Table 1.

Natural products (1–81) regulated mitochondria by different mechanisms in cancer cells.

No.	Isolated Compound	Origin	Cell Line	Mechanism	Reference
Terpenoids
1	Ganoleuconin O	Ganoderma leucocontextum	Huh7.5	Fatty acid immobilization, loss of the mitochondrial lipid cardiolipin	[30]
2	Lupeol	Bombax ceiba	SK-RC-45	Mitochondrial hyper fission	[31]
3	Betulinic acid	Betula alba	HeLa	Cardiolipin modification, ROS generation, Bad, caspase 9	[32,33]
4	Alisol B-23-acetate	Alisma orientale	A549, NCI-H292	ROS generation, Bcl-2↓, Bax↑, activation of caspase-3, -9, release of cytochrome c/AIF	[34]
5	Genipin	Gardenia jasminoides	N18TG2	Activation of dicarboxylate carrier, decreased activity of UCP1, UCP3, and complex III of the respiratory chain, UCP2 inhibition	[35]
6	Alternol	Yew tree	PC-3	Decrease of mitochondrial respiration, isocitric acid, fumaric acid and malic acid, ATP production	[36,37]
7	Cyathin Q	Cyathus africanus	HCT116	Bcl-2↓, Bax↑, Bcl-xL↓, ROS generation, release of cytochrome c	[38]
8	3α-hydroxy-19α-hydrogen-29-aldehyde-27-lupanoic acid	Potentilla discolor	HepG2	Bcl-2↓, Bax↑, release of cytochrome c	[39]
9	Uvedafolin	Smallanthus sonchifolius	HeLa	MMP loss, release of cytochrome c	[40]
10	Heteronemin	Hippospongia sp.	Molt4	ROS generation	[41]
11	Jatrogossone A	Jatropha gossypiifolia	KOPN-8	MMP loss, ROS generation	[42]
12	Walsuronoid B	Walsura robusta	Bel-7402, HepG2	ROS generation, mitochondrial and lysosomal dysfunction	[43]
13	Ferruginol	Podocarpus ferruginea	MDA-T32	ROS generation, MMP loss, Bcl-2↓	[44,45]
14	Lobocrassin B	Lobophytum crassum	CL1-5, H520, BEAS-2B	Bcl-2↓, Bax↑, ROS generation, MMP loss, release of cytochrome c, activation of caspase-3	[46]
15	Aellinane	Euphorbia aellenii	Caov-4	Bcl-2↓, Bax↑, ROS generation, MMP loss	[47]
16	Tingenin B	Maytenus sp.	MCF-7s	Bcl-2↓, Bax↑, MMP loss	[48]
17	3-O-trans-p-coumaroyl alphitolic acid	Ziziphus jujuba	PC-3	ROS generation	[49]
18	Zerumbone	Zingiber zerumbet	PC-3, DU-145	Tubulin binding and crosstalk between endoplasmic reticulum stress and mitochondrial insult	[50,51]
Flavonoids
19	Isoquercitrin	Hibiscus cannabinus	MDA-MB-231	LSD1-induced mitochondrial-mediated apoptosis pathway	[52,53]
20	Luteolin	Cauliflower, peanut, and carrot	SW1990	Inhibitor of Bcl-2, mitochondrial permeabilization	[54]
21	Dihydromyricetin	Ampelopsis grossedentata	HepG2	Akt/Bad signal pathway, mitochondrial apoptotic pathway, Bax↑, Bad↑, inhibition of the phosphorylation of Bad at Ser136 and Ser112	[55,56]
22	Artonin E	Artocarpus elasticus	SKOV-3	Release of cytochrome c, Activation of caspases-3, -8, and -9, Bax↑, Bcl-2↓, HSP70↓, survivin↓	[57]
23	Myricetin	Fruits and vegetables	SNU-80	Bax/Bcl-2↑, release of AIF	[58]
24	Xanthones	Garcinia xanthochymus	HepG2	Bax↑, Bcl-2↓, Bcl-xL↓, Mcl-1↓, and survivin↓	[59]
25	Cycloartobiloxanthone	Artocarpus gomezianus	H460	Bax↑, Bcl-2↓, Mcl-1↓	[60]
26	Paratocarpin E	Euphorbia humifusa	MCF-7	Bax↑, Bcl-2↓, release of cytochrome c	[61]
27	Puerarin 6′’-O-xyloside	Pueraria lobata	SW480	Bax↑, Bad↑, Bcl-2↓, caspase-3 and -9 activation	[62]
28	α-mangostin	Cratoxylum arborescens	HeLa	ROS generation, MMP loss, release of cytochrome c	[63]
29	Chrysin	Honey and propolis	Mitochondria isolated from hepatocytes of HCC rats	ROS generation, MMP loss, release of cytochrome c, swelling in mitochondria	[64,65]
30	Fisetin	Strawberries, apples, grapes, onions, and cucumbers	SCC-4	ROS generation, Ca2+ production, MMP loss, Bcl-2↓, Bax↑, Bid↑, release of cytochrome c, AIF, and Endo G	[66,67]
