Targeting STAT-3 signaling pathway in cancer for development of novel drugs: Advancements and challenges

Arshad, Sundas; Naveed, Muhammad; Ullia, Mahad; Javed, Khadija; Butt, Ayesha; Khawar, Masooma; Amjad, Fazeeha

doi:10.1590/1678-4685-GMB-2018-0160

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Human and Medical Genetics • Genet. Mol. Biol. 43 (1) • 2020 • https://doi.org/10.1590/1678-4685-GMB-2018-0160 copy

Targeting STAT-3 signaling pathway in cancer for development of novel drugs: Advancements and challenges

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Signal transducers and activators of transcription 3 (STAT-3) is a transcription factor that regulates the gene expression of several target genes. These factors are activated by the binding of cytokines and growth factors with STAT-3 specific receptors on cell membrane. Few years ago, STAT-3 was considered an acute phase response element having several cellular functions such as inflammation, cell survival, invasion, metastasis and proliferation, genetic alteration, and angiogenesis. STAT-3 is activated by several types of inflammatory cytokines, carcinogens, viruses, growth factors, and oncogenes. Thus, the STAT3 pathway is a potential target for cancer therapeutics. Abnormal STAT-3 activity in tumor development and cellular transformation can be targeted by several genomic and pharmacological methodologies. An extensive review of the literature has been conducted to emphasize the role of STAT-3 as a unique cancer drug target. This review article discusses in detail the wide range of STAT-3 inhibitors that show antitumor effects both in vitro and in vivo. Thus, targeting constitutive STAT-3 signaling is a remarkable therapeutic methodology for tumor progression. Finally, current limitations, trials and future perspectives of STAT-3 inhibitors are also critically discussed.

Keywords:
STAT-3; DNA binding domain; apoptosis; drug discovery STAT-3 inhibitors

Activators				Inhibitors
Cytokines	Growth factors	Carcinogens	Others	Synthetic	Natural	Others
Cardiotrophin-1	EGF	Diesel & exhaust particles	Bile acids	AG 490	Caffeic acid	EKB569
IFN-γ	PDGF	Tobacco	Diazoxide	Aurothiomalate	Chalcone	Rituximab
IL-6	TGF-α	UVB	Genistein3	BMS-354825	Cucurbitacin	GQ-ODN
IL-10	G-CSF	HCV	Isoliquiritigenin	CADPE	Emodin	TKS –050
IL-11	GM- CSF	LPS	Leptin	Ethanol	Genistein	STA21
IL-21	RUNX1	RSV	Morphine sulfate	PDP	Indirubin	Retinoic acid
IL-27	ISRE	HPV	Olanzapine	PS-341	Parthenolide	TGF-β1
LIGHT	CRE	CNTF	Black soy peptides	S31-M2001	Piceatannol	17β-estradiol
MIP-1α	FGF1	LIF	CaMKIIg Acid	Sodium	Resveratrol	COX-2
RANTES	FGF2		Sphingomyelinase Acid	Statin	Capsaicin
SLF25	IGF-IR		Ceramidase	T40214	CDDO-Me
MCP-1	CSF1R		Colivelin	Atiprimod	Curcumin
CNTF	AgtR2		Ruxolitinib Phosphate	Auranofin	EGCG
IL-5	GPCRs			Stattic	Flavopiridol
IL-9				Dobesilate	Ursolic acid
IL-12				Platinum compounds	Guggulsterone
IL-22				Y(p)LPQTV	Magnolol
TNF-α

