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

Table 1 Overviews of investigations on the effects of small molecule ligands or biomolecules based on G-quadruplex targets in esophageal cancer

Ligands/biomolecules	Cell lines	Targeting gene/G-quadruplex	Effects on G-quadruplex	Effects on genes	Anticancer phenotypes	Ref.
2,6-bis[3-(N-Piperidino) propionamido] anthrace- ne-9,10-dione	BIC-1, SEG-1	Telomere	Not detected	Shortened telomeres	Inhibited telomerase activity, arrested cell proliferation, reduced colony number and size, and promoted cell apoptosis	[127]
Zinc benzoate erpyridine complexes (1-6)	Eca-109	G2T4G2CA, G2GT4G2T	Bound with G-quadruplex	Not detected	Inhibited cell proliferation	[128]

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.

Table 3 Overviews of investigations on the effects of small molecule ligands or biomolecules based on G-quadruplex targets in hepatocellular carcinoma

Ligands/biomolecules	Cell lines	Targeting gene/G-quadruplex	Effects on G-quadruplex	Effects on genes	Anticancer phenotypes	Ref.
Platinum(II) complexes with tridentate ligands	HepG2	c-MYC	Bound and stabilized G-quadruplex	Inhibited c-MYC expression	Cytotoxicity	[160]
Prolinamide derivatives containing triazole	HepG2	c-MYC	Bound and stabilized G-quadruplex	Inhibited c-MYC expression	Cytotoxicity	[161]
A series of novel 9-O-substituted-13-octylberberine derivatives	HepG2, Sk-Hep-1, Huh-7	c-MYC	Bound and stabilized G-quadruplex	Not detected	Cytotoxicity, blocked cell cycle, induced apoptosis, inhibited tumor growth of H22 xenografts	[162]
Series of novel 9-N-substituted-13-alkylberberine derivatives	HepG2, Sk-Hep-1, Huh-7, Hep3	c-MYC	Bound and stabilized G-quadruplex	Not detected	Cytotoxicity, blocked cell cycle, induced apoptosis, inhibited tumor growth of H22 xenografts	[163]
Thiazole orange derivatives	HepG2	Telomere	Bound and stabilized G-quadruplex	Not detected	Cytotoxicity	[164]
Peptidomimetic ligands	HepG2	c-kit1	Had high affinity with G-quadruplex	Not detected	Inhibited cell proliferation, induced apoptosis	[165]
A 7, 11-disubstituted quinazoline derivative HZ-6d	HepG2, SMMC-7721	HERC5	Bound and stabilized G-quadruplex	Inhibited HERC5 expression	Inhibited cell growth, migration, induced apoptosis, suppressed tumor growth of SMMC-7721 xenografts	[166]
DDX5	HepG2, Huh7, Snu387, Snu423, HepaRG, HepAD38	STAT1 mRNA	Unwound G-quadruplex	Promoted translation of STAT1	Upregulated expression of STAT1 and enhanced IFN-α mediated antiviral effects	[167]
Nucleolin	Huh7.5.1, Huh7.5	Viral core RNA, G-quadruplex	Directly interacted with G-quadruplex	Inhibited viral RNA replication	Suppressed wild-type viral replication and expression	[168]

IFN: Interferon.

Table 4 Overviews of investigations on the effects of small molecule ligands or biomolecules based on G-quadruplex targets in gastric cancer

Ligands/biomolecules	Cell lines	Targeting gene/G-quadruplex	Effects on G-quadruplex	Effects on genes	Anticancer phenotypes	Ref.
Benzo[a]phenoxazines	HGC-27	c-kit	Bound with G-quadruplex	Inhibited c-MYC transcription	Cytotoxicity	[169]
Quinazolone derivatives	HGC-27	c-kit	Stabilized G-quadruplex	Inhibited c-kit transcription	Cytotoxicity	[170]
3-(4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-3-(ptolyl)-1Hpyrazol-1-yl)-N,N-dimethylpropan-1-amine (13d)	AGS	Telomere, c-kit, BCL-2	Stabilized G-quadruplex	Induced telomere dysfunction, DNA damage response	Inhibited cell proliferation, migration, and invasion, promoted cell apoptosis and autophagy by blocking the Akt/mTOR pathway	[171]
G-quadruplex antibody	AGS	G-quadruplex	Not detected	Inhibited transcription of hTERT and BCL-2	Inhibited cell proliferation, migration, invasion and expression of hTERT and BCL-2, induced apoptosis, blocked cell cycle	[172]

BCL-2: B-cell lymphoma 2; hTERT: Human telomerase reverse transcriptase; mTOR: Mammalian/mechanistic target of rapamycin.

