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2019

Dietary Phytochemicals Targeting Cancer Stem Cells

https://www.mdpi.com/1420-3049/24/5/899/htm

Dietary Phytochemicals Targeting Cancer Stem Cells

Table 1. Markers of CSCs in various tissues.

Cancer TypeMarkerReferences

Brain cancer	CD34+/CD38−/CD133+/CD44+	[6,23]
Breast cancer	CD44+/CD24−/Lineage-/ALDH1+/ EpCAM+	[18,20,23]
Colon cancer	CD133+/CD44+/CD166+/ ALDH1+/LGR5+/EpCAM+	[6,18,19]
Leukemia	CD34+/CD38−/CD90−	[6,18,19]
Liver	CD133+/CD90+/EpCAM+	[6]
Lung	CD133+/CD44+/CD90+	[2,18]
Ovary	CD44+/ALDH1+/CD133+	[6,18]
Pancreas	CD44+/CD24+/CD133+/EpCAM+	[18,23]

Explanatory notes: + presence; − absence. Abbreviations used: ALDH1-Aldehyde dehydrogenase 1; CD24/34/38/44/90/133/166-Cluster of Differentiation 24/34/38/44/90/133/166; EpCAM-Epithelial Cell Adhesion Molecule.

 

able 2. Cancer stem cells signaling pathways aberrantly regulated in selected malignancies.

Signaling PathwayCancer TypeMechanism of ActionReferences

Notch	Brain cancer	↑Notch1 ↑JAG1 ↑DLL1	[6,40,44]
	T cell acute lymphoblastic leukemia	↑ Notch1
	Breast cancer	↑Notch1 ↑JAG1,
	Pancreatic cancer	↑Notch1 ↑Notch3 ↑Jag1 ↑Jag2 ↑Hes1
	Non-Small Lung Cancer	↑ Notch3
Wnt/β-catenin	Breast cancer	↑LEF-1 ↑TCF-4 ↑cyclin D1 ↑β-catenin ↓SFRP	[6,40,41,47]
	Colorectal carcinoma Brain tumor Prostate cancer	Mutations in APC/β-catenin site
	Hematologic cancer Skin cancer Lung cancer	↓ WIF-1 ↓SFRP-1 ↓ DKK ↓AXIN2
Hedgehog	Colon cancer	↑sHH ↑GLI2	[6,40]
	Medulloblastoma predisposition	Mutations in PTCH1
	Myeloma	↑SMO ↑GLI1
	Glioma	↑GLI1 ↑SHH ↑PTCH1
PI3K/Akt/mTOR	Gastric cancer	↑Akt1	[19]
	Ovarian cancer Pancreatic cancer	↑Akt2
	T cell acute lymphoblastic leukemia Melanoma Endometrial carcinoma Prostate cancer Glioblastoma	Mutations in PTEN
JAK/STAT	Breast cancer Gastric cancer Glioblastoma	↑STAT3	[53,54,40]

Explanatory notes: ↓decrease; ↑increase.

 

Figure 2. Mechanisms involved in stem-like maintenance and death resistance of CSCs.

Table 3. Anticancer mechanisms of dietary phytochemicals (isolated or mixtures) targeting CSCs.

