Table 2.

List of CTXs purified from venoms of Naja species and their mechanism of action.

Cobra Species	Cytotoxin	UniProt ID	Mechanism	Methodology/Tested Model	References
N. naja	CTX1	P01447	Interaction with erythrocyte membrane via ‘head groove’ and ‘loop groove’ of loop II	Molecular dynamics simulation	[75]
	CT13Nn	A0A0U4N5W4	Transformation from the “water” conformation to the “membrane” conformation in loop II during insertion into lipid membranes	X-ray crystallography and molecular dynamics simulation	[57]
	CTX2a	P86538	Complex formation with PLA2 and NTX and entry into cells via specific binding of the PLA2 to Vimentin	L6 rat myogenic cells	[72]
N. oxiana	CT1	P01451	Insertion into lipid membranes primarily with either the tip of loop I or both ends of loops I and II	NMR spectroscopy and molecular dynamics simulation	[76]
			Contractions of papillary muscles	Cardiomyocytes from right ventricles of rat hearts	[77]
			Formation of non-selective pores in the cell membrane that facilitates the influx of Ca2+ and stimulation of cardiomyocyte contracture	Isolated rat heart	[66]
			Alteration of mitochondrial permeability and signaling, ultimately leading to the mitochondrial fragmentation and stimulation of intrinsic apoptosis	Bovine cardiomyocytes, MCF-7 breast cancer cells, Hep-G2 hepatocellular carcinoma cells	[78,79]
	CT2	P01441	Insertion into lipid membranes via immersion of loop I	Molecular dynamics simulation	[80]
			Contractions of papillary muscles	Cardiomyocytes from right ventricles of rat hearts	[77]
			Formation of non-selective pores in the cell membrane that facilitates the influx of Ca2+ and stimulation of cardiomyocyte contracture	Isolated rat heart	[66]
			Alteration of mitochondrial permeability and signaling, ultimately leading to mitochondrial fragmentation and stimulation of intrinsic apoptosis	Bovine cardiomyocytes, MCF-7 breast cancer cells	[78,81]
			Increase in lysosomal membrane permeability and cathepsin B protease activity, and necrosis	MCF-7 breast cancer cells, HepG2 liver cancer cells, DU-145 prostate cancer cells, HL-60 leukemia cells, MDCK Madin–Darby canine kidney cells	[79]
N. atra	Cardiotoxin 1/CTX1	P60304	Upregulation of FasL and Fas expression leading to extrinsic apoptosis	HL-60 and U937 leukemia cells	[82]
			Increase in lysosomal membrane permeability and cathepsin B protease activity, and necrosis	16HBE human bronchial epithelial cells, MCF-7 breast cancer cells, K562 and P388 leukemia cells, H22 liver cancer cells	[83]
			Increase in lysosomal membrane permeability and release of cathepsin B, and necroptosis	KG1a and HL-60 leukemia cells	[84]
	CTX A2	P01442	Interaction with low sulfated heparin domains of cell membrane for internalization	H9C2 rat cardiomyocytes and Chinese hamster ovary (CHO) cells	[85]
	CTX A4/CTX4	P01443	Interaction with fully sulfated heparin domains of cell membrane for internalization	H9C2 rat cardiomyocytes and Chinese hamster ovary (CHO) cells	[85]
			Activation of L-type calcium channels for the influx of Ca2+ and subsequent activation of calcium-dependent cardiomyocyte contraction	Rat aortic ring preparation	[86]
			ROS generation followed by alteration in mitochondrial permeability, cytochrome c release and activation of intrinsic apoptosis	SK-N-SH human neuroblastoma cells	[87]
	Cardiotoxin III/CTX3	P60301	Cell cycle arrest at sub-G1 stage	HL-60 leukemia cells	[88]
			Downregulation of cyclin B1, cyclin A, Cdc25C, and Cdk 1 expression	K562 leukemia cells and Ca9–22, SAS, and CAL27 oral squamous carcinoma cells	[89,90]
			Upregulation of pro-apoptotic proteins (Bad, Bax, endonuclease G) and downregulation of anti-apoptotic proteins (Mcl-1, Bcl-2, survivin, Bcl-XL and XIAP) leading to intrinsic apoptosis	Ca9–22 oral squamous cell carcinoma cells, MDA-MB-231 breast cancer cells, A549 lung cancer cells, colo 205 colorectal cancer cells, and K562 leukemia cells	[90,91,92,93,94]
			ROS generation followed by alteration in mitochondrial permeability, cytochrome c release and activation of intrinsic apoptosis	SK-N-SH human neuroblastoma cells	[87]
			Ca2+ influx, phosphorylation of AMPK, mitochondrial fragmentation, cytochrome c release, and intrinsic apoptosis	U937 leukemia cells	[95]
	RP-HPLC fraction containing CTX isoforms	Unavailable	Dermonecrosis	Littermate ICR (CD-1) mice	[96]
N. kaouthia	NK-CT1	P0CH80	Interaction with oligonucleotide–human DNA topoisomerase II alpha complex for arresting cell growth	Molecular modelling and docking	[97]
			Cell cycle arrest at sub-G1 stage	U937 and K562 leukemia cells	[98]
N. haje	NHV-Ic	P01389	Alteration of mitochondrial permeability and signaling, ultimately leading to mitochondrial fragmentation and stimulation of intrinsic apoptosis	1301 leukemia cells	[99]
N. sumatrana	SumaCTX	A0A7T7DMY7	Alteration of mitochondrial permeability and signaling, ultimately leading to mitochondrial fragmentation and stimulation of intrinsic apoptosis	MCF-7 breast cancer cells	[100]
			Upregulation of peptidyl–prolyl isomerase and heat shock proteins thereby leading to necroptosis	MCF-7 breast cancer cells	[101]
N. nigricollis	RP-HPLC fraction containing CTX and PLA2	Unavailable	Dermonecrosis	CD-1 mice	[102]