Table 5 Overviews of investigations on the effects of small molecule ligands or biomolecules based on G-quadruplex targets in colorectal cancer

Ligands/biomolecules	Cell lines	Targeting gene/G-quadruplex	Effects on G-quadruplex	Effects on genes	Anticancer phenotypes	Ref.
BRACO-19	HCT116, Flavopiridol-resistant HCT116	Telomere	Stabilized G-quadruplex	Not detected	Rapid inhibition of cell growth	[173]
RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate) and RHPS4-derivatives	HT29, HCT116	Telomere	Bound with G-quadruplex	Induced DNA damage	Stabilized TOPO1, cytotoxicity, inhibited cell proliferation, had synergistic anticancer effects with TOPO1 inhibitors	[174-177]
A series of anthracene derivatives substituted with one or two 4,5-dihydro-1H-imidazol-2-yl-hydrazonic groups	LoVo	Telomere	Induced G-quadruplex structures, bound and stabilized G-quadruplex	Induced DNA damage	Cytotoxicity, telomerase inhibition	[178]
EMICORON	HT29, HCT116, A90 colon epithelial tumor cell line	Telomere	Bound with G-quadruplex	Increased telomere damage	Cytotoxicity, inhibited cell proliferation and tumor growth of patient-derived tumor xenograft	[179,180]
Chromene derivatives	HT29	Telomere RNA	Bound with G-quadruplex	Not detected	Cytotoxicity	[181]
TMPyP4	SW480, SW620	c-MYC	Stabilized the mutated G-quadruplex structure	Inhibited c-MYC expression	Silenced c-MYC expression	[182]
CX-3543 (quarfloxin)	HT29	c-MYC	Not detected	Inhibited c-MYC expression	Reduced CCAT1 expression, promoted cell apoptosis, inhibited cell proliferation and tumor growth of HT29 xenografts	[183]
CX-5461 (pidnarulex)	HT-29, DLD-1, CT26	Telomere, c-MYC, c-kit	Bound with G-quadruplex	Caused DNA damage	Inhibited tumor growth of CT26 xenografts	[184]
Dihydrochelerythrine and its derivatives	HCT116	c-MYC, c-kit	Stabilized G-quadruplex	Not detected	Inhibited cell proliferation	[185]
Unsymmetrical bisacridines derivatives	HCT116	c-MYC, KRAS	Bound and stabilized G-quadruplex	Not detected	Induced cytotoxicity, apoptosis and senescence	[144,186]
7-carboxylate indolo[3,2-b] quinoline tri-alkylamine derivatives	HCT116, SW620	KRAS, HSP90A	Stabilized G-quadruplex	Decreased KRAS and HSP90 mRNA expression, and KRAS transcription	Inhibited cell proliferation and protein expression of KRAS and HSP90A, promoted apoptosis	[187]
3-[2-(Diethylamino)ethyl]-12-methyl-6-oxo-2,3,6,12-tetrahydro-1H-benzo[4,5]imidazo[1,2- a]imidazo[1’,2’:1,6]pyrido[2,3-d]pyrimidin-14-ium bromide	HCT116	KRAS	Bound and stabilized G-quadruplex	Decreased KRAS mRNA expression	Inhibited cell proliferation	[188]
Naphthalene diimides compound T5	Colorectal cancer cell	rDNA	Had high affinity with G-quadruplex	Impaired RNA Pol I elongation, inhibited Pol I transcription	Inhibited cell growth by inducing a rapid inhibition of Pol I transcription, nucleolus disruption, proteasome-dependent Pol I catalytic subunit A degradation and autophagy	[189]
Thiosugar naphthalene diimide conjugates	HT29	Telomere, c-MYC, KRAS	Bound and stabilized G-quadruplex	Not detected	Cytotoxicity	[190]
Gallic acid	SW480 SW620	rDNA, c-MYC	Bound and stabilized G-quadruplex	Inhibited expression of rDNA and c-MYC	Cytotoxicity, inhibited tumor growth of SW480 xenografts	[191]
HnRNPA1	HCT116	TRA2B promoter	Destabilized G-quadruplex	Stimulated TRA2B transcription	Promoted cell proliferation and expression of TRA2B	[192]
SNRPA	HCT116	BAG-1 mRNA	Bound with G-quadruplex	Inhibited translation of BAG-1	Inhibited cell proliferation	[193,194]
PPRHs	SW480	c-MYC	Bound and stabilized G-quadruplex	Inhibited transcription of c-MYC	Inhibited cell proliferation	[159]

