Application of G-quadruplex targets in gastrointestinal cancers: Advancements, challenges and prospects

Table 2 Overviews of investigations on the effects of small molecule ligands or biomolecules based on G-quadruplex targets in pancreatic cancer

Ligands/biomolecules	Cell lines	Targeting gene/G-quadruplex	Effects on G-quadruplex	Effects on genes	Anticancer phenotypes	Ref.
Tetrasubstituted naphthalene diimide ligands	PANC-1, MIA PaCa-2, HPAC, BxPc-3	Telomere	Induced formation of a parallel G-quadruplex	Inhibited the binding of hPOT1 and topoisomerase IIIα to telomeric DNA	Cytotoxicity	[129]
Tetrasubstituted naphthalene diimide derivatives (compounds 3d)	MIA PaCa-2	Telomere	Retained high affinity to human telomeric G-quadruplex	Upregulated some DNA damage responsive genes, downregulated some telomere maintenance genes	Induced cellular senescence but did not inhibit telomerase activity	[130]
Naphthalene diimide isomer ligands (compounds 2-5)	MIA PaCa-2, PANC-1	HSP90	Stabilized G-quadruplex structure	Not detected	Inhibited cell proliferation	[131]
Tetrasubstituted naphthalene diimide derivative (MM41)	MIA PaCa-2	BCL-2, K-RAS	Bound and stabilized G-quadruplex structure	Downregulated expression of BCL-2, K-RAS	Promoted cell apoptosis, decreased tumor growth of MIA-Pa-Ca2 xenografts	[132]
Tetrasubstituted naphthalene diimide derivative (CM03)	MIA PaCa-2, PANC-1	Not detected	Increased presence of nuclear G-quadruplex	Induces DNA damage, downregulated expression of Gli4, PLXNA1, PRKCZ, MAPK11, PARD6A, CBFA2T3	Decreased tumor growth of MIA-Pa-Ca2 xenografts	[133-135]
Tetrasubstituted naphthalene diimide derivative (SOP1812)	MIA PaCa-2, PANC-1, Capan-1, BXPC-3	hTERT, telomere	Had affinity with G-quadruplex	Downregulated expression of WNT5B, DVL1, AXIN1, APC2, GLI1, MAPK11, BCL-2, hTERT	Inhibited cell proliferation, reduced MIA PaCa-2 xenograft growth	[135]
Tetrasubstituted naphthalene diimide derivative (BMSG-SH3)	MIA PaCa-2	HSP90	Stabilized G-quadruplex structure	Not detected	Reduced telomerase activity and HSP90 expression, 50% decreased tumor growth of MIA-Pa-Ca2 xenografts	[136]
Cationic alkyl-substituted porphyrin compound C14	PANC-1	KRAS	Bound with G-quadruplex and protoxidized the guanines	Downregulated expression of KRAS	Induced cell growth arrest	[137]
Alkyl cationic porphyrins	MIA PaCa-2, PANC-1	KRAS mRNA, NRAS mRNA	Bound G-quadruplex	Downregulated expression of KRAS, NRAS only if photoactivated	Activated apoptosis, reduced the metabolic activity of pancreatic cancer cells and the growth of a PANC-1 xenograft	[138]
Porphyrin derivative (Octaacetyl)	PANC-1, MIA PaCa-2	KRAS	Bound and stabilized G-quadruplex	Downregulated expression of KRAS	Cytotoxicity, induced apoptosis, blocked metastasis by inhibiting epithelial to mesenchymal transition	[139]
Porphyrin derivative (Tetrakis)	PANC-1, MIA PaCa-2	KRAS	Bound and stabilized G-quadruplex	Downregulated expression of KRAS	Cytotoxicity, induced apoptosis, blocked metastasis by inhibiting epithelial to messenchymal transition	[139]
Porphyrin derivative (5Me)	PANC-1	Telomere, Bcl-2, c-MYC, KRAS	Bound and stabilized G-quadruplex	Not detected	Inhibited cell proliferation, arrest G2/M phase cell cycle	[140]