Site of action	Class	Preclinical Data	Clinical Data	Challenges
Inhibitors of STAT-3 stimulation	JAK1/2 inhibitor Ruxolitinib	Tumor xenograft models	primary myelofibrosis (phase III)	Unfeasible in most cancers
Inhibitors of STAT-3 stimulation	Small-molecule JAK inhibitors (LS-104, AG490, CEP701and ICNB18424)		(phase II)	Insignificant myelosuppression and a minor but recurrent GI toxicity
SH2 domain dimerization inhibitors	Peptides	Src-transformed	Nil	Poor cellular permeability in vivo stability
	(XpYL)	fibroblasts
	Peptidomimetics	Breast, NSCLC
	(ISS610)	Src-transformed
		fibroblasts
	Small molecule	Breast, sarcoma, Nil	Lack of potency and specificity
	inhibitor	GBM
	STA-21 and	GBM
	analogues	Breast
	LLL-3	Breast, HCC, GI
	S3I-201	Breast
	Static	CRC
	OPB-31121	Liver
	OPB-51602	Lung
	Natural	RCC	Advanced hematologic and solid tumors (Phase I)	Unexpected toxicities Unpredictable PK properties
	compounds	Breast
	Curcumin	Pancreas, HCC,
	Curcumin	GI
	analogues	NSCLC
	(FLLL11, FLLL12, FLLL32)
N terminal domain inhibitors	Synthetic analogues for STAT-3 helix 2	Inhibited cell growth and apoptosis of human MCF-7, MDA-MB-435 and MDA-MB-231 breast cancer cells		Peptides interaction with N-terminal domain and their mechanisms of action are still unknow
	Synthetic peptide
	ST3-H2A2	Cause blockage of STAT-3 dimerization and apoptosis in prostate cancer cell lines
Upstream tyrosine kinase inhibitors	Small molecule	EGFR NSCLC		Neurologic dose-limiting toxicities
Upstream tyrosine kinase inhibitors	inhibitors	NSCLC	Phase I	Toxicity and lack of efficacy
	AZD1480	HNSCC	Phase II	Lack of potency and specificity
	(JAK1/2)
	Dasatinib (Src)
	Natural	HCC, breast,	Nil
	compounds	pancreas
	Butein Capsaicin	Prostate, gastric
Inhibitors of Nuclear Translocation	Karyostatin		Nil	Inhibition of general trafficking through the nuclear membrane is probable to be harmful
	1ARajtadoneB	Human lung
	Leptomycin	carcinoma cell
	Bimax1, bimax2	lines
		mouse
		neuroblastoma
		cell lines
		HeLa cell lines
STAT3 pathway oligonucleotides	Antisense oligonucleotide	Lymphoma	Phase I/II	Rapid degradation, not amenable to systemic administration
STAT3 pathway oligonucleotides	AZD9150			Rapid degradation, not amenable to systemic administration

			Phase 0
	STAT3 decoy oligonucleotide	NSCLC
	(DNA-binding)	NSCLC, colorectal
		glioma
	STAT3 post-transcriptional	Breast, brain, SCC
	(siRNA)
STAT3 DNA-binding domain	Platinum IV compounds,	Breast
		Colon	Nil	Lack of specificity
	IS3295,	NSCLC
	CPA-1,
	CPA-7,

Domain	Function
N-terminus domain	The N-terminus comprises a domain (ND) that facilitates STAT dimer–dimer communications in tetramer establishment that is vital to stabilize the dimers binding to DNA.
Coiled-coil domain	The coiled-coil domain (CCD) connects the (ND) N-terminus domain to the (DBD) DNA-binding domain and also take part in the communications with other proteins
The DNA-binding Domain	The DBD creates physical connection with SRE in target genes promoters and is associated to the Src homology 2 domains via the linker domain (Linker).
SH2 domain	The SH2 domain is central for dimerization of two STAT3 monomers.
Tyr (Y) residue	On phosphorylation of the specific Tyr (Y) residue in the transcriptional activation domain (TAD), the pTyr residue of one monomer and the Src homology 2 domains of a different monomer involve in shared pTyr-SH2 domain interaction
The transactivation domain	The transactivation domain assists the transcriptional stimulation of target genes and can comprise a serine residue essential for utmost transcriptional activity in the circumstance of some STAT proteins, including STAT3.

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[1] Send correspondence to Dr. Muhammad Naveed. University of Lahore, Department of Allied Health Sciences, Gujrat Campus, Pakistan. Email: dr.naveed@ucp.edu.pk