31	Baicalein	Scutellaria baicalensis, Scutellaria radix	A2780	Combination therapy with baicalein and taxol had much higher antitumor effects compared with the monotherapy. Release of cytochrome c, and caspase-3 and -9 activation	[68,69]
32	Alpinetin	Zingiberaceous plants	A549	Bcl-2↓, Bax↑, Bcl-xL↓, XIAP↓, PI3K/Akt signaling pathway, sensitized drug-resistant lung cancer cells	[70,71]
33	Chamaejasmin B	Stellerachamaejasme	KB, KBV200	Bcl-2↓, Bax↑, MMP loss, release of cytochrome c and AIF	[72]
34	Mensacarcin	Streptomyces bacteria	SK-Mel-28, SK-Mel-5, HCT-116	Release of cytochrome c, energy production and mitochondrial function rapidly disturbed	[73]
Saponins
35	Gracillin	Dioscorea gracillima	H226B, H460	Targeting mitochondrial complex II, suppressing ATP synthesis, ROS generation	[74]
36	Polyphyllin I	Paris polyphylla	MDA-MB-231	Mitochondrial translocation of DRP1, mitochondrial fission, release of cytochrome c, mitochondrial PTEN-induced kinase 1↑	[75,76]
37	Frondoside A	Cucumaria frondosa	CA46	Bcl-2↓, survivin↓, release of HtrA2/Omi and cytochrome c, ROS generation	[77]
38	3β-O-α-l- arabinopyranoside	Clematis ganpiniana	MCF-7, MDA-MB-231	Release of cytochrome c and Apaf-1, upregulation of caspase-9 and caspase-3	[78]
39	Sakuraso-saponin	Aegiceras corniculatum	LNcaP, 22RV-1, C4-2	Bcl-xL↓	[79,80]
40	Ginsenoside compound K	Panax ginseng	SK-N-BE(2), SH-SY5Y	Bcl-2↓, Bcl-xL↓	[81]
41	Escin	Aesculus hippocastanum	786-O, Caki-1	G2/M arrest and ROS-modulated mitochondrial pathways	[82]
42	α-Hederin	Hedera helix	SW620	NF-κB signaling pathway, Bcl-2↓, Bax↑, release of cytochrome c	[83,84]
Alkaloids
43	Cathachunine	Catharanthus roseus	HL60	ROS-dependent mitochondria-mediated intrinsic pathway, Bcl-2/Bax↓, ROS generation, MMP loss, release of cytochrome c	[85]
44	Berberine	Rhizoma coptidis	T98G, LN18	ERK1/2-mediated impairment of mitochondrial aerobic respiration	[86,87]
45	Papuamine	Haliclona sp.	H1299	Intracellular ATP depleted by causing mitochondrial dysfunction, mitochondrial superoxide production	[88]
46	Bis (2-ethyl hexyl) 1H-pyrrole-3, 4-dicarboxylate	Tinospora cordifolia	MDA-MB-231	ROS generation, increase in intracellular calcium, phosphorylation of p53, mitochondrial membrane depolarization, MPTP, and cardiolipin peroxidation, Bcl-2↓, Bax↑, release of cytochrome c, caspase activation, DNA fragmentation	[89]
47	Unantimycin A	Found in the fraction library of microbial metabolites	Semi-intact cells with specific substrates for each complex of the mitochondrial electron transport chain	Targeted inhibition of mitochondrial complex I	[90]
48	NPL40330	Found in chemical library	Semi-intact cells with specific substrates for each complex of the mitochondrial electron transport chain	Targeted inhibition of mitochondrial complex III	[90]
49	Boholamide A	Marine mollusks	U87MG	Influx of Ca2+	[91]
50	Cernumidine	Solanum cernuum	T24	Cytotoxicity and chemosensitizing effect of cernumidine to cisplatin. Bcl-2↓, Bax↑, MMP loss	[92]
51	Lycorine	Amaryllidaceae plant family	HepG2	mPTP opening, MMP loss, ATP depletion, release of Ca2+ and cytochrome c, caspase activation	[93]
52	Lagunamides A	Lyngbya majuscule	A549	MMP loss, ROS generation	[94]
53	Cordycepin	Cordyceps	OVCAR-3	Downregulation of mitochondrial function and limitation of energy production; metastasis and migration suppressed	[95,96]
Coumarins
54	2,3-Dihydro-7- hydroxy-2R*,3R*- dimethyl-2-[4,8-dimethyl-3(E),7- nonadienyl]-furo[3,2-c]coumarin	Ferula ferulaeoides	C6	MMP loss, Bcl-xL↓, Bcl-2↓, Bax↑, cleavage of Bid, FAS↑, FADD↑	[97]
