Review of Natural Product-Derived Compounds as Potent Antiglioblastoma Drugs

Table 1

Apoptotic effect of natural products.

Family names	Medical plants	Compounds/extracts	Dose/duration	Target molecules and additional efficacy	Cell lines	References
Hypericaceae	Hypericum perforatum L. (H. perforatum)	Hyperforin (HP), polyphenolic procyanidin B2 (PB-2), hypericin (HY)	HP 20 µM for 24 h; PB-2 80 µM for 24 h; (Annexin V-binding analysis)	Annexin V positive cells	LN229	[21]
Apiaceae	Angelica sinensis	n-Butylidenephthalide (BP)	75 µg/mL for 6, 12, 24 h (cell cycle analysis); 75 µg/mL for 24, 48, 72 h (Cell Death Detection Kit, POD); 75 µg/mL for 0, 1.5, 3, 6, 12, 24, 48 h (Western blot analysis)	DBTRG-05MG, DBTRG 8401 (human); ↑p53, p16, Bax, AIF protein induce Fas expression, caspase-8 (dose-dependent), procaspase-9, procaspase-3; ↓cdk2, cdk4, cdk6, cyclin D1, cyclin E,; RG2 (rat); ↑p27, Bax, AIF induce Fas expression, caspase-8 (maximum expression at 24 h), procaspase-9, procaspase-3; ↓cdk2, cdk4, cdk6, cyclin D1, cyclin E, p21; cell cycle arrest (G0-G1 phase)	DBTRG-05MG, GBM 8401 (human), RG2 (rat)	[22]
Ericaceae	Vaccinium macrocarpon (cranberry)	Flavonoid-rich fraction 6 (Fr6), proanthocyanidins (PAC) fraction	Fr6 concentration: 0, 50, 100, 150, 200, 250, 300 mg/L for 24 and 48 h (cell cycle distribution analysis) (Annexin V, PI); PAC concentration: 0, 20, 40, 60, 80, 100, 120, 140, 160 mg/L for 24, 48 h (cell cycle distribution analysis) (Annexin V, PI)	↑G1 phase; ↓S phase; cell cycle arrest (G1 phase)	U87MG	[23]
Menispermaceae	Tinospora cordifolia	Ethanol extract	250 μg/ml, 350 μg/ml for 72 h	↑GFAP, NCAM,; ↓MMP-2,9, cyclin D1, Bcl-xl	C6, U87 MG	[24]
Ranunculaceae	Nigella sativa	Thymoquinone	20 μM, 40 μM for 24 h	↑p62, cathepsin B	T98G, U87 MG	[25]
		Niclosamide	1.5 μm/L for 48 h	↓WNT/CTNNB1-, NOTCH-, mTOR-, NF-kB	LN229, T98G, U87MG, U138, and U373 MG	[26]
Fabaceae	Caesalpinia sappan	Brazilin	10 μg/ml, 15 μg/ml, 20 μg/ml for 24 h	↑PARP; ↓caspase-3, caspase-7	U87 MG	[27]
Cannabaceae	Marijuana (cannabis)	Δ(9)-Tetrahydrocannabinol (THC) and cannabidiol (CBD)	75 mg MPs (biodegradable polymeric microparticles) every 5 days	↓KI67, CD31	U87 MG	[28]
		Hopeaphenol, r2-viniferin	20 μg/ml (hopeaphenol), 100 μg/ml (r2-viniferin) for 120 h	↓caspase-9, caspase-3/7	D-GBM	[29]
Lamiaceae	Scutellaria baicalensis	Wogonin	0–100 μM; for 24 h	↑ AMPK, p53; ↓mTOR, 4E-BP1; G0/G1 phase arrest	U87 MG, U343 MG, U373 MG, T98G, MCF-10A	[30]
Rosaceae	Aronia melanocarpa	Chokeberry extract, curcumin	10 μg/ml (curcumin), 50 μg/ml (polyphenolics from Aronia melanocarpa)	↓MMP-2, -14, -16, -17	U373 MG	[31]
(1) Fabaceae; (2) Polygonaceae; (3) Lamiaceae; (4) Asteraceae; (5) Rutaceae; (6) Dioscoreaceae	(1) Sophora tonkinensis; (2) Polygonum bistorta; (3) Prunella vulgaris; (4) Sonchus brachyotus; (5) Dictamnus dasycarpus; (6) Dioscorea bulbifera	ZSP (Zeng Sheng Ping)	0, 50, 100 mg/kg/day	↓notch 2, Hes1, CD133	U87 MG, HSR-GBM1 JHH-GBM10, JHH-GBM14	[32]