PPRHs: Polypurine reverse Hoogsteen hairpins; TOPO: Topoisomerase; KRAS: Kirsten rat sarcoma viral oncogene homologue; HSP90: Heat shock protein 90.

Table 6 Overview of investigations on the effects of small molecule ligands based on G-quadruplex targets in gastrointestinal stromal tumor

Ligands/biomolecules	Cell lines	Targeting gene/G-quadruplex	Effects on G-quadruplex	Effects on genes	Anticancer phenotypes	Ref.
6-Substituted indenoisoquinolines	GIST882	c-kit	Stabilized G-quadruplex	Inhibited c-kit transcription	Cytotoxicity, inhibited expression of c-kit protein	[196]
N,N’-Bis(2-(pyrrolidin-1-yl)ethylamino)-2,6-bis(2-(pyrrolidin-1-yl)ethylamino)-1,4,5,8-naphthalenetetracarboxylic acid diimide	GIST882, GIST48, GIST62	c-kit, BCL-2, BCL-2 mRNA	Stabilized G-quadruplex	Not detected	Cytotoxicity, inhibited expression of c-kit and BCL-2 proteins	[197,198]

BCL-2: B-cell lymphoma 2.

Table 7 G-quadruplexes as anticancer agents

Tumor model	G-quadruplex name	Sequence (5’-3’)	Protein target	Cells	Anticancer phenotype	Ref.
Pancreatic cancer	T-22AG	GGAGGGGGAGAAGGGAGAAGGG	Nuclear protein	Panc-1	Reduces cell growth	[199]
	AS1411	GGTGGTGGTGGTTGTGGTGGTGGTGG	Nucleolin	PANC-1	Inhibited cell proliferation	[200]
Gastric cancer	AS1411	GGTGGTGGTGGTTGTGGTGGTGGTGG	Nucleolin	KATOIIIe, HGC27	Inhibited cell proliferation	[200]
Colorectal cancer	AS1411	GGTGGTGGTGGTTGTGGTGGTGGTGG	Nucleolin	HCC 2998, HT-29, KM12, HCT-116, SW620, HCT-15, LS174T	Inhibited cell proliferation	[200]
	TBA	GGTTGGTGTGGTTGG	uL3	HCT 116p53-/-	Impaired ribosomal RNA processing, leading to the accumulation of pre-ribosomal RNAs, arrested cells in the G2/M phase and induced early apoptosis	[201]
	L-TBA	GGTTGGTGTGGTTGG
	LQ1	GGTTGGTGTGGTTGG
	LQ2	GGTTGGGTGTGGTTGG
	LQ3	GGTTGGGTGTGGTTGG
	INT-B (T30175)	GTGGTGGGTGGGTGGGT	Not detected	HCT 116p53-/-	Inhibited cell proliferation	[202]
	INT-BS2	GSGGTGGGTGGGTGGGT
	INT-BS5	GTGGSGGGTGGGTGGGT
	INT-BS9	GTGGTGGGSGGGTGGGT
	INT-BS13	GTGGTGGGTGGGSGGGT
	INT-BS17	GTGGTGGGTGGGTGGGS
	TT-INT-B	TTGTGGTGGGTGGGTGGGT
	Qnat	GGGTGGGTGGGTGGGT	Not detected	HCT 116p53-/-	Inhibited cell proliferation	[203]
	QS4	GGGSGGGTGGGTGGGT
	QS8	GGGTGGGSGGGTGGGT
	QS12	GGGTGGGTGGGSGGGT
	QS16	GGGTGGGTGGGTGGGS