Glutathione S-transferase π: a potential role in antitumor therapy

Figures & data

Figure 1 The two binding sites (G and H) of GSTπ.

Note: The G-site represents a GSH-binding site and the H-site a substrate-binding site.
Abbreviation: GST, glutathione S-transferase.

Figure 2 Involvement of GSTπ in the detoxification of exogenous and endogenous substrates.

Note: In the process, Pgp or MRPs (eg, MRP2) give assistance to GSTπ to excrete the complex out of the cell.
Abbreviation: GST, glutathione S-transferase.

Figure 3 The process of S-glutathionylation.

Notes: In this process, low-pKA cysteine-residue proteins are targeted upon exposure to nitrosative or oxidative stress. The cysteine residues are oxidized to produce protein sulfinic (P–OOH) and sulfenic (P–OH) acids. GSH functions as a thiol donor to facilitate GSTπ-mediated S-glutathionylation, protecting the target protein from further damage. This reaction is also influenced by enzymes involved in deglutathioylation, such as sulfiredoxin (Srx), glutaredoxin (Grx), and thioredoxin (