Table 3.

Mechanisms involved in the cytotoxic effects of lectins on cancer cells.

Lectin	Mechanism	Ref.
(Abrus precatorius) Abrin	Abrin (type II RIP) induced the caspase 3-dependent but caspase 8-independent apoptotic pathway, mitochondrial membrane potential damage and production of ROS in Jurkat cells.	[165]
(Abrus precatorius) A. p. lectin	Peptides from A. p. lectin induced drastic loss of mitochondrial membrane potential and increase in ROS, leading to symptoms of early apoptosis through a deregulation of Akt and activation of both JNK, MAPK, p53 and autophagy in HeLa cells.	[166]
(Abrus precatorius) Abrin P2	Abrin P2 suppressed the proliferation of colon HCT-8 cell line and provoked a cell cycle arrest at the S and G2/M phases. Abrin P2 inhibited cell proliferation via the down-regulation of cyclin B1 and the nuclear antigen Ki67, and the up-regulation of P21. The abrin P2-induced apoptosis was dose- and time-dependent.	[167]
(Abrus precatorius) agglutinin AGG	AGG administered to human breast xenografted athymic nude mice mediated anti-tumorigenic effects through induction of extrinsic apoptosis via Akt-dependent ROS generation, and inhibition of angiogenesis via inhibition of expression of the pro-angiogenic factor IGFBP2 in an AKT-dependent manner.	[168]
(Agrocybe aegerita) lectin AAL	AAL inhibited the growth of different tumor cell lines HeLa, SW480, SGC-7901, MGC80-3, BGC-823 and HL-60 and induced apoptosis in HeLa cells. It also displayed DNAse activity.	[35]
(Arachis hypogaea) peanut agglutinin PNA	PNA induced autophagy and apoptotic cell death in HeLa cells, associated to a concomitant increase in ROS.	[169]
(Artocarpus integrifolia) jacalin	Rounding of A431 (epidermoid carcinoma) and HT29 (colorectal carcinoma) cells due to the stress-induced phosphorylation of caveolin-1 and p38 and down-regulation of EGFr.	[155]
(Bauhinia forficata) lectin BfL	BfL inhibited the adhesion of breast cancer MCF7 cells on laminin, collagen I and fibronectin, decreased the α1, α6 and β1 integrin subunit expression and increased the α5 subunit expression. BfL caused necrosis of MCF7 cells with caspase-9 inhibition, DNA fragmentation and cell cycle arrest in the G2/M phase.	[170]
(Glycine max) soybean agglutinin SBL	SBL-mediated autophagy, apoptosis and DNA damage in HeLa cells depend on the generation of ROS. Pre-treatment of HeLa cells by the ROS scavenger N-acetylcysteine reduced both SBL-induced autophagy, apoptosis and DNA damage.	[171]
(Momordica charantia) lectin MCL	MCL induced apoptosis, DNA fragmentation, G1 phase arrest and mitochondrial injury in nasopharyngeal carcinoma NPC cells in vitro and in vivo, associated with regulation of p38 MAPK, NK and ERK phosphorylation and NO production. MCL increased cytochrome c release in the cytosol, activated caspase-3, -8 and -9 and enhanced production of PARP.	[157]
(Momordica charantia) lectin MCL	MCL treatment induced G2/M phase arrest, autophagy, DNA fragmentation, mitochondrial injury and apoptosis in HCC cells. Activation of caspase and MAPK pathway was involved in the MCL-induced apoptosis. Up-regulation of truncated Bid (tBid) was shown to occur during the MCL treatment.	[172]
(Momordica charantia) RIP MAP30	MAP30 from Momordica charantia promotes apoptosis in both Hep G2 cells (hepatocellular carcinoma) and Hep G2-bearing mice. The contribution of both caspase-8 regulated extrinsic and caspase-9 intrinsic caspase cascades was evidenced.	[173]
(Momordica charantia) α-momorcharin and MAP30	Both RIPs induced cell cycle arrest in S-phase, DNA fragmentation and apoptosis in A549 lung carcinoma cells. Inhibition of cell proliferation was dose- and time-dependent.	[158]
(Sambucus nigra) agglutinin SNA	SNA activates the signaling pathways of AKT and ERK1/2 in ovarian carcinoma cells. The mitochondrial outer membrane permeabilization resulted in ROS generation and cytochrome c release in the cytosol. The perturbed mitochondrial respiration resulted in the G2/M phase cell cycle arrest.	[174]
