미토콘드리아를 표적으로 하는 천연물

Natural Products Targeting the Mitochondria in Cancers

2020

 

https://www.mdpi.com/1420-3049/26/1/92/htm

Natural Products Targeting the Mitochondria in Cancers

 

 

 

천연물에 의한 미토콘드리아 관련 세포 사멸의 조절. 

 

천연물의 활성과 관련된 세포 사멸에는 세포자멸사, 미토파지, 미토콘드리아 기능장애 등이 포함됩니다.

세포자멸사는 Bcl-2(B-세포 림프종-2) 계열 단백질의 수준, 사이토크롬 c의 방출 및 카스파제 활성화에 의해 조절됩니다. 

Mitophagy는 autophagy 작용에 의한 표적 식균 작용 및 미토콘드리아 파괴이며 일반적으로 미토콘드리아 상태 관리의 주요 메커니즘으로 간주됩니다. 

에너지 생산의 감소, 활성 산소 종(ROS)의 증가 및 투과성 전이 기공(PTP) 개방은 미토콘드리아 기능 장애로 이어질 수 있습니다.

 

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

 

No.Isolated CompoundOriginCell LineMechanismReference

Terpenoids
1	Ganoleuconin O	Ganoderma leucocontextum		Fatty acid immobilization, loss of the mitochondrial lipid cardiolipin	[30]
2	Lupeol	Bombax ceiba		Mitochondrial hyper fission	[31]
3	Betulinic acid	Betula alba		Cardiolipin modification, ROS generation, Bad, caspase 9	[32,33]
4	Alisol B-23-acetate	Alisma orientale		ROS generation, Bcl-2↓, Bax↑, activation of caspase-3, -9, release of cytochrome c/AIF	[34]
5	Genipin	Gardenia jasminoides		Activation of dicarboxylate carrier, decreased activity of UCP1, UCP3, and complex III of the respiratory chain, UCP2 inhibition	[35]
6	Alternol	Yew tree		Decrease of mitochondrial respiration, isocitric acid, fumaric acid and malic acid, ATP production	[36,37]
7	Cyathin Q	Cyathus africanus		Bcl-2↓, Bax↑, Bcl-xL↓, ROS generation, release of cytochrome c	[38]
8	3α-hydroxy-19α-hydrogen-29-aldehyde-27-lupanoic acid	Potentilla discolor		Bcl-2↓, Bax↑, release of cytochrome c	[39]
9	Uvedafolin	Smallanthus sonchifolius		MMP loss, release of cytochrome c	[40]
10	Heteronemin	Hippospongia sp.		ROS generation	[41]
11	Jatrogossone A	Jatropha gossypiifolia		MMP loss, ROS generation	[42]
12	Walsuronoid B	Walsura robusta		ROS generation, mitochondrial and lysosomal dysfunction	[43]
13	Ferruginol	Podocarpus ferruginea		ROS generation, MMP loss, Bcl-2↓	[44,45]
14	Lobocrassin B	Lobophytum crassum		Bcl-2↓, Bax↑, ROS generation, MMP loss, release of cytochrome c, activation of caspase-3	[46]
15	Aellinane	Euphorbia aellenii		Bcl-2↓, Bax↑, ROS generation, MMP loss	[47]
16	Tingenin B	Maytenus sp.		Bcl-2↓, Bax↑, MMP loss	[48]
17	3-O-trans-p-coumaroyl alphitolic acid	Ziziphus jujuba		ROS generation	[49]
18	Zerumbone	Zingiber zerumbet		Tubulin binding and crosstalk between endoplasmic reticulum stress and mitochondrial insult	[50,51]
Flavonoids
19	Isoquercitrin	Hibiscus cannabinus		LSD1-induced mitochondrial-mediated apoptosis pathway	[52,53]
20	Luteolin	Cauliflower, peanut, and carrot		Inhibitor of Bcl-2, mitochondrial permeabilization	[54]
21	Dihydromyricetin	Ampelopsis grossedentata		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		Release of cytochrome c, Activation of caspases-3, -8, and -9, Bax↑, Bcl-2↓, HSP70↓, survivin↓	[57]
23	Myricetin	Fruits and vegetables		Bax/Bcl-2↑, release of AIF	[58]
