DHA

20–60  μM

↓PARP, Sp1;

↑caspase8, caspase9, caspase3

[72]

 

HepG2 and Huh-7 cells

DHA

0–150  μM

↓ΔΨm, Mcl-1;

↑Bim, cytochrome c, caspase8, caspase9,caspase3, ROS, Bak

[73]

 

Hep3B and Huh-7 cells

ART

10–150  μM

↑ROS, Bax, MOMP, cytochrome c, caspase 9, caspase3

[74]

 

HepG2 cells

ART

10–150  μM

↓ΔΨm, Bcl-2/Bcl-xl; ↑Bax, caspase8, ROS, caspase9, caspase3

[75]

 

HuH-7 cells and PLC/PRF/5 cells

ART

1–300 μM

↓Bcl-2;

↑Bax, caspase-3/7, cleaved PARP1

[76]

CCA

QBC939 cells, HUCCT-1 and FRH201 cells

DHA

20  μM ol/L

↑Mcl-1S, Mcl-1S/Mcl-1L, apoptotic rate

[57, 77]

Effects on angiogenesis, invasion, metastasis

 HCC

SK‐HEP1, SM7721, HepG2, and Huh7 cells

ART

100  μM

↓N/E-cadherin, MMP9, vimentin, EMT

[81]

 

HepG2215 cells

DHA

100  μM

↓Migration ability;

[55]

 

HCCLM3 and MHCC97H cells

ART

25–100  μM

↓N-cadherin, MMP2, MMP9, Snail, E-cadherin

[60]

 

HCCLM6 cells

DHA

50–100  μM

↓FN1, ITGB1

[59]

 

HepG2 and SMMC-7721 cells

ART

12.5–75  μM

↓MMP2;

↑TIMP2

[82]

 

HepG2 cells

ART

6.25–50 mmol/L

↓VEGF, PIGF

[83]

 

HepG2 and Huh7 cells

ART

25  μM , 125  μM

↓Cell migration

[84]

Effects on hepatic stellate cells

 Liver fibrosis

Mouse HSCs and LX-2 cells

ART

25–75  μM

↓Cell vaibility, GSH, GPX4, NADPH, α-SMA, collagen 1, fibronectin, desmin, FTH1, NCOA4, p62;

↑cell death, Fe2+ accumulation, LPO, MDA, ROS, ferroptosis,

LC3; mitochondria morphology change

[87]

 

HSC-T6 cells

ARM

10–40 ug/ml

↓α-SMA, collagen 1, fibronectin, TGF-β, PDGF-β, EGF, cell viability, GSH, NADPH, Gpx4, SLC7A11;

↑cell death, Fe2+, ROS1, ferroptosis, p53; mitochondria morphology change

[88]

 

LX-2 cells

ARM

10–40 ug/ml

↓cell activation;

↑cell death, Fe2+, ROS, MDA, LPO, ferroptosis, IRP2

[89]

 

LX-2 cells

ART

12.5–50 ug/ml

↓cell activation, α-SMA, collagen 1, p-Akt, p-FAK, p-GSK-3β

[64]

 

LX-2 cells

ART

350umol/L

↓hydroxyproline;

↑ceramide synthase protein, ceramide, PPAR-γ, caspase-3

[90]

 

LX-2 cells

ART

50–200  μM

↓cell viability, Col1a1, Col3a1, OGDH, CS, IDH2, mitochondrial function, NDUFB8, UQCRC2;

↑Cell apoptosis

[91]

Effects on cell autophagy

 Liver fibrosis

Primary rat HSCs

DHA

5–20  μM

↓P62, inflammatory factors, GSH/GSSG; ↑autophagosome, autophagic flux, LC3-II, ROS, p-JNK1/2

[54]

 

Primary rat HSCs

DHA

5–20  μM

↑autophagosome, p-ULK1, p-mTOR, Atg6/Beclin1, LC3-II, p53, GATA6, cell senescence

[99]

 HCC

HepG2215 cells

DHA

100  μM

↓p-AKT, p-mTOR, p-p70S6K, p-4EBP1;

↑LC3, p-AMPK, p62

[55]

 

HepG2215 cells

DHA

21.5  μM

↓p62/SQSTM1;

↑LC3B-II

[56]

Effects on chemsensitization to chemotherapeutic agents

 HCC

SM-7721, SK-hep1 cells

ART

50  μM

Chemosensitize with Sor, ↓IC50, cell viability, p-RAF, p-ERK, p-AKT, p-mTOR;

↑cell apoptosis, p-PARP

[93]

 

HepG2 cells

Huh7 cells

ART

25 μM

125 μM

Chemosensitize with Sor, ↓IC50, VEGFR2;

↑cell apoptosis, cleaved caspase-9, cleaved PARP

[84]

 

HepG2 and Hep3B cells

ART and DHA

10 μmol/L

Chemosensitize with gemcitabine, ↓cell survival

[51]

 

Hep3B cells

DHA

5 μM

Chemosensitize with ADM, ↓cell viability, clone, P-gp, p-ERK1/2, p65;

↑cell apoptosis

[95]