Acanthaceae	Andrographis paniculata	Andrographolide	10 μM	↓PI3K/AKT, caspase-3; G2/M phase arrest	U251, U87 MG	[33]
	Macaranga schweinfurthii	3-Deoxyschweinfurthin B (3dSB), 3-deoxyschweinfurthin B-like p-nitro-bis-stilbene (3dSB-PNBS)	3dSB (500 nM), 3dSB-PNBS (500 nM), DMP-PNBS (1 M), or Y-27632 (10 M) for 48 h	↑PARP, GRP78, PDI; ↓caspase-9	SF-295	[34]
Asteraceae	Artemisia argyi	Jaceosidin	100 μM/L for 24 h	↑p53, Bax, cytochrome c, caspase-3; G2/M phase arrest	U87 MG	[35]
		Resveratrol	30 μM for 48 h	↑ Atg5, beclin-1, LC3-II, PI3k class III; ↓CD133, OCT4, mTor/AKT/p70S6K; S-G2/M phase arrest	U-87 MG, U-251, U-138 MG	[36]
Asteraceae	Tithonia diversifolia	Tagitinin C	10 μg/mL for 12 h	↑PARP, p-p38, ULK1, LC3-II	U373 MG	[37]
Apiaceae	Angelicasinensis	(Z)-N-(2-(Dimethylamino)ethyl)-2-(3-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)phenoxy)acetamide (PCH4)	50 µg/ml for 24 h	↓Nur77, JNK	DBTRG-05MG, GBM 8401	[38]
Clusiaceae	Garcinia mangostana	γ-Mangostin	80 μM for 8 h	↑NK cell, ROS; ↓PGE2, COX-2, NO	U87 MG, GBM 8401	[39]
	High-fiber foods (such as corns, cereals, legumes, nuts, oil seed, soybean)	Inositol hexaphosphate (IP6)	0.5, 1 mM for 24 h	↑Bax, Bax: Bcl-2 ratio, cytosolic level of cytochrome c, Smac/Diablo (in the cytosol), 80 kD calpain, caspase-9, 85 kD PARP fragment; ↓cytochrome c, Smac/Diablo, Bcl-2, BIRC-2, hTERT	T98G	[40]
Anacardiaceae	Spondiaspinnata	Methyl gallate	1 to 30 μg/ml for 48 h	ERK1/2 activation, apoptosis	U87MG	[41]
Rutaceae	Rutagraveolens L.	R. graveolens a.e.	1 mg/ml for 24, 48, 72 hours	ERK1/2, AKT activation, apoptosis in A1 mes-c-myc cells	U87MG, C6, U138	[42]
Lamiaceae	Rabdosiarubescens	Oridonin	5 μM for 12 h	↓RNA transferation, RanGTP	U87MG	[43]
Berberidaceae	Dysosmaversipellis	Deoxypodophyllotoxin (DPT)	30 nM for 72 h	↓Cdc2, cyclin B1, Cdc25c	U87MG, SF126	[44]
Primulaceae	Ardisiapusilla A.DC	Ardipusilloside I (ADS-I)	(20 μL, 5 mg/mL) for 4 h	↓vascular endothelial growth factor, C-reactive protein, tumor necrosis factor-α, interleukin-6, interleukin-2	rat C6 glioma cells (in vivo)	[45]
Curcuma	Curcumaamada Roxb.	Supercritical CO2 extract of mango ginger (CA)	0–100 mg/mL for 48 h	↓STAT3, Bcl-2, mutant p53 expression; ↑ratio of Bax/Bcl-2	U87MG	[46]
		Curcumin, temozolomide	7.5 μM for 72 h	↓phosphorylation of cyclin B1, cyclin D1; G2/M arrest	C6, U251MG; U87MG	[47]
Rubiaceae	Hedyotisdiffusa Willd	HDW extract	0, 4, 8 mg/ml for 24 h	↓Bcl-2/Bax ratio, AKT suppression ↑caspase-3, Bcl-2, Bax and ERK; S/G2-M phase arrest, MMP collapse	U87MG	[48]
Berberidaceae	Epimediiherba	Icariin	0, 5, 10, 20 μM for 2 h	↓NF-kB, piwil4, Rac1; vasodilator-stimulated phosphoprotein (VASP)	U87MG	[49]
		Hispidulin	10 μM for 2 h	↓Bcl2; ↑AMPK; G2 cell cycle arrest	Human GBM; SHG44	[50]
Oleaceae	Oleaeuropaea	Olea europaea leaf extract (OLE)	1 mg/ml, 2 mg/ml for 24 h	↑ miR-153, miR-145, miR-137	T98G,; U-138MG,; U-87MG	[51]
Moraceae	Ficuscarica Latex	FCL extract	0.125 mg/ml for 24 and 48 h	↓HMGA2, VEGFA ↑HMGA2, VEGFA	T98G,; U-138 MG,; U-87 MG	[52]
