Table 2.

Summary of some natural products for the treatment of breast cancer by inhibiting the PI3K/AKT pathway.

Drugs	Sources	In Vitro	In Vivo	Dose	Treatment Time	Mechanism	Refs.
Chrysin	Passiflora caerulea	MDA-MB-231 cell and BT-549 cell	-	5, 10, 20 μM	48 h	Inhibits p-AKT, vimentin and snail expression, inhibits metastasis	[121]
Epigallocatechin-3-gallate	Green tea	T47D cell and HFF cell	-	20, 40, 80 μM	72 h	Inhibits AKT and hTERT expression, induced apoptosis	[122]
Luteolin	Reseda luteola	MCF7-TamR cells	-	20, 30 μM	72 h	Inhibition of PI3K/AKT/mTOR, RAS expression, reverses tamoxifen-resistance in ER+ breast cancer cells	[123]
Quercetin	Capparis spinosa	MCF-7 cells and CD44+/CD24−CSCs	-	50 μM	24 h or 48 h	Inhibits PI3K/AKT/mTOR, promotes apoptosis, attenuates breast cancer stem cell cloning and mammary gland production	[124]
Resveratrol	Blueberries	MDA-MB-231, MDA-MB-453, MDA-MB-436, BT549 cells,	nude mice	25, 50 μM cell and 40 mg/kg mice	48 h or 72 h, 8 weeks	Inhibits PI3K/AKT/mTOR, decreases vimentin, slug, and MMP2, decreases cell viability and migration	[125]
Formononetin	Trifolium pratense	MCF-7 cells	nude mice	40, 80 μM cell and 15, 30, 60 mg/kg/day	48 h, 20 days	Inhibits cell proliferation, induces cell arrest in G0/G1 phase, reduce cyclin D1, p-IGF-1R, and p-AKT expression, inhibits local tumor growth in vivo	[126]
Curcumin	Curcuma longa	MDA-MB-231	-	25 μM	3 h, 6 h, or 24 h	Reduces the content of AKT protein, accelerates AKT ubiquitination, and affects AKT aggregation, impairs cellular UPS function, participates in the activation of autophagy, Inhibits the growth and migration of breast cancer cells	[127]
Curcumin	Curcuma longa	MDA-MB-468 cells and HBL100 cells	-	10 μM, 20 μM, 40 μM	24 h or 48 h	Reduces the phosphorylation of AKT and EGFR, inhibits the activities of ERK1, ERK2, and JNK, induces cell arrest in S and G2/M phases, triggers apoptosis of breast cancer cells	[128]
Shikonin	Lithospermum erythrorhizon	MDA-MB-231 and BT549 cells	-	1 μM, 5 μM	24 h	Decreases the expression of p-Akt, downregulates miR-17-5p, inhibits TNBC cell migration, invasion, and EMT, miR-17-5p binds to the 3’UTR of PTEN to downregulate its expression	[129]
Anthricin	A. sylvestris (L.) Hoffm	MCF-7 cell and MDA-MB-231 cell	-	25 μM, 50 μM	12 h or 24 h	Decreases phosphorylation of Akt, p70S6K, and mTOR, induces cell arrest in the G2/M phase, increased protective autophagy and apoptosis	[130]
Lupiwighteone	Glycyrrhiza glabra	MCF-7 cell and MDA-MB-231 cell	-	10 μM, 20 μM, 40 μM	48 h	Inhibits PI3K/Akt/mTOR signaling pathway, inhibits cell proliferation, induces caspase-dependent cell death	[131]
Piperine	Piper nigrum Linn	SKBR3 cell and MCF-7 cells	-	25 μM, 50 μM	24 h or 48 h	Reduces the expression of p-Akt, p-p38, and mmp-9 induced by EGF, enhances the effect of paclitaxel on breast cancer cytotoxicity, downregulates the expression of SREBP-1, and FAS and HER2, inhibits the migration of breast cancer cells	[132]
Ginsenoside Rd	Panax ginseng	HUVECs cell and MDA-MB-231 cell,	xenograft mouse	25 μM, 50 μM cell, 3 and 10 mg/kg/day mice	48 h,28 day	Inhibit Akt/mTOR/p70S6K and HIF-1α activation, prevent VEGF-induced HUVECs migration, invasion, and formation of capillary-like structures, reduces VEGF-induced VEGFR2 activation in HUVECs	[133]
Ginsenoside Rg3	Panax ginseng	MDA-MB-231 cell	-	30 μM	24 h	Inhibits the phosphorylation of ERK and Akt, reduces the transcriptional activity of NF-κB and the nuclear translocation of the p65 subunit, inhibits the degradation of IκBα and the catalytic activity of IKKβ, enhances the interaction between p53 and a negative regulator (Mdm2)	[134]
Notoginsenoside R1	Panax notoginseng	MCF-7 cell and MDA-MB-231 cell	-	75 μ, 150 uM	24 h or 48 h	Reduces p-PI3K and p-AKT levels, downregulates the expression of CCND2 and YBX3, and increase the cells arrested in the G1 phase, decreases YBX3 and expression of KRAS, inhibit the proliferation, migration, invasion, and angiogenesis ability of breast cancer cells	[135]