24	Xanthones	Garcinia xanthochymus		Bax↑, Bcl-2↓, Bcl-xL↓, Mcl-1↓, and survivin↓	[59]
25	Cycloartobiloxanthone	Artocarpus gomezianus		Bax↑, Bcl-2↓, Mcl-1↓	[60]
26	Paratocarpin E	Euphorbia humifusa		Bax↑, Bcl-2↓, release of cytochrome c	[61]
27	Puerarin 6′’-O-xyloside	Pueraria lobata		Bax↑, Bad↑, Bcl-2↓, caspase-3 and -9 activation	[62]
28	α-mangostin	Cratoxylum arborescens		ROS generation, MMP loss, release of cytochrome c	[63]
29	Chrysin	Honey and propolis		ROS generation, MMP loss, release of cytochrome c, swelling in mitochondria	[64,65]
30	Fisetin	Strawberries, apples, grapes, onions, and cucumbers		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		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		Bcl-2↓, Bax↑, Bcl-xL↓, XIAP↓, PI3K/Akt signaling pathway, sensitized drug-resistant lung cancer cells	[70,71]
33	Chamaejasmin B	Stellerachamaejasme		Bcl-2↓, Bax↑, MMP loss, release of cytochrome c and AIF	[72]
34	Mensacarcin	Streptomyces bacteria		Release of cytochrome c, energy production and mitochondrial function rapidly disturbed	[73]
Saponins
35	Gracillin	Dioscorea gracillima		Targeting mitochondrial complex II, suppressing ATP synthesis, ROS generation	[74]
36	Polyphyllin I	Paris polyphylla		Mitochondrial translocation of DRP1, mitochondrial fission, release of cytochrome c, mitochondrial PTEN-induced kinase 1↑	[75,76]
37	Frondoside A	Cucumaria frondosa		Bcl-2↓, survivin↓, release of HtrA2/Omi and cytochrome c, ROS generation	[77]
38	3β-O-α-l- arabinopyranoside	Clematis ganpiniana		Release of cytochrome c and Apaf-1, upregulation of caspase-9 and caspase-3	[78]
39	Sakuraso-saponin	Aegiceras corniculatum		Bcl-xL↓	[79,80]
40	Ginsenoside compound K	Panax ginseng		Bcl-2↓, Bcl-xL↓	[81]
41	Escin	Aesculus hippocastanum		G2/M arrest and ROS-modulated mitochondrial pathways	[82]
42	α-Hederin	Hedera helix		NF-κB signaling pathway, Bcl-2↓, Bax↑, release of cytochrome c	[83,84]
Alkaloids
43	Cathachunine	Catharanthus roseus		ROS-dependent mitochondria-mediated intrinsic pathway, Bcl-2/Bax↓, ROS generation, MMP loss, release of cytochrome c	[85]
44	Berberine	Rhizoma coptidis		ERK1/2-mediated impairment of mitochondrial aerobic respiration	[86,87]
45	Papuamine	Haliclona sp.		Intracellular ATP depleted by causing mitochondrial dysfunction, mitochondrial superoxide production	[88]
46	Bis (2-ethyl hexyl) 1H-pyrrole-3, 4-dicarboxylate	Tinospora cordifolia		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		Targeted inhibition of mitochondrial complex I	[90]
48	NPL40330	Found in chemical library		Targeted inhibition of mitochondrial complex III	[90]
49	Boholamide A	Marine mollusks		Influx of Ca2+	[91]
50	Cernumidine	Solanum cernuum		Cytotoxicity and chemosensitizing effect of cernumidine to cisplatin. Bcl-2↓, Bax↑, MMP loss	[92]
51	Lycorine	Amaryllidaceae plant family		mPTP opening, MMP loss, ATP depletion, release of Ca2+ and cytochrome c, caspase activation	[93]
52	Lagunamides A	Lyngbya majuscule		MMP loss, ROS generation	[94]
