Table 1.

Natural compounds targeting mitochondrial dysfunction by in various experimental models of gliomas.

S. No.	Name of Natural Compound	Experimental Model System	Observed Cytotoxic Range	Probable Mechanisms of Action	Observations	Refs.
1.	Curcumin	U87MG glioblastoma cell line U87 MG cells along with TRAIL T98G glioblastoma multiforme	25-50µM Sublethal conc. 25- 50µM	Enhanced Bax-Bcl2 ratio, caused cytochrome c, Smac, Diablo release, Decreased cIAP2, caspase 9 activation Release of cytochrome c, caspase 9, 3,8 activation Caused cytochrome c, smac, Diablo, AIF release, Enhanced Bax-Bcl2 ratio, decreased cIAP1,cIAP2, caspase 9 activation	Decrease in cell viability, induction of apoptosis Sensitizes to cytotoxic action of TRAIL, induction of apoptosis Decrease in cell viability, induction of apoptosis	[48] [49] [50]
2.	Mahanine	U87MG, LN229 In vivo U87 MG xenografts	5-20 µM	Mitochondrial electron transport chain complex III inhibition, decreased oxygen consumption, elevated ROS, decreased MMP, activation and up regulation of Chk1/chk2, down regulation of CDK4/CDK6, cyclin D1/D3, CDC25A	Decrease in proliferation, G0/G1 arrest, decreased invasion, induction of differentiation in vivo Reduced tumor burden in models	[54]
3.	PEITC (Phenethyl isothiocyanate)	GBM 8041 cells U87MG cells Ln229 cells	4-8 μM 2.5 μM 10, 20 μM	ROS generation, rise in [ca2+] I, promotion of Fas, FasL, FADD, TRAIL, caspases 8,9,3, increase in apoptotic proteins (Bax, Bak, Bid) inhibition of anti apoptotic proteins(Bcl2, Bcl-xl), release of cytochrome c, AIF, Endo G, decrease in mitochondrial membrane potential, Enhanced ROS generation, up regulation of DR5, enhanced activities of caspase 3, 8, 9, increase in mitochondrial superoxide levels Induction of ROS, inhibition of SOD and glutathione and enhancement of caspase 3 activity	Inhibition of growth, induction of apoptosis Enhancement of cytotoxicity of TRAIL at sub toxic concentrations of PEITC Inhibition of proliferation, induction of apoptosis, cell cycle arrest	[61] [62] [63]
4.	Aloe emodin	U87	58.6 µg/ml	Collapse of mitochondrial membrane potential, S phase cell cycle arrest	Decrease in cell proliferation, induction of apoptosis	[68]
5.	Dioscin	Rat glioma c6 cells in vitro and in vivo	1.25-5 µg/ml in vitro and 30mg/kg oral in vivo	ROS generation, ca++ release, mitochondrial structural changes, mitochondrial permeability changes, release of cytochrome c, PDCD5, increase of Bax, Bak, Bid Decrease of Bcl-2, Bcl-xl, increased activity of caspase 9, 3	Inhibition of cell proliferation, Induction of apoptosis, in vivo- Increase of survival time of rodents, decrease of tumor volume	[72]
6.	α-bisabolol	U87	2.5-10 µM	Dissipation of mitochondrial membrane potential, release of cytochrome c, PARP cleavage	Inhibition of cell viability, induction of apoptosis	[73]
7.	Dantron	C6	10-100 µM	Induction of ROS, disruption of mitochondrial membrane potential, release of cytochrome c, AIF, Endo G, increase in caspase 3, 9 activities	Decrease in cell viability, induction of apoptosis	[74]
8.	Flavopiridol	Murine glioma GL261 in vitro and in vivo	100-400nM in vitro and in vivo 5mg/ kg	Mitochondrial damage, release of cytochrome c, nuclear translocation of apoptosis inducing factor	Inhibition of cell growth and inhibition of migration In vivo decrease of tumor volume	[76, 77]
9.	Xanthohumol	T98G cells	1-50 μM	ROS generation, depolarization of mitochondria, mitochondrial permeability transition, cytochrome c release, decrease in Bcl-2, activation of caspase-9,	Decrease of cell viability, induction of apoptosis	[79]
10.	Shikonin	U87MG cells	2-8 μM	Induction of ROS, disruption of mitochondrial membrane potential, mitochondrial superoxide generation, inhibition of complex II of mitochondrial ETC, GSH depletion, catalase down regulation, SOD1 up regulation, modulation of Bcl-2 family proteins	Induction of apoptosis	[81, 82]