Magnoliaceae	Magnoliaofficinalis	Honokiol	10, 20 µg/ml for 12 or 24 h	↓STAT3 signaling, ERK1/2,; ↑p38 MAPK signaling pathway; G0/G1 phase cell cycle arrest	U87MG, U251,; T98G	[53]
Apocynaceae/Zingiberaceae	Rhazyastricta, Zingiberofficinale	Crude alkaloid (CAERS), flavonoid (CFEZO)	10 µg/mL/for 24, 48, 72 h	↓nuclear NF-kB, p65, survivin, XIAP, cyclin-D1,; ↑mitochondrial cytochrome c, Bax : Bcl-2 ratio, activities of caspase-3 and -9, and PARP-1 cleavage, p53, p21, Noxa	U251	[54]
Primulaceae	Ardisiapusilla A.DC	Ardipusilloside I	20 µg/mL for 24 h	↑Beclin 1, LC3; arrest at G2/M phase	U373, T98G	[55]
Berberidaceae	Berberisamurensis	Berbamine derivative, BBMD3	1 µg/mL/24 h or 48 h	↑miRNA-4284, JNK/AP-1 signaling, caspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP) microRNA-4284 (miR-4284), phosphorylation of the cJun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK)	Cancer stem-like cells (CSCs) from four GBM patients (PBT003, PBT008, PBT022, and PBT030)	[56]
Solanaceae		Withaferin A (WA)	0.025–3 μM for 72 h	↓G2/M cell cycle arrest, phosphorylation of AKT, mTOR, p70 S6K, c-Met, EGFR, Her2	U87MG, U251, T98G	[57]
Amaryllidaceae	Sternbergialutea	Lycorine		↓actin, CYP3A4 cytostatic effect	B16F10 melanoma (mice)	[58]
	Lavandin, peppermint, spearmint, sage, cherries, cranberries, Perilla (Perillafrutescens), lemongrass, wild bergamot, gingergrass, savin, caraway, celery seeds//lemon	Perillyl alcohol (monoterpene alcohol) //		Perillyl alcohol: ↑TGF-β; Limonene: ↓isoprenylation, coenzyme Q synthesis		[59]
Apiaceae	Angelica sinensis	Methanol extract of Angelicasinensis	100 µL for 72 h	↑p16 and p53, CDK inhibitors; cell cycle arrest at the G0-G1 phase	DBTRG-05MG, BALB/3T3	[20]
	4,6-Dichloro-5-aminopyrimidine	Thiazolo5,4-d pyrimidines	48 h		T98G	[60]
Apiaceae	Bupleurum scorzonerifolium (Nan-Chai-Hu)	Isochaihulactone	No concentration (all cell ER stress Western); 80 μM for 0, 24, 48 h (cell cycle); 20, 40, 80 μM for 24 h (Annexin V-PI double stain); 50, 200 mg/kg daily for 30 d (in vivo)	↑DDIT3, NAG-1, PARP, caspase-3/9/7; ↓pERK, Bcl-2; cell cycle arrest G2/M phase, subG1 population increase (naturally pERK induce DDIT3. But DDIT3 increased with low pERK. There is new pathway to increase DDIT3)	GBM cell lines; 8401, 8901, U87MG, G2T, 131TXM, 1XM, RG2, GL261; (each cell for ER stress Western, 2 cells for cell cycle)	[61]
Solanaceae	Lycium chinense (Lycii radicis [Cortex])	Kukoamine A	0, 5, 10, 20 μM for 48 h (cell cycle); 40, 60, 80 μM for 48 h on U251; 10, 20, 30 μM for 48 h on WJ1 (Annexin V-PI double stain, cell activation observed, Western)	↑Bax, caspase-3, E-cadherin; ↓5-Lipoxygenase (5-LOX), Bcl-2, CCAAT/enhancer binding protein β (C/EBPβ), N-cadherin, vimentin, twist and snail+slug; Proliferation, colony formation, migration, invasion, growth of tumors all decreased, cell cycle arrested G0/G1 phase, less cell cycle S phase, less cytotoxic for C6	Human GBM cells U251 & WJ1,; rat glioma cells (C6)	[62]