TMPyP4	MIA PaCa-2	Intermolecular G-quadruplex	Not detected	Shortened telomeres	Cytotoxicity, arrested cell proliferation, induced anaphase bridges, cellular senescence and apoptosis	[141]
Telomestatin	MIA PaCa-2	Intramolecular G-quadruplex	Not detected	Shortened telomeres	Cytotoxicity, arrested cell proliferation, and induced cellular senescence and apoptosis	[141]
Nitidine	AsPC-1, BxPC-3, MIA PaCa-2, PANC-1	KRAS	Bound and stabilized G-quadruplex structure	Downregulated expression of KRAS	Cytotoxicity	[142]
4,11-bis(2-Aminoethy- llamino)anthra[2,3-b]furan-5,10-dione(2a),11-bis(2-aminoethylamino) anthra[2,3b]thiophene-5,10-dione (2b)	PANC-1	KRAS mRNA	Bound and stabilized G-quadruplex	Inhibited translation of KRAS	Induced apoptosis, inhibited cell growth and colony formation	[143]
Unsymmetrical bisacridines derivatives	PANC-1, MIA PaCa-2, BXpC-3, AsPC-1, Capan-2	Telomere, c-MYC, KRAS	Bound and stabilized G-quadruplex	Not detected	Inhibited cell proliferation, reduced PANC-1 and MIA PaCa-2 xenograft growth in vivo	[144]
Copper(ii) l/d-valine-(1,10-phen) complexes (complex 1a, 1b)	BxPC3, AsPC1	Telomere	Had affinity with G-quadruplex	Not detected	Cytotoxicity	[145]
CX-5461 (Pidnarulex)	MIA PaCa-2, PANC-1	Telomere, c-MYC, c-kit	Bound with G-quadruplex	Not detected	Inhibited cell proliferation	[146,147]
CX-3543 (Quarfloxin)	MIA PaCa-2	Nucleolin/ribosomal DNA G-quadruplex complexes	Disrupts nucleolin/G-quadruplex complexes on ribosomal DNA	Inhibited rRNA synthesis	Inhibited proliferation, inhibited Pol I transcription, induced apoptosis, decreased tumor growth of MIA PaCa-2 xenografts	[148,149]
Antihelminthic pyrvinium pamoate	PANC-1, Capan-1, HS766T, CFPAC, MIA PaCa-2	Mitochondrial DNA	Bound G-quadruplex	Inhibited transcription of mitochondrial RNA	Inhibited cell viability, mitochondrial pathways, tumor growth of MIA PaCa-2 xenografts	[150]
NSC 317605 and novel indoloquinolines	AsPc1, PANC1, BxPc3, MIA PaCa-2	c-MYC, KRAS	Bound and stabilized G-quadruplex	Downregulated expression of KRAS	Cytotoxicity	[151]
Quinazoline-pyrimidine derivatives	Tumor-naïve pancreatic stellate cells	Telomere, c-MYC, c-kit, KRAS, BCL-2	Bound and stabilized G-quadruplex	Not detected	Inhibited tumor growth	[152]
hnRNPA1 and integrinlinked kinase	AsPC-1, PANC-1, MIA PaCa-2, Capan-2	KRAS	Destabilized G-quadruplex	Stimulated transcription of KRAS	Promoted KRAS-E2F1-ILK-hnRNPA1 circuitry, tumor growth and aggressive phenotypes	[153-155]
Poly [ADP-ribose] polymerase 1	PANC-1	KRAS	Destabilized G-quadruplex	Stimulated transcription of KRAS	Activated a ROS-G-quadruplex-PARP-1 axis	[156]
Apurinic/apyrimidinic endonuclease 1	PANC-1, BxPc3, MIA PaCa-2	KRAS	Bound and stabilized G-quadruplex	Upregulated expression of KRAS	Did not sensitize pancreatic cancer cells to chemotherapeutic drugs in vitro and in vivo	[157]
Polypurine reverse Hoogsteen hairpins	AsPc-1, MIA PaCa-2	KRAS, c-MYC	Bound and stabilized G-quadruplex	Inhibited transcription of KRAS and c-MYC	Inhibited cell proliferation	[158,159]

hPOT1: Human protection of telomeres 1; ILK: Integrinlinked kinase; BCL-2: B-cell lymphoma 2; KRAS: Kirsten rat sarcoma viral oncogene homologue; HSP90: Heat shock protein 90; hTERT: Human telomerase reverse transcriptase; NRAS: Neuroblastoma RAS viral oncogene homolog; ROS: Reactive oxygen species.