(Sclerotium rolfsii) lectin SRL	SRL caused dose-dependent inhibition of proliferation of MCF-7 and ZR-75 breast cancer cells via induction of cellular apoptosis. Inhibitors of caspase-3, -8 and -9 prevented the apoptosis to occur.	[164]
(Viscum album) Korean mistletoe lectin VCA	VCA elicited apoptosis in SK-Hep-1 p53-positive and Hep 3B p53-negative hepatocarcinoma cell lines by down-regulation of Bcl-2 and up-regulation of Bax functioning upstream of caspase-3. Down-regulation of telomerase activity occurred in both VCA-treated cells.	[141]
(Viscum album) Mistletoe lectin-1 ML-1	CM-1 induced apoptosis in colorectal cancer cells by down-regulating the miR-135a&b miRNAs expression. The expression of β-catenin was up-regulated.	[149]
(Viscum album) Recombinant aviscumine	The mechanism of aviscumin-mediated cell death on multiple cell types was solely induced by the toxic A-chain. The mechanism is independent from the death receptor Fas and independent of the activity of the anti-apoptotic transcription factor NFκB. Treatment with aviscumine inhibited growth in various metastases mouse models including C8 colon carcinoma, Lewis lung sarcoma, Renca renal sarcoma, etc.	[175]
(Viscum album) Korean mistletoe lectin VCA	Treatment of B16BL6 and B16F10 melanoma cells with VCA resulted in G0/G1 phase arrest and induced an increase in both early and late apoptosis. Both VCA and mistletoe extracts increased activated multiple caspases (caspase-1, 3, 4, 5, 6, 7, 8 and 9) and a decrease of procaspase 3 and 8.	[176]
(Ricinus communis) agglutinin RCA and ricin A-chain	Treatment of cancer cells in vitro by ricin and ricin A-chain activates caspase 3 and caspase 8, but not caspase 9. In vivo, cell death depends on the necrotic effect of the RIP.	[177]
(Ricinus communis) ricin	Ricin inhibited the proliferation of HeLa cells by inducing apoptosis, chromatin condensation and nuclear fragmentation.	[178]
(Ricinus communis) ricin and riproximin	Unfolding protein response UPR to endoplasmic reticulum stress was induced in both HCT116 and MDA-MB-231 cells. Apoptosis was induced by concentrations of RIPs-II at which the UPR-related genes are still translated.	[179]
(Viscum album) Korean mistletoe lectin-II	Lectin-II induced the activation of caspase-3, -8 and -9 of myeloleukemic U937 cells in a time- and dose-dependent manner.	[180]
(Viscum album) mistletoe lectin-II	Apoptotic cell death of U937 cells was induced by the generation of pro-oxidants mediating the JNK/SAPK activation, cytochrome c release, activation of caspase-9- and -3-like proteases, and PARP cleavage.	[181]
(Viscum album) Korean mistletoe lectin VCA	Induction of apoptosis in A253 cells through activation of caspase-3 and inhibition of telomerase activity through transcriptional down-regulation of hTERT. Inhibition of telomerase activity resulted from dephosphorylation of Akt.	[182]
(Viscum album) European mistletoe lectin-containing extracts	In vitro and ex vivo treatment of Ewing sarcoma cells by mistletoe extracts inhibited proliferation and induced a dose-dependent apoptosis via intrinsic and extrinsic apoptotic pathways, as evidenced by activation of both caspase-8 and caspase-9.	[183]
(Viscum album) European mistletoe lectin-containing extracts	Treatment of Ewing sarcoma cells by mistletoe extracts impacted both gene and protein expression. Cell response to oxidative stress induced the activation of the MAPK signaling pathway.	[184]
(Ximenia americana) riproximin	Riproximin induced cytotoxic effects on breast cancer cell lines MDA-MB-231 and MCF-7. Riproximin treatment caused arrest in S phase and nuclear fragmentation of the cell, induced cytokine IL24/MDA-7 and ER-stress-related GADD genes. An inhibition of the genes involved in migration of colony was observed.	[185]