53	Cordycepin	Cordyceps		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		MMP loss, Bcl-xL↓, Bcl-2↓, Bax↑, cleavage of Bid, FAS↑, FADD↑	[97]
55	Dentatin	Clausena excavate		Bcl-xL↓, Bcl-2↓, Bax↑, release of cytochrome c	[98,99]
56	Aesculetin	Cortex Fraxini		Bcl-2↓, Bax↑	[100]
Quinones
57	Quambalarine B	Quambalaria cyanescens		Inhibition of mitochondrial complex I and II, inhibition of mitochondrial respiration, metabolism reprogramming	[101,102]
58	Plumbagin	Plumbago zeylanica		ROS generation, Bcl-2↓, Bax↑, Bcl-xL↓, and Bak↓, endoplasmic reticulum stress	[103]
59	Shikonin	Lithospermum erythrorhizon		Bcl-2↓, Bax↑, survivin↓	[104]
60	2,7-dihydroxy-3-methylanthraquinone	Hedyotis diffusa		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		Bcl-2↓, Mcl-1↓, Bax↑	[106]
62	Thymoquinone	Nigella sativa		Bcl-2↓, Bax↑, release of cytochrome c and AIF	[107]
Miscellanea
63	Methylsulfonylmethane	Fruits and vegetables		Bcl-xL↓, Bcl-2↓, Bax↑, release of cytochrome c, MMP loss	[108,109]
64	Parameritannin A-2	Urceola huaitingii		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		Enhanced antitumor activities of cisplatin; Induced apoptosis	[111,112]
66	Oleuropein	Olea europaea		Bcl-2/Bax↓, release of cytochrome c, activation of caspase-3	[113,114]
67	Homoisoflavanone-1	Polygonatum odoratum		Mitochondria-caspase-dependent and ER stress pathways, Bcl-2/ Bak↓	[115]
68	Gallic acid	Green tea, grapes, red wine		ROS-dependent mitochondrial apoptotic pathway	[116]
69	Hierridin b	Cyanobium sp.		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		MMP loss, ATP depletion and ROS overload generation	[119]
71	Magnolol	Magnolia officinalis		P53, Bcl-2/Bax↓, release of cytochrome c, caspase activation, ROS generation	[120]
72	Oblongifolin C	Garcinia yunnanensis		Mitochondrial dysfunction	[121]
73	Amorfrutin C	Glycyrrhiza foetida		mPTP opening, mitochondrial oxygen consumption and extracellular acidification increased	[122]
74	Allyl isothiocyanate	Cruciferous vegetables		ROS and Ca2+ production, MMP loss, release of cytochrome c, AIF, and Endo G, Bcl-2↓, Bax↑	[123,124]
75	α-conidendrin	Taxus yunnanensis		ROS generation, p53↑, Bax↑, Bcl-2↓, MMP loss, release of cytochrome c, activation of caspases-3 and -9	[125]
76	Dehydrobruceine B	Brucea javanica		MMP loss, release of cytochrome c, cleavage of caspase-9, caspase-3, and poly (ADP-ribose) polymerase (PARP)	[126]
77	Frugoside	Calotropis procera		ROS generation	[127,128]
78	Methyl caffeate	Solanum torvum		Bcl-2↓, Bax↑, Bid↑, p53↑, cleavage of caspase-3 and PARP, release of cytochrome c	[129]
79	Tetrahydrocurcumin	Curcuma longa		ROS generation, Bcl-2↓, PARP↓, Bax↑, release of cytochrome c, MMP loss	[130]
80	Phloretin	Apple tree leaves and Manchurian apricot		Bcl-2↓, Bax↑	[131]
81	Sesamol	Sesame seeds		Bcl-2↓, Bax↑, MMP loss, H2O2 production, PI3K Class III/Belin-1 pathway	[132]

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