Table 4.

Activities and mechanisms of action of most researched emerging plant-derived alkaloids on cancer cell lines.

Alkaloid	Plant Source	Type of Cancer	Cell Lines (IC50/ED50)	Mechanism of Action	References
Oxymatrine	Sophora flavescens Ait.	breast	MCF7	↑Bax and ↓Bcl-2	[82]
		ovarian	OVCAR-3	Cleavage of caspase-3, ↑miR-29b and ↓matrix metalloproteinase-2 (MMP2)	[83]
		prostate	DU145, PC-3	↑Bax, ↑p53, and ↓Bcl-2	[84]
		colorectal	RKO HCT116 SW480	Regulation of EMT markers (↑E-cadherin, ↓Snail and ↓N-cadherin) Inhibition of NF-κB activation, ↓p65	[85]
		lung	A549	↑Bax and ↓Bcl-2	[86]
		gastric	MKN-45 BGC823 SGC7901 HEK293	G1 cell cycle arrest Disruption of mitochondrial membrane potential Inhibition of EGFR (p-Tyr845) ↓CyclinD1, ↓CDK4/6 ↑Bax and ↓Bcl-2 ↑ caspases-3 and -9 mRNA level ↓phospho-Cofilin (Ser3), phospho-LIMK1 (Thr508) levels, and ↓MMP2	[87]
		cervical	CaSki	G0/G1 and S cell cycle arrest ↓HPV16E7	[94]
		cervical	HeLa	↓IMPDH2 ↓intracellular GTP	[88]
		human hepatoma carcinoma	Hep-G2 (1.32 mg/mL) SMMC-7721 (1.21 mg/mL)	↑Bax and ↓Bcl-2 and ↑caspase-3 mRNA level	[90]
		laryngeal squamous cell carcinoma	Hep-2 (7 mg/mL)	G0/G1 cell cycle arrest ↓HPV16E7 gene	[91]
		Pancreatic	PANC-1 (1 mg/mL)	Inhibition of NF-κB activity, ↓VEGF	[89]
		osteosarcoma	MNNG/HOS (72.50 μg/mL)	↑Bax and ↓Bcl-2 Disruption of mitochondrial membrane potential Efflux of cytochrome c Cleavage of caspases-3 and -9 Inactivation of PI3K/Akt pathway ↑Bax and ↓Bcl-2	[92]
		osteosarcoma	MG-63 (0.75 mg/mL)	Disruption of mitochondrial membrane potential Cleavage of caspases-3 and -9 ↑Bax and ↓Bcl-2	[116]
		hemangioma	HDEC	↓HIF-1ɑ, ↓VEGF, ↑Bax and ↑p53, and ↓Bcl-2 G0/G1 cell cycle arrest and ↓cyclinD1	[93]
		breast	MCF-7	↓SP and ↓Wnt/β-catenin signaling pathways	[96]
Piperine	Piper nigrum L. Piper longum L.	colon	CaCo-2 (54 μM) SW480 (126 μM) HCT116 (118 μM) HT-29 (53 μM)	G1 cell cycle arrest Disruption of mitochondrial membrane potential Cleavage of caspases-3, -9 and PARP ↑ROS Induction of endoplasmic reticulum stress	[98]
		triple-negative breast cancer	MDA-MB-468 T-47D MCF-7	Disruption of mitochondrial membrane potential Efflux of cytochrome c G1/S and G2/M cell cycle arrest Induction of caspase-dependent apoptosis ↓p-Akt, ↑p21Waf1/Cip1 ↓MMP-2/-9 mRNA levels	[99]
		HER2-overexpressing breast cancer	SKBR3 (50 μM) BT-474 (50 μM) MCF-7 (200 μM) MDA-MB-231	Cleavage of caspase-3 and PARP ↓SREBP-1 and ↓FAS mRNA levels ↓HER2 Inhibition of Akt, MAPK, AP-1 and NF-κB activation Suppression of migration	[104]
		osteosarcoma	HOS (72 μM) U2OS (126 μM)	G2/M cell cycle arrest ↓cyclinB1, ↑p-CDK1, ↑p-Chk2 Inhibition of p-Akt Activation of c-JNK, p38MAPK- ↑TIMP-1/-2 and ↓MMP-2/-9	[100]
		prostate	DU145 (74.4 μM) PC-3 (226.6 μM) LNCaP (111 μM)	G0/G1 cell cycle arrest Cleavage of caspase-3 Induction of autophagy via ↑LC3B-II and formation of LCb3 puncta ↑p21Cip1, ↑p27Kip1, ↓cyclin D1, ↓cyclin A	[101]
		lung	A549 (122 μg/mL)	G2/M phase cell cycle arrest Cleavage of caspases-3 and -9 ↑Bax, ↑p53, and ↓Bcl-2	[102]
		rectal	HRT-18	G0/G1cell cycle arrest ↑ROS	[103]
Piperlon-gumine	Piper longum L.	gastric	SGC-7901 (2.3 μM) BGC-823 (3.9 μM) KATO III: (6.0 μM)	G2/M cell cycle arrest ↓MDM-2, ↓Cyclin B1, and ↓Cdc2 ↑ROS and ↓TrxR1 Cleavage of caspase-3 ↑Bax and ↓Bcl-2 Induction of ROS-dependent endoplasmic reticulum stress Induction of ROS-dependent mitochondrial dysfunction	[113]
		head and neck	AMC-HN SNU HN30 HN31	↑ROS ↑p53, ↑PUMA, ↑p-JNK, ↓GSTP1 and ↑p21Waf1/Cip1 Cleavage of PARP	[114]
		glioma	HGG 1123 HGG MD13	↑ROS levels ↓PRDX4	[107]
		large B cell lymphoma ABC-DLBCL	OCI-Ly10 U2932 DB	Inhibition of TNF-α and p65 nuclear import ↓NF-κB activity ↓survivin, Bcl-2, ↑Bax, nd ↑p21 Cleavage of caspases-3 and -9	[109]
		breast myeloid leukemia	MCF7 (0.9 μM) MDA-MB-453 (0.9 μM) T-47D (2.7 μM), Kasumi-1 (3.7 μM)	↓ p-STAT3 Inhibition of STAT3 binding to its immobilized phosphopeptide ligand Cleavage of caspase-3 ↑p53, ↓survivin, ↓Bcl-2, ↓Bcl-x, ↓XIAP, and ↓CIAP mRNA levels	[108]
		gastric	AGS HGC27	↑ROS Cleavage of caspases-3, -7, -9 and PARP G2/M cell cycle arrest and ↑GADD45ɑ ↓CyclinB1, ↓cdc2, ↓XIAP, and ↑p21 ↓telomerase reverse transcriptase gene Induction of endoplasmic reticulum stress	[106]
		renal carcinoma	786-O PNX0010 (ED50: 1.6, 2.3 μM respectively)	↓c-Met ↑ROS Inhibition of Erk/MAPK, STAT3, Akt/mTOR and NF-κB pathways	[110]
		prostate	PC-3 DU-145 (ED50: 4.9, 3.4 μM respectively)	Inhibition of TNF-α and p65 nuclear import Inhibition of NF-κB pathway ↓Il-6, ↓IL-8, ↓MMP-9 Inhibition surface expression of ICAM-1	[111]
		colon	HT-29 (10.1 μM) HCT 116 (6.4 μM)	Cleavage of caspase-3 Induction of ERK signaling pathway via ↑p-ERK	[112]