TABLE 3.

HIF-1 related signaling pathway inhibitors in BC.

Component	Dose	IC50	Model	Duration of treatment	Routes of treatment	Type of study	Mechanism	Results	References
Honokiol	0–40 uM	—	MCF-7, MDA-MB-231	3–24 h	—	in vitro	downregulated HIF-1α protein expression	Inhibited cell proliferation and clonogenicity, as well as induced apoptosis of cancer cells	Yi et al. (2022)
	25 mg/kg/day	—	Mouse model (MCF-7)	4 weeks	ip	in vivo	decrease HIF-1α protein level	Suppressed tumor growth and HIF-1α-mediated glycolysis
Sinomenine	0.75 mM	—	stem-like side population (SP) cells gained from MDA-MB-231	24 h	—	in vitro	downregulating HIF-1α	Inhibit the migration and vasculogenic mimicry, and hold back epithelial-mesenchymal transition process	Song et al. (2022)
Polydatin (PD) combined with 2-deoxy-D-glucose (2-DG)	PD 100 μmol/L, 2-DG 5 mmol/L (4T1) or 10 mmol/L (MCF-7)	PD: 66.56uM(4T1)/103.1 uM (<CF-7), 2-DG: 5.53 mM(4T1)/8.67 mM (MCF-7). (24 h)	MCF-7 and 4T1	0–72 h	—	in vitro	inhibit HIF-1alpha/HK2 to suppress glycolytic metabolism	Induced cell apoptosis and inhibited cancer cells proliferation, migration and invasion	Zhang et al. (2019)
Polydatin (PD) combined with 2-deoxy-D-glucose (2-DG)	PD (100 mg/kg every other day), 2-DG (100 mg/kg ip every other day)	—	Mouse model (4T1)	3 weeks	ip	in vivo	anti-proliferative and anti-angiogenic activity, promoted apoptosis	Inhibit cancer growth in vivo	Zhang et al. (2019)
bishonokiol A	2.5–10 uM	—	MCF-7, MDA-MB-231	24–48 h	—	in vitro	hold back HIF-1a expression and its protein synthesis	Inhibit cancer cell invasion and migration	Li H. M et al. (2019)
	100 mg/kg/3 days	—	Mouse model (MDA-MB-231)	16 days	ip	in vivo	—	Antitumor activity and low toxicity
Alkaloid derivative ION-31a	0–75 uM	—	MDA-MB231, 4T1	24 h–48 h	—	in vitro	downregulate HIF-1α/VEGF signaling pathway	Inhibit cell migration, invasion, adhesion, and VEGF secretion	Ni et al. (2021)
Alkaloid derivative ION-31a	25–100 mg/kg	—	Mouse model (4T1)	26 days	ig	in vivo	—	Depress tumor growth and metastasis with slightly bodyweight change
HS-1793	0–50 uM	MCF-7: 26.3 ± 3.2; MDA-MB-231: 48.2 ± 4.2 uM	MCF-7 and MDA-MB-231	24 h	—	in vitro	downregulate HIF-1a protein level and its target gene VEGF expression	inhibit cancer cells proliferation, and decrease the angiogenesis	Kim et al. (2017)
	0–20 mg/kg/twice a week	—	Mouse model (MDA-MB-231)	4 weeks	ip	in vivo	downregulate HIF-1a protein level	Inhibit tumor growth, and suppress microvessel formation
Salinomycin	0–30 uM	—	MCF-7, T47D, MDA-MB-231, MDA-MB-468, 4T1	12–24 h	—	in vitro	decreased the HIF-1α transcription factor DNA binding activity	Inhibit cell proliferation, invasion, and migration	Dewangan et al. (2019)
	5–10 mg/kg/3 days a week	—	Mouse model (4T1)	3 weeks	ip	in vivo	inhibited hypoxia-induced HIF-1α/VEGF signaling axis	inhibits breast cancer growth and tumor angiogenesis
HS-146	—	—	MCF-7	—	—	in vitro	depress hypoxia-induced HIF-1α/VEGF signaling axis	Inhibit cancer cell proliferation, migration and invasion in a dose-dependent manner	Kim et al. (2020)
Baicalein	0–25 uM	—	T-47D, BT-474 and ZR-75–1	24–72 h	—	in vitro	inhibit HIF-1α–mediated aerobic glycolysis and mitochondrial dysfunction	—	Chen et al. (2021)
	30 mg/kg/3 days	—	Mouse model (MCF-7TR)	30 days		in vivo	inhibit HIF-1α–mediated aerobic glycolysis and mitochondrial dysfunction	Baicalein increases the inhibitory effects of TAM on the growth of MCF-7TR cells in vivo
Chiral ionone alkaloid derivatives	0–30 uM	0.035 μM ± 0.004	MDA-MB-231	0–24 h	—	in vitro	inhibit HIF-1α/VEGF/VEGFR2/Akt pathway	Depress cancer cell migration, adhesion, migration and invasion	Liu J. J et al. (2021)
Cardamonin	—	24.458–52.885 uM	MDA-MB-231	24–72 h	—	in vitro	inhibit HIF-1a expression on mRNA and protein level	Inhibit cancer cell viability and promotes apoptosis	Jin et al. (2019)
	3 mg/kg/day	—	Mouse model (MDA-MB-231)	4 weeks	ip	in vivo	suppress HIF-1α/PDHK1 axis by inhibit the mTOR/p70S6K pathway	Inhibit tumor growth
AT-533	0–75 uM	—	MDA-MB-231, MCF-7	12–72 h	—	in vitro	downregulate HIF-1α/VEGF signaling pathway	Inhibit breast cancer cells viability	Zhang et al. (2020)
	10 mg/kg/2 days	—	Mouse model (MDA-MB-231)	12 days	ip	in vivo	block the HIF-1α/VEGF/VEGFR-2-mediated signaling pathway	Inhibit growth of breast cancer xenografts in vivo
Rhaponticin	0–100 uM	—	MDA-MB231	48 h	—	in vitro	decreased HIF-1α accumulation and HIF-1α nuclear expression	suppress cancer cells colony formation, migration, invasion and angiogenesis	Kim and Ma, (2018)