Phytochemical(Isolated or Mixture)Cell Line/Animal ModelMechanismReferences

EGCG	A549, H1299	↓β-catenin ↓CD133 ↓CD44 ↓ALDH1A1 ↓Nanog ↓Oct4	[66]
EGCG/ EGCG and cisplatin	HNSC CSCs BALB/c nude mice	↓Oct4 ↓Sox2 ↓Nanog ↓CD44 ↓ABCC2 ↓ABCG2	[67]
Resveratrol	MCF-7, SUM159 NOD/SCID xenografted mice	→autophagy ↓Wnt/β-catenin	[69]
	GBM2, GBM7, G144, G179, G166, GliNS2, GBM04	↓β-catenin ↓c-Myc ↓Twist1 ↓Snail1	[70]
	MNNG/HOS. MG-63, hFOB1.19	↓JAK2/STAT3 ↓CD133	[71]
Pterostilbene	MCF7, MDA-MB-231	↓NF-κB ↓Twist1 ↓vimentin ↑E-cadherin	[72]
	HCC Mahlavu	↓c-Myc ↓COX-2 ↓vimentin ↓CXCR4 ↓Twist1	[43]
Genistein	MCF-7 Nude mice	↓SMO ↓GLI1	[74]
	SKOV3 Nude mice	↓CD 163 ↓p-STAT3 ↓IL-10 ↑IL-12 ↓CD133 ↓CD44	[52]
	GCSLCs	↓ Twist1 ↓N-cadherin ↑E-cadherin ↓CD133 ↓CD44 ↓ALDH1	[75]
Curcumin	BL41-3, Ramos, DG-75, THP-1	↓ALDH+ cells ↓GLI1 ↓Notch1 ↓cyclin D1	[78]
	MCF-7, MDA-MB-231 Athymic mice	↓ABCG2 ↓ABCC1	[79]
	U87, T98G U87-implanted nude mice	↓sHH ↓SMO ↓GLI1 ↓cyclin D1 ↓Bcl-2 ↓FoxM1 ↑Bax/Bcl-2 ratio	[49]
	DU-145	↓cyclin D1 ↓CDK2 ↓Bcl-2 ↑p21 ↑p27 ↑p53	[80]
Sulforaphane	NOD/SCID/IL2Rgamma mice	↓SMO ↓GLI1 ↓GLI2 ↓Nanog ↓Oct-4 ↑Bcl-2 ↓Zeb-1 ↓E-cadherin ↓VEGF ↓PDGFRα	[83]
	BalbC/nude mice	↓CR1 ↓CR3 ↓Nanog ↓ALDHH1A1 ↓Wnt3 ↓Notch4	[85]
	BEAS-2B, H460, H1299, A549	↓c-Myc	[84]
Phenethyl isothiocyanate	DLD-1 SW480	↓size/number of cell spheroids ↓CD133+	[77]
	293T, NCCIT, HCT116 Xenograft model	↓Oct4 ↓Sox-2 ↓Nanog	[86]
Diallyl trisulfide	SW48, DLD-1	↓β-catenin ↓c-Myc ↓cyclin D1	[87]
	MCF-7, SUM159	↓CD44 ↓ALDH1A1 ↓Nanog ↓Oct4	[88]
Capsosiphon fulvescens	AGS	↓Wnt-1 ↓β-catenin → G0/G1 arrest	[90]
Origanum vulgare	NMU-induced rat mammary carcinogenesis	↓CD24 ↓EpCAM	[91]
Syzygium aromaticum	NMU-induced rat mammary carcinogenesis	↓CD24 ↓CD44 ↑ALDH1	[92]
Pomegranate extract	DMBA-induced rat mammary carcinogenesis	↓ER-α:ER-β↓β-catenin ↓cyclin D1 ↓COX-2 ↑Nrf2 IκBα degradation and NF-κB translocation blockage	[93]
Trianthema portulacastrum extract	DMBA-induced rat mammary carcinogenesis	↓COX-2 ↑Nrf2 IκBα degradation and NF-κB translocation blockage	[94]
Pao Pereira extract	PANC-1, MIA PaCa-2, AsPC-1, HPAF-II, BxPC-3 in immunocompromised mice	↓Nanog ↓β-catenin	[95]
Rauwolfia vomitoria extract	PANC-1, AsPC-1, HPAF-II, BxPC-3 and MiA PaCa-2 in immunocompromised mice	↓Nanog ↓β-catenin	[96]
Chinese bayberry leaf proanthocyanidins (BLPs)	OVCAR-3	↓β-catenin ↓cyclin D1 ↓c-Myc →G1 arrest	[97]
HT-EA, SA-EA, PT-EA	Panc-1, MiaPaCa-2, Panc-3.27, and BxPC-3 Athymic NCr-nu/nu nude mice	↓Nanog ↓Oct-4 ↓Sox2 ↓N-cadherin	[98]
Water extract of Gynura divaricata (GDE)	Huh7, Hep3B	↓β-catenin	[99]
Resveratrol (RSV) and grape seed extracts (GSE)	Human colon CSCs Azoxymethane-induced mice	↓ nuclear translocation of β-catenin ↓c-Myc ↓cyclin D1 ↑p53 ↑Bax/Bcl-2	[100]

Explanatory notes: ↓ decrease; ↑ increase; → induction. Abbreviations used: ABCC1-ATP Binding Cassette Subfamily C Member 1; ABCC2-ATP Binding Cassette Subfamily C Member 2; ABCG2-ATP Binding Cassette Subfamily G Member 2; ALDH1A1-Aldehyde Dehydrogenase 1 Family Member A1; Bcl-2-B-cell Lymphoma Protein Family CD136/133/44/24, Cluster of Differentiation 136/133/44/24; CDK2-Cyclin-dependent Kinase 2; c-Myc, MYC protoonkogene; COX-2-Cyclo- oxygenase 2; CR1-CRIPTO-1/TDGF1, Teratocarcinoma-derived Growth Factor 1, CR3, CRIPTO-3/TDGF1P3, Putative Teratocarcinoma-derived Growth Factor 3; CXCR4-Chemokine Receptor Type 4; EpCAM-Epithelial Cell Adhesion Molecule; ERα-Estrogen Receptor Alfa; ERβ-Estrogen Receptor Beta; FoxM1-Forkhead Box Protein M1; GLI1/2-Zinc Finger Protein 1/2; IL-10/12-Interleukin 10/12; JAK-Janus kinase; NF-κB-Nuclear Factor Kappa-light-chain-enhancer of Activated B cells; Notch1-4-Notch receptors; NRF2-Nuclear Factor Erythroid 2–related Factor 2; p21-Cyclin-dependent Kinase Inhibitor 1; p27-Cyclin-dependent Kinase Inhibitor 1B; p53-Tumour Protein p53; PDGFRα-Platelet-derived Growth Factor Receptor Alpha; pSTAT3-Phospho-Signal Transducer and Activator of Transcription 3; sHH- Sonic Hedgehog; SMO- Transmembrane protein SMOOTHENED; Snail1-Zinc Finger Protein; STAT-Signal Transducer and Activator of Transcription; Twist1-Twist family BHLH Transcription Factor 1/gene; VEGF-Vascular Endothelial Growth Factor; Zeb-1-Zinc finger E-box-binding Homeobox 1.