Table 2.

Natural products targeting the phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin signaling pathway in triple negative breast cancer

Natural product class	Natural product name	Mechanism of action/inhibition	Ref.
Flavonoids	Prenylated xanthones	Decrease the levels of PI3K, AKT, and mTOR in both total protein and phosphorylated forms	[75]
	Ononin	Reverse EMT through down-regulation of EMT markers and matrix metalloproteinases, attenuate EGFR phosphorylation and inhibit the PI3K/Akt/mTOR pathway	[76]
	Myricetin	Inhibit the PI3K/Akt/mTOR pathway to enhance the anti-cancer efficacy of Myricetin	[77]
	Quercetin	Decrease cell viability, colony formation, angiogenesis, and increase apoptosis. Inhibit the activation of IGF1R and its downstream kinases AKT and ERK1/2. Suppress E-mediated proliferation and migration of TNBC cells by blocking β2-AR/ERK1/2 pathway	[78,80,81]
Terpenoids	PAB	Induces apoptosis through mitochondrial apoptosis and the PI3K/Akt/mTOR pathway	[87]
	Ezhu	Inhibit the proliferation, invasion, migration, and EMT of MDA-MB-231 cells through the PI3K/Akt/mTOR signaling pathway	[89]
	Tan IIA	Enhance the antitumor efficacy of doxorubicin by interfering with the PI3K/AKT/mTOR signaling pathway and inhibiting topoisomerase II	[79]
Alkaloids	RTEs	Enhance the sensitivity of resistant TNBC cells to Taxol through their inhibitory effect on PI3K/Akt/mTOR-mediated autophagy. Suppress MDA-MB-468/Taxol cells autophagy and reduce tumor growth	[91]
	BJE	Inhibit the proliferation, induce apoptosis, and promote the phosphorylation of mTOR, PI3K, and Akt in MDA-MB-231 TNBC cells	[68]
	PIP	Suppress the pro-survival AKT pathway and induce caspase-dependent apoptosis via the mitochondrial pathway. Impair the in vitro migratory capacity of TNBC cells and reduce MMP-2 and MMP-9 mRNA expression. The combination of doxorubicin and PIP can increase necrosis while downregulating PTEN, inhibiting PI3K levels, and the immunoreactivity of p-Akt, mTOR, and ALDH-1	[98,99]
	BBM	Impede TNBC development through regulation of the PI3K/Akt/MDM2/p53 and PI3K/Akt/mTOR signaling pathways	[100]
	HHT	Downregulate p-AKT, p-mTOR, and Bcl-2 expression, while upregulating TP53, Bax, cleaved caspase-3, and caspase-9 expression, and inhibiting the PI3K/AKT/mTOR pathway	[101]

PAB: Pseudolaric acid B; Tan IIA: Tanshinone IIA; RTEs: Radix tetrastigma extracts; BJE: Brucea javanica seed; PIP: Piperine; BBM: Berbamine; HHT: Homoharringtonine; PI3K: Phosphoinositide 3-kinase; Akt: Protein kinase B; mTOR: Mechanistic target of rapamycin; EMT: Epithelial-mesenchymal transition; EGFR: Epidermal growth factor receptor; IGF1R: Insulin-like growth factor-1 receptor; ERK: Extracellular signal-regulated kinase; TNBC: Triple negative breast cancer; MMP: Matrix metalloproteinase; PTEN: Phosphatase and tensin homolog; PIP: Piperine; MDM2: Murine double minute 2; ALDH-1: Aldehyde dehydrogenase-1.