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2021

Phytomedicines Targeting Cancer Stem Cells:

Therapeutic Opportunities and Prospects for Pharmaceutical Development.

https://europepmc.org/article/med/34358102

Phytomedicines Targeting Cancer Stem Cells: Therapeutic Opportunities and Prospects for Pharmaceutical Development. - Abstract -

CSCs and their overexpressed biomarkers.

 

 

 

Curcumin/Cinnamic acid와 같은 CSC에서 항암제 내성의 주요 조절자를 표적으로 하는 식물의약 화합물:

 

 Curcumin/Cinnamic acid: Wnt;

Glabridin: SMAD2;

Curcumin/Ovatodiolide/Lusianthridin: JAK/STAT;

Ovatodiolide/Carnosol/N-butylidenephthalide: EMT;

N-butylidenephthalide/Atractylenolide I: PI3K/Akt;

Morusin: NF-κB;

Berberine: Ras/RAF.

Table 2

Phytomedicinal compounds targeting the key regulators of anti-cancer drug resistance in CSCs.

Plant SourceExtractBioactive CompoundMode of ActionIn Vivo DoseCells/ModelReferences

Alstonia scholaris	Fruit extract	Scholarisine Q(1) and R(2)	Induction of apoptosis	------	Glioma stem cells	[40]
Anisomeles indica	------	Ovatodiolide	Induction of apoptosis Modulation of EMT process Downregulation of CD44, CD133, Sox2, and Oct4 Dysregulation of JAK2/STAT3 pathway	------	Glioblastoma stem-like cells	[26]
			Induction of apoptosis Downregulation of Sox2 and Oct4 Increase of E-cadherin Dysregulation of JAK2/STAT3 pathway	------	CSC population in nasopharyngeal carcinoma	[23]
			Induction of apoptosis Downregulation of CD133, Klf4, Oct4, Nanog, and JARID1B Dysregulation of JAK2/STAT3 pathway	3.6 mg/kg	Oral CSCs and xenograft tumor mice	[24]
Cruciferous vegetables	------	Phenethyl isothiocyanate	Downregulation of Oct4, Nanog, and Sox2	20 mg/kg	Colon CSCs and xenograft tumor mice	[41]
			Promotion of oxidative stress Suppression of Sp1 transcription factor	10 µM	Cervical CSCs and Xenograft NOD-SCID tumor mice	[42]
Atractylodes macrocephala Koidz	Rhizome extract	Atractylenolide I	Downregulation of the phosphorylation of proteins related to the AKT/mTOR pathway Alteration of apoptosis, glucose metabolism, and stem-like behavior	25 mg/kg and 75 mg/kg	Stemness of colon cancer cells and xenograft tumor mice	[43]
Fructus viticis	------	Flavonoids	Decrease the phosphorylation level of Akt Downregulation of CD133, CD44, and ALDH1, Bmi1, Nanog, and Oct4, Twist1, and Snail1	------	Lung CSCs	[44]
Pigeon pea	------	Cajaninstilbene acid derivatives	Cytotoxic (pathway not deduced)	------	Breast cancer stem-like cells	[45]
Berberis libanotica Ehrenb	Root extract	------	G0–G1 arrest Inhibition of cellular migration and sphere formation	------	Prostate CSCs	[46]
Berberis, Arcangelisia Hydrastis	------	Berberine	G0/G1 cell cycle arrest Cancer stemness inhibition (attenuation of CD133, β-catenin, n-myc, Sox2, Notch2, and nestin) EMT reversal by downregulation of PI3/Akt and Ras-Raf-ERK signaling.	------	Stemness in neuroblastoma cells	[32]
Dendrobium venustum	Stem extract	Lusianthridin	Downregulation of Src-STAT3-c-Myc pathways Pro-survival suppression and pro-apoptotic induction Abolishment of stemness (decrease in CD133, ABCG2, and ALDH1A1)	------	Lung CSCs	[22]
Curcuma longa	------	Curcumin	Downregulation of expression of Vimentin, Fibronectin, β-catenin, and upregulation of E-cadherin Decreased expression of Sox2, Nanog, and Oct4	------	Breast CSCs	[47]
	------	Curcumin	Reduction in the expression of ABC transporters ABCG2 and ABCC1	------	Breast CSCs	[48]
	------	Curcumin	Induction of apoptosis Dysregulation of JAK/STAT3 signaling pathway	------	Papillary thyroid CSCs	[49]
	------	Curcumin	Induction of apoptosis	5 mg/kg	Glioblastoma stem cells and xenograft tumor mice	[50]
Walsura pinnata Hassk	Bark extract	Betulonic acid	Induction of intrinsic apoptosis	18, 36, or 54 μM	Leukemia stem cells and xenotransplanted zebrafish	[16]
Costus speciosus	Rhizome extract	------	Induction of apoptosis G0/G1 and G2/M arrest	------	Stemness of prostate cancer cells	[51]
Viola odorata	Hydro-alcoholic extract of aerial part	------	Induction of apoptosis	------	Breast CSCs	[52]
Polygonum cuspidatum	Root extract	2-Ethoxystypandrone	Induction of apoptosis Inhibition of STAT3 signaling	------	Hepatocellular CSCs	[53]
Cinnamomum cassia	------	Cinnamic acid	Downregulation of CSC-associated markers (OCT4, NANOG, ABCB1, and ALDH1A) and the proportion of CSCs (SP cells, CD44- and CD133-positive cells)	------	Colon CSCs	[19]
Glycyrrhiza glabra	------	Glabridin	Epigenetic regulation of miR-148a/SMAD2 signaling	20 mg/kg	Breast cancer stem-like cells and xenograft tumor mice	[54]
Morus australis	------	Morusin	Induction of apoptosis Attenuation of NF-κB activity	------	Cervical CSCs	[55]
Lithospermum erythrorhizon	------	Shikonin	Involvement of JNK/c-Jun pathway	2 mg/kg	Glioblastoma stem cells and xenograft tumor mice	[56]
Rosmarinus officinalis	------	Carnosol	Induction of apoptosis via p53 functional reactivation Modulation of EMT	------	Glioblastoma CSCs	[57]
PienTze Huang	------	------	Inhibition of ABCB1 and ABCG2	------	Colorectal CSCs	[58]
Allium sativum	------	Allicin (diallyl thiosulfinate)	Increased expression of cyclin D1	------	Melanoma stem-like cells	[25]

------ = NA.

Phytomedicinal compounds targeting Wnt, Sonic Hedgehog, and Notch signaling pathways in CSCs.

 

Abrus agglutinin, Sanguinarine, Diallyl-trisulfide, Koenimbin, Evodiamine, Gomisin M2, Chelerythrine chloride, Sulforaphane, and Ginsenoside-Rb1 inhibit the Wnt/β-catenin signaling pathway.

 

Baicalein, Curcumin, Withaferin A, and Honokiol inhibit the Sonic Hedgehog signaling pathway, and

 

Psoralidin inhibits the Notch signaling pathway.

 

Table 3

Phytomedicinal compounds targeting Wnt/β-catenin, Notch, and Sonic Hedgehog signaling pathways in CSCs.

Plant SourceExtractBioactive CompoundMode of ActionIn Vivo DoseCell Line/ModelReferences

Abrus precatorius	Seed extract	Abrus agglutinin	p73 suppressed Snail expression, leading to EMT inhibition Induction of intrinsic and extrinsic apoptosis Inactivation of Wnt/β-catenin signaling pathway	50 μg/kg	Oral squamous carcinoma stem-like cells and xenograft tumor mice	[63]
Celandine (TCM)	------	Sanguinarine	Downregulation of Wnt/β-catenin signaling pathway	0.5 mg/20 g	Lung CSCs and xenograft tumor mice	[67]
Gynura divaricata	Aqueous extract of aerial part	------	Downregulation of Wnt/β-catenin signaling pathway	300 mg/kg	Hepatocellular CSCs and xenograft tumor mice	[20]
Panax quinquefolius	------	Ginsenoside-Rb1	Inhibition of Wnt/β-catenin signaling Inhibition of EMT	50 mg/kg	Ovarian CSCs and xenograft tumor mice	[62]
Allium sativum	------	Diallyl-trisulfide	Induction of apoptosis Modulation of Wnt/β-catenin signaling pathway	------	Colorectal CSCs	[61]
Murraya koenigii (L) Spreng	Leaf extract	Koenimbin	Induction of apoptosis by intrinsic pathway Downregulation of Wnt/β-catenin self-renewal pathway	------	Breast CSCs	[21]
			Induction of apoptosis via intrinsic pathway G0/G1 phase arrest	------	Prostate CSCs	[80]
Chelidonium majus/Macleaya cordata	------	Chelerythrine chloride	Downregulation of β-catenin	------	Non-small cell lung carcinoma stem-like cells	[66]
Evodiae rutaecarpa	------	Evodiamine	Inhibition of Wnt Signaling	------	Gastric CSCs	[70]
Evodiae fructus	------	Evodiamine	Induction of apoptosis Suppression of Notch and Wnt Signaling	------	Colon CSCs	[69]
Baizuan (TCM)	------	Gomisin M2	Downregulation of Wnt/β-catenin signaling pathway Induction of apoptosis	10 μM	Breast CSCs and zebrafish xenograft	[68]
Cruciferous vegetables	------	Sulforaphane	Downregulation of DNA methyltransferase1 Restoring the expression of Wnt inhibitory factor 1	60 mg/kg	Nasopharyngeal CSCs and xenograft tumor mice	[64]
			Suppression of miR-19 and Wnt/β-catenin pathway	------	Lung CSCs	[65]
			Modulation of Sonic hedgehog–Gli pathway Inhibition of pluripotency markers, angiogenesis markers, and EMT markers	------	Pancreatic CSCs	[18]
Curcuma longa	------	Curcumin	Suppression of Sonic Hedgehog pathway Induction of apoptosis Decreased expression of CSC markers	------	Bladder CSCs	[50]
Withania somnifera	Leaf extract	Withaferin A	Hh signal inhibition	------	Pancreatic, prostate, and breast CSCs	[75]
BRM270	Alcohol extract	------	Suppression of Sonic Hedgehog pathway Induction of apoptosis	5 mg/kg	Pancreatic ductal adenocarcinoma stem cells and xenograft tumor mice	[77]
Qingyihuaji (TCM)	------	Baicalein	Modulation of Sonic Hedgehog pathway	20 or 60 mg/kg	Pancreatic CSCs and xenograft tumor mice	[78]
Qingyihuaji (TCM)	Aqueous extract	------	Downregulation of Notch-4 and Jagged-1 in Notch signaling pathway	36 g/kg	Pancreatic cancer stem-like cells and xenograft tumor mice	[71]
Xiaotansanjie (TCM)	------	------	Inhibition of Notch-1	1.46, 2.92, and 5.84 g/mL	Gastric CSCs and xenograft tumor mice	[72]
Psoralea corylifolia	------	Psoralidin	Inhibition of Notch-1 signaling Inhibition of EMT	------	Breast CSCs	[74]
PienTze Huang (TCM)	------	------	Induction of apoptosis Suppression of Notch-1 signaling pathway	------	Colorectal CSCs	[73]
MSC500	------	------	Suppression of ALDH, ABCB5, Oct4, Sox2, β-catenin, Gli-1, and Notch-1	------	Glioblastoma stem cells	[79]

------ = NA.

Table 4

Clinical status of phytomedicinal compounds targeting CSCs.

Clinical Trial No.Sponsors and CollaboratorsTitle of the StudyClinical StatusYear of Study(Start Date–Completion Date)

Cruciferous Vegetable/Sulforaphane
NCT00982319	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Study to Evaluate the Effect of Sulforaphane in Broccoli Sprout Extract on Breast Tissue	Phase 2	2009–2013
NCT03665922	University of Pittsburgh	Biomarkers of Sulforaphane/Broccoli Sprout Extract in Prostate Cancer	Recruiting (Phase not applicable)	2019–2024
2. Curcumin
NCT01740323	Andrew H Miller and National Cancer Institute	Phase II Study of Curcumin vs. Placebo for Chemotherapy-Treated Breast Cancer Patients Undergoing Radiotherapy	Phase 2	2015–2018
NCT03980509	Medical University of South Carolina	A “Window Trial” on Curcumin for Invasive Breast Cancer Primary Tumors	Phase 1	2020–2021
NCT03072992	National Center of Oncology, Armenia, and BRIU GmbH	“Curcumin” in Combination with Chemotherapy in Advanced Breast Cancer	Phase 2	2017–2019
3. Cruciferous Vegetable/Phenethyl isothiocyanate (PEITC)
NCT01790204	Georgetown University	A Study of the Effects of PEITC on Oral Cells with Mutant p53	Phase 2	2012–2014
NCT00691132	University of Minnesota and National Cancer Institute	Phenethyl Isothiocyanate in Preventing Lung Cancer in Smokers	Phase 2	2009–2013
4. Garlic
NCT00079170	National Cancer Institute	Docetaxel Plus Garlic in Treating Patients with Locally Advanced or Metastatic Breast Cancer	Pilot study (Phase not applicable)	2004–2007
5. Berberine
NCT02226185	Shanghai Jiao Tong University School of Medicine	Study of Berberine Hydrochloride in Prevention of Colorectal Adenomas Recurrence	Phase 3	2014–2018
6. Licorice
NCT00176631	Rutgers, The State University of New Jersey, and National Cancer Institute	Licorice Root Extract and Docetaxel in Treating Patients with Metastatic Prostate Cancer That Did Not Respond to Hormone Therapy	Phase 2	2007–2008
7. N-butylidenephthalide
NCT03234595	Everfront Biotech Co., Ltd.	A Phase I/IIa Study of Cerebraca Wafer Plus Adjuvant Temozolomide (TMZ) in Patients with Recurrent High-Grade Glioma	Phase 2	2017–2021
8. Ginsenoside
NCT02714608	Tasly Pharmaceuticals, Inc.	A Study of Ginsenoside H Dripping Pills for Advanced Non-Small Cell Lung Cancer (NSCLC)	Phase 2	2016–2018
9. Ashwagandha
NCT00689195	Tata Memorial Hospital and Pharmanza Herbals Pvt Limited (PHPL)	Pilot Study of Curcumin Formulation and Ashwagandha Extract in Advanced Osteosarcoma (OSCAT)	Phase 2	2008–2013

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