55	Dentatin	Clausena excavate	HepG2	Bcl-xL↓, Bcl-2↓, Bax↑, release of cytochrome c	[98,99]
56	Aesculetin	Cortex Fraxini	THP-1	Bcl-2↓, Bax↑	[100]
Quinones
57	Quambalarine B	Quambalaria cyanescens	Jurkat E6.1	Inhibition of mitochondrial complex I and II, inhibition of mitochondrial respiration, metabolism reprogramming	[101,102]
58	Plumbagin	Plumbago zeylanica	MG63	ROS generation, Bcl-2↓, Bax↑, Bcl-xL↓, and Bak↓, endoplasmic reticulum stress	[103]
59	Shikonin	Lithospermum erythrorhizon	HGC-27	Bcl-2↓, Bax↑, survivin↓	[104]
60	2,7-dihydroxy-3-methylanthraquinone	Hedyotis diffusa	SGC-7901	Bcl-xl↓, Bcl-2↓, Bax↑, Bad↑, release of cytochrome c	[105]
61	3-hydroxy-1,5,6-trimethoxy-2-methyl-9,10-anthraquinone	Prismatomeris connate	A549, H1299	Bcl-2↓, Mcl-1↓, Bax↑	[106]
62	Thymoquinone	Nigella sativa	T24, 253J	Bcl-2↓, Bax↑, release of cytochrome c and AIF	[107]
Miscellanea
63	Methylsulfonylmethane	Fruits and vegetables	YD-38	Bcl-xL↓, Bcl-2↓, Bax↑, release of cytochrome c, MMP loss	[108,109]
64	Parameritannin A-2	Urceola huaitingii	HGC27	Enhanced doxorubicin-induced mitochondria-dependent apoptosis, inhibition of the PI3K/Akt, ERK1/2 and p38 pathways, Bcl-2↓, Bcl-xl↓, Bax↑, Bid↑, release of cytochrome c, caspase activation	[110]
65	Resveratrol	Polygonum cuspidatum, Veratrum nigrum, Cassia obtusifolia	H838, H520; K562	Enhanced antitumor activities of cisplatin; Induced apoptosis	[111,112]
66	Oleuropein	Olea europaea	H1299	Bcl-2/Bax↓, release of cytochrome c, activation of caspase-3	[113,114]
67	Homoisoflavanone-1	Polygonatum odoratum	A549	Mitochondria-caspase-dependent and ER stress pathways, Bcl-2/ Bak↓	[115]
68	Gallic acid	Green tea, grapes, red wine	H446	ROS-dependent mitochondrial apoptotic pathway	[116]
69	Hierridin b	Cyanobium sp.	HT-29	Proteomics identified 21 differentially expressed proteins belonging to the categories protein folding/synthesis and cell structure and reduced mitochondrial activity and as confirmed by morphological analysis of mitochondrial parameters	[117,118]
70	Deoxyarbutin	Ecklonia cava	B16F10	MMP loss, ATP depletion and ROS overload generation	[119]
71	Magnolol	Magnolia officinalis	OS-RC-2, 786-O	P53, Bcl-2/Bax↓, release of cytochrome c, caspase activation, ROS generation	[120]
72	Oblongifolin C	Garcinia yunnanensis	QBC939	Mitochondrial dysfunction	[121]
73	Amorfrutin C	Glycyrrhiza foetida	HT-29	mPTP opening, mitochondrial oxygen consumption and extracellular acidification increased	[122]
74	Allyl isothiocyanate	Cruciferous vegetables	MCF-7, MDA-MB-231	ROS and Ca2+ production, MMP loss, release of cytochrome c, AIF, and Endo G, Bcl-2↓, Bax↑	[123,124]
75	α-conidendrin	Taxus yunnanensis	MCF-7 and MDA-MB-231	ROS generation, p53↑, Bax↑, Bcl-2↓, MMP loss, release of cytochrome c, activation of caspases-3 and -9	[125]
76	Dehydrobruceine B	Brucea javanica	A549, NCI-H292	MMP loss, release of cytochrome c, cleavage of caspase-9, caspase-3, and poly (ADP-ribose) polymerase (PARP)	[126]
77	Frugoside	Calotropis procera	M14, A375	ROS generation	[127,128]
78	Methyl caffeate	Solanum torvum	MCF-7	Bcl-2↓, Bax↑, Bid↑, p53↑, cleavage of caspase-3 and PARP, release of cytochrome c	[129]
79	Tetrahydrocurcumin	Curcuma longa	MCF-7	ROS generation, Bcl-2↓, PARP↓, Bax↑, release of cytochrome c, MMP loss	[130]
80	Phloretin	Apple tree leaves and Manchurian apricot	EC-109	Bcl-2↓, Bax↑	[131]
81	Sesamol	Sesame seeds	HepG2	Bcl-2↓, Bax↑, MMP loss, H2O2 production, PI3K Class III/Belin-1 pathway	[132]