Valerianaceae	Nardostachys jatamansi [Rhizome]	N/A	0, 20, 40, 60, 80 µg/mL for 24, 48, 72 h (cell counting, AO/EB Dual Fluorescence Staining); 0, 20, 40, 60, 80 µg/mL for 24 h (cell cycle analyses); 0, 20, 40, 60, 80 µg/mL for 1 week (clonogenic assay); 10–70 µg/mL for 24 h (DNA Fragmentation); No concentration measured for 24 h (Western immunoblotting)	↓caspase-3/9, PARP; cell shrinkage, membrane blebbing, echinoid processes, pyknosis, myorrhexis, low density (~40 µg/mL) early apoptosis, high density (60 µg/mL) late apoptosis, G0/G1 arrest 60, 80 µg/mL	U87M (every experiment), U373MG	[63]
N/A	N/A	Myricetin	200 μM for continuous time (over 90 h) (real-time cell analyser instrument); 25, 50, 100, 200 μM for 24 h (Western)	↑Bax, cleaved caspase-3, caspase-9, Bad; ↓cytochrome c, Bcl-2, MDM2, K-Ras, Raf-1, ERK, pERK	DBTRG-05MG, U251, U87MG; (DBTRG-05MG for every experiment, 3 cells for real-time cell viability)	[64]
Lamiaceae	Melissa officinalis	Rosmarinic acid (RA) // luteolin-7-glucoside, caffeic acid, rosmarinic acid, protocatechuic acid, caftaric acid, ferulic acid, cichoric acid, Dulbecco’s modified Eagle’s medium (DMEM), Ampliflu Red, 2′,7′-Dichlorofluorescin diacetate (DCFH2-DA), 3-(4,5-dimethylthiazol2-yl)-2,5-diphenyl-tetrazolium bromide (MTT), HPLC grade acetonitrile, trifluoroacetic acid (TFA)	0, 50, 100, 140, 170, 200, 250, 300, 400 μM for 24, 48 h (RA cell viability); 0, 50, 100, 140, 170, 200 μM for 24, 48 h (N1 cell viability); 0, 10, 25, 40, 50, 75, 100 μM for 24, 48 h (N2, N3 cell viability); (highest density is 0% survive)	↑intracellular reactive species (RS) (high density); ↓intracellular reactive species (RS) (low density); cell proliferation decrease, at low density cell viability increase, at middle density apoptosis & antioxidant effect, at high density prooxidant effect & necrosis; RA < Aqueous < Ethanolic 40% < Ethanolic 70% (effect); (pure RA, aqueous (N1), ethanolic 40% (N2), ethanolic 70% (N3), 4 kinds compared)	C6 rat glioblastoma	[65]
N/A	N/A	β-Escin; temozolomide (TMZ)	0, 2, 4, 6, 8, 10 μM for 48 h (cell viability); 0, 2, 4, 6, 8, 10 μM β-escin + 0, 2, 4, 6, 8, 10, 50, 100 μM TMZ for 48 h (β-escin, TMZ combined cell viability); No measurement of concentration for 24 h (Western only PARP-1)	↑cleaved PARP-1; synergy with TMZ	(Patient-derived) glioblastoma-initiating cells (GIC), U87MG	[66]
Araceae	Acori graminei [Rhizoma]	N/A	0, 50, 100 μg/mL for 48 h on A172; 0, 100, 200 μg/mL for 48 h on U251 (Annexin V-PI double stain); 0, 25, 50, 100 μg/mL for 48 h on A172; 0, 50, 100, 200 μg/mL for 48 h on U251 (Western)	↑Bax, cleaved caspase-3/8/9, mTOR (A172 only), LC3II/I, atg5, beclin-1, p-AMPK (both); ↓Bcl-2, p-p70S6K, p-mTOR (A172 only), p62 (both); Etop inhibition pathway is contrasted with each experiments dependent/independent confirm	A172, U87MG, U251, U118,; 4 cell MTT (all experiments)	[67]
Araliaceae	Panax ginseng	Ginsenoside Rg3; temozolomide (TMZ)	10, 20, 40, 80, 120, 180 μg/mL TMZ or RG3 for 24, 48, 72, 96, 120, 144 h; 10, 80, 180 μg/mL TMZ&RG3 1 : 1 for 24, 48, 72, 96, 120, 144 h (proliferation inhibition)	↓VEGF; Synergy with TMZ	Primary human umbilical vein endothelial cells (HUVECs), rat C6 glioma cell	[68]