11.	Resveratrol	U251 cells	10-100 μM	Release of cytochrome c from mitochondria, activation of caspase 9, up regulation and translocation of Bax to mitochondria	Cytotoxic action, induction of apoptosis, inhibition of proliferation	[84]
12.	Quercetin	U373MG	25-100 μM	Decrease in mitochondrial membrane potential, upregulation and translocation of P53 to mitochondria, release of cytochrome c, increase in activities of caspase 9, 3.	Inhibition of cell proliferation, induction of apoptosis and cytoprotective autophagy	[86]
13.	Hydroxygenkwanin	c6 glioma	25 μM	Loss of mitochondrial membrane potential, mitochondrial damage including swelling, over expression of Bak, Bid, reduced expression of Bcl-xl	Inhibition of cell proliferation, apoptosis	[89]
14.	Alantolactone	U87, U373, LN229 Kumming mice	40 μM 100mg/kg/ day	ROS generation, dissipation of mitochondrial membrane potential, cardiolipin oxidation, GSH depletion, release of cytochrome c, upregulation of p53, Bax, down regulation of Bcl2, increase in activities of caspase 9, 3	Induction of cell death, apoptosis induction No hepatotoxicity, nephrotoxicity	[91]
15.	Kaempferol	T98G, U373MG, LN229	50 μM	ROS generation, loss of mitochondrial membrane potential, down regulation of Bcl2	Inhibition of cell viability, induction of apoptosis, potentiation of doxorubicn’s cytotoxic effects	[93]
16.	Honokiol	DBTRG-05MG	20-80 μM	Increased ROS accumulation, decrease of mitochondrial membrane potential, release of cytochrome c, increase in activities of caspase 9, 3 and elevation of intracellular calcium	Induction of apoptosis	[94, 95]
17.	Parthenolide	U87MG, U373 Intracerbral glioblastoma xenograft model U138MG, U87, U373 and C6	0.1-50 μM 10mg/kg/day i.p daily for 3 weeks 5-50 μM	Increased expression of Bax, Bak, down regulation of Bcl2, Increased activities of caspase 9, 3 Reduction in VEGF, MMP-9 Loss of mitochondrial membrane potential, release of cytochrome c, decrease in Bcl-xl	Reduction of proliferation, suppression of invasion and angiogenesis Reduction of tumor growth, angiogenesis Decrease in cell viability, induction of apoptosis	[97] [97] [98]
18.	Phloretin	U251, T9 glioma	50, 100 μM	Mitochondrial swelling, loss of ATP, induction of paraptosis (cellular swelling along with vacuolization), BK channel activation, over expression of heat shock proteins(HSP 60, 70,90)	Reduction in cell viability	[101, 102]
19	Gossypol	U87, U373, MZ-54 U87MG-luc2 xenograft along with TMZ	10-30 μM 30mg/kg/day	Induction of autophagic cell death, decrease in mitochondrial membrane potential, release of cytochrome c Decrease in TUNEL positive, Ki67positive cells, decrease in micro vessel density	Cytotoxic action, autophagic cell death Reduction of tumor burden, increase in apoptosis	[103] [104]
20	Berberine	T98G	50-200 μM 50, 100 mg/kg/day	Enhanced oxidative stress, Ca2+ levels, loss of mitochondrial membrane potential, enhanced Bax-Bcl2 ratio, increased caspase 9,3 activities Senescence induction, decrease in Ki67 and EGFR	Decreased cell viability, Induction of apoptosis Inhibition of tumor growth	[107] [108]

(AIF- Apoptosis inducing factor; Bax- BCL2-Associated X Protein; Bak- Bcl-2 antagonist/killer-1; Bid- BH3 interacting domain death agonist; BK channel- Big Potassium channel; CDC25A- cell division cycle 25 homolog A; CDK- Cyclin-dependent kinase; cIAP- Cellular inhibitor of apoptosis 2; Diablo- Direct IAP binding protein with low pI; DR5- Death Receptor 5; Endo G- Endonuclease G; ETC-Electron transport chain; Fas- Apoptotsis stimulating fragment; FasL –Fas ligand; FADD- Fas-Associated protein with Death Domain; MMP9- Matrix metallopeptidase 9; PARP- Poly ADP ribose polymerase; PDCD5- Programmed cell death protein 5; ROS-reactive oxygen species; Smac- Second Mitochondria-Derived Activator of Caspases; SOD- Superoxide dismuatase; VEGF- Vascular endothelial growth factor; TRAIL- TNF-related apoptosis-inducing ligand; TUNEL- Terminal deoxynucleotidyl transferase dUTP nick end labeling).