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Table 1 Summary of current therapeutic strategies for some natural products and their chemical derivatives in GSCs. The structure, biological targets, analysis methods, clinical phase andchanism of 38 natural compounds/or derivatives are described

From: Role of glioblastoma stem cells in cancer therapeutic resistance: a perspective on antineoplastic agents from natural sources and chemical derivatives

Compound Therapeutic/structure Biological targets/mechanism of action Evaluated Clinical trials Ref.
1 Cyclopamine (11-deoxojervine)
Target Hedgehog pathway.
Promote inhibition of side and aldefluor-positive populations.
In vitro and in vivo No [114,115,116]
PubChem CID:
442972
2 Guggulsterone
Promote intrinsic apoptosis of GSCs and sensitize cells to SANT-1.
Targeting Ros/NF-κB and Hedgehog.
In vitro No [115, 117]
PubChem CID:
6450278
3 CX-4945 (Silmitasertib)
Target several GSC factors and markers
Casein kinase 2 selective inhibitor.
In vitro and in vivo Yes [118,119,120,121]
PubChem CID:
24748573
4 SCH 900776
DNA repair inhibitors
Promote radio-chemosensitivity.
Promote CHK1 inhibition.
In vitro and in vivo Yes [122,123,124,125]
PubChem CID:
46239015
5 SAR-020106
DNA repair inhibitor
Promote CHK1 inhibition
In vitro and in vivo Yes [124, 125]
PubChem CID: 44203948
6 AZD7762
DNA repair inhibitor
Promote radio-chemosensitivity.
Promote CHK1, CHK2, and ATM protein inhibition.
In vitro and in vivo Yes [120, 124]
PubChem CID:
11152667
7 Debromohymenialdisine (DBH)
DNA inhibitors
Promote radio-chemosensitivity.
Promote CHK1, CHK2, and ATM protein inhibition.
In vitro and in vivo Yes [43, 126,127,128]
PubChem CID:
135451156
8 Erlotinib
EGFR inhibitors
Promote proliferation and self-renewal inhibition.
Promote cell death.
In vitro and in vivo Yes [126,127,128,129,130,131,132]
PubChem CID:
176870
9 Gefitinib
EGFR inhibitors
Promote proliferation and self-renewal inhibition.
Promote cell death.
In vitro and in vivo Yes [126,127,128,129,130,131,132]
PubChem CID:
123631
10 Rapamycin (Sirolimus)
Promote GSC differentiation.
Reduce stem cell markers.
Promote radiosensitivity.
In vitro and in vivo Yes [36, 67, 69, 97, 130, 133,134,135]
PubChem CID:
5284616
11 Chloroquine (CQ)
Promote radiosensitivity
Inhibit autophagy process.
In vitro and in vivo Yes [124, 136, 137]
PubChem CID:
2719
12 Cilengitide
Promote αv integrin inhibition.
Promote GSCs autophagy, cytotoxicity, and cell death
Promote radiosensitivity.
In vitro and in vivo Yes [138]
PubChem CID:
176873
13 AZD2014 (Vistusertib)
Promote mTORC1/2 inhibition.
Promote radiosensitivity.
Promote DNA double-strand break repair inhibition.
In vitro and in vivo Yes [133, 139,140,141]
PubChem CID:
25262792
14 Eckol
Promote radiosensitivity and TMZ sensitivity.
Reduce neurosphere formation and stem cell markers
Target PI3-kinase-Akt and Ras-Raf-1-Erk signaling pathways.
In vitro and in vivo No [107]
PubChem CID:
145937
15 Nordy
Promote GSC differentiation.
Reduce proliferation, stem cell markers, and self-renewal
Target ALOX5
In vitro and in vivo No [108]
PubChem CID:
319062914
16 Resveratrol
Promote radiosensitivity and differentiation of GSCs.
HIF inhibitor.
Induce apoptosis of CD133+ cells.
Target STAT3 pathway
In vitro and in vivo No [106, 109]
PubChem CID:
445154
17 STX-0119
Promote inhibition of GSCs proliferation.
Reduce stem cell markers.
STAT3 inhibitor.
In vitro and in vivo Yes [142]
PubChem CID:
4253236
18 ER400583-00
HIF inhibitors
Reduce neurosphere formation and stem cell markers
Inhibit VEGF signaling
Promote microenvironment modulation.
Reduce HIF-1 expression.