Lamiaceae	Zataria multiflora	Thymol, carvacrol	0, 25, 50, 100, 150, 200 μg/ml for 2 h and 0, 3, 6 Gy Ionizing radiation (IR). After IR incubated for 48 h in fresh medium (MTT)	ZM treatment strengthen IR antiproliferation	A172	[69]
Boraginaceae	Lithospermum	Shikonin	2.5, 5, 7.5 μmol/L for 0, 12, 24, 36, 48, 72 h (Cell proliferation); 0, 2.5, 5, and 7.5 μmol/L for 0, 24, 48 h (scratch wound-healing assays); 2.5, 5, 7.5 μmol/L for 48 h (Western)	↑p-β-catenin Y333 (U251 only); ↓MMP-2, MMP-9, p-AKT, p-PI3K (both), p-β-catenin Y333 (U87 only); scratch wound-healing assay: higher density shikonin less regrowth	U87MG, U251	[70]
Zingiberaceae	Curcuma longa	Curcumin (diferuloylmethane); temozolomide (TMZ)	20, 50, 100 μM curcumin for 72 h; 100, 300, 500 μM TMZ for 72 h (MTT)	↑N/A; ↓N/A; Synergy with TMZ	U87MG	[89]
	Taiwanese propolis (Erhmei (in central Taiwan), Fangliao (in southern Taiwan))	Prenylflavanone (propolin G), Taiwanese propolis (TP)	0, 2.5, 5, 10 µg/mL/72 h (cell cycle analysis). 7.5 µg/mL/24 h (morphological analysis of apoptotic cells). 12.5 µg/mL/0, 4, 5, 6, 7 h (activity of caspase. Rat C6 glioma). 0, 2.5, 5, 7.5, 10 µg/mL/48 h (Western blotting assay). 2.5, 5, 10, 20, 40 µM with 1.0 mL of 0.3 mM DPPH in methanol (DPPH free radical scavenging activity)	↑sub-G1 cell population, caspase-3, caspase-8, caspase-9, cleavage form of PARP (85 kDa), p21waf1, ↓ procaspase-3, procaspase-8, procaspase-9, Bid, cyclin B1, cyclin D1, EC50 (20.5 µM)/caspase-dependent signal pathway, mitochondrial-dependent pathway, modulation of cell cycle regulators’ gene expression, ROS	rat C6 glioma, DBTRG-05MG (human)	[71]
		Curcumin	20 µmol/L/12, 24 h (cell cycle analysis). 0, 5, 10, 15, 20, 25 µmol/L/2 h (Western blot). 20 µmol/L/0, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 48 h (Western blot). 20 µmol/L/0, 15, 30, 60, 120 min (Western blot). 20 µmol/L/0, 5, 15, 30, 60 min (Western blot)	↑G1 phase, p21, Egr-1, phosphorylated ERK1/2, JNK1/2, p38, phosphorylated Elk-1, ↓S phase, G2-M phase, cyclin D1/cell cycle arrest (G1 phase), ERK and JNK MAPK/Elk-1/Egr-1 signal cascade (p53-independent transcriptional activation of p21Waf1/Cip1)	U-87MG	[47]
Ranunculaceae	Coptischinensis, Hydrastiscanadensis	Berberine	50, 75, 100, 150 µg/ml/48 h (cell cycle analysis). 0, 50, 100, 150, 200 µg/ml/24 h (Western blot, caspase-3 colorimetric protease assay)	↑G1 phase, p27, Bax, caspase-9, caspase-3, PARP, ↓G2/M phase, S phase, CDK2, CDK4, cyclin D, cyclin E, Bcl-2 family, procaspase-9/cell cycle arrest (G1 phase), apoptosis (disruption of the mitochondrial membrane potential, activation of caspase pathways)	T98G	[72]
	Hypericum polyanthemum	Three benzopyrans (6-isobutyryl-5,7-dimethoxy-2,2-dimethyl-benzopyran (1), 7-hydroxy-6-isobutyryl-5-methoxy-2,2-dimethyl benzopyran (2), 5-hydroxy-6-isobutyryl-7-methoxy-2,2-dimethyl-benzopyran (3))	10 µg/ml/96 h (cell cycle analysis)	↑% sub-G1/cell cycle arrest (G2/M phase)	U-373MG	[74]