In vitro and in vivo No [57, 106, 111, 143,144,145,146,147,148]
Not available on PubChem
19 WP1193
Analog of natural product caffeic acid benzyl ester
Reduce proliferation and stem cell markers
Induce apoptosis
Promote G1 arrest decrease of cyclin D1 and p21(Cip1/Waf-1) increase
Inhibit JAK2/STAT3
In vitro and in vivo No [112]
Not available on PubChem
20 All-trans-retinoic acid (Vitamin A acid)
Promote differentiation
Reduce proliferation and nestin stem cell markers
Promote apoptosis
Target ERK1/2 signaling
In vitro and in vivo No [149,150,151,152,153,154]
PubChem CID:
444795
21 Tanshinone IIA
Promote suppression of GSC proliferation.
Reduce stem cell markers.
Promotes the increase of GSCs differentiation markers.
Induce GSCs apoptosis.
Reduce the IL6/STAT3 signaling pathway.
In vitro and in vivo No [155]
PubChem CID:
164676
22 Oleanolic acid
Promote suppression of JAK-STAT3 activation in M2 polarization of tumor-associated macrophages. In vitro No [156]
PubChem CID:
10494
23 WP1066
Promote STAT3 inhibition
Decrease the surviving fraction of GSC
In vitro and in vivo Yes [157, 158]
Not available on PubChem
24 Bevacizumab
>Bevacizumab light chain
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>Bevacizumab heavy chain
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
Promote disruption of vascular niche and reduce tumor proliferation.
Promote radiosensitivity.
Reduce proliferation and block GSC ability to induce endothelial cell migration.
VEGF inhibitor
In vitro and in vivo Yes [113, 124, 132, 159,160,161,162,163]
DrugBank:
DB00112
25 Cediranib (AZD2171)
Promote disruption of the vascular niche and reduce tumor proliferation.
Promote radiosensitivity.
Reduce proliferation and block GSC ability to induce endothelial cell migration.
VEGF inhibitor
In vitro and in vivo Yes [164,165,166]
PubChem CID: 9933475
26 Honokiol
Promote PI3K/mTOR signaling inhibition.
Promote proliferation inhibition of side positive populations.
Promote TMZ-resistant cell sensitivity.
Promote DNA double-strand break repair inhibition.
In vitro and in vivo Yes [75, 95, 167,168,169]
PubChem CID:
72303
27 Manassantin B
Target hypoxia-inducible factor-1. In vitro No [111]
PubChem CID:
10439828
28 Curcumin
Induce GSCs apoptosis.
Target hypoxia-inducible factor-1.
In vitro and in vivo No [145, 148, 170]
PubChem CID:
969516
29 SU5416 (Semaxinib)
Reduce neurosphere formation and stem cell markers
Reduce HIF-1 expression
Inhibit VEGF signaling
Target PI3K/AKT/p70S6K1 signaling pathway
In vitro and in vivo No [147]
PubChem CID:
5329098
30 Cannabinoids therapies
Promote differentiation.
Inhibit gliomagenesis.
Target cannabinoid type 1 (CB1) and type 2 (CB2) receptors.
In vitro and in vivo No [157]
PubChem CID:
9852188
31 Vorinostat (SAHA)
Promote GSC differentiation.
Promote G1/S arrest of GSCs.
Inhibit histone deacetylases (HDACs).
In vitro and in vivo Yes [150, 164, 165, 171]
PubChem CID:
5311
32 Sahaquine
Promote HDAC inhibition
Reduce GSC viability
Reduce invasiveness
In vitro No [138]
Not available on PubChem
33 VX680
Pan-AURK inhibitor
Induce apoptosis
Reduce tumor growth
In vitro and in vivo No [172]
PubChem CID
5494449
34 MLN8237 (Alisertib)
Promote GSC colony formation inhibition.
Promote radiosensitivity and TMZ sensitivity.
Aurora-A kinase inhibitor.
In vitro and in vivo No [173,174,175]
PubChem CID:
24771867
35 Metformin
Promote inhibition of GSC self-renewal.
Reduce GSC viability.
Promote inhibition of CD133+ proliferation.
In vitro and in vivo No [176,177,178,179,180,181]
PubChem CID:
4091
36 Telomestatin
Polyketide component
Induce apoptosis and impair the migration potential of GSCs.
Promote telomeric and nontelomeric DNA damage in GSCs.
In vitro and in vivo No [182]
PubChem CID:
443590
37 Harmine
Alkaloid component
Promote self-renewal inhibition.
Promote GSC differentiation.
Promote neurosphere formation inhibition.
In vitro and in vivo No [183]
PubChem CID:
5280953
  1. * For chemical structures, SDF files were retrieved from PubChem [184], and 2D structures were built on MarvinSketch (MarvinSketch 19.27.0, 2019, ChemAxon (http://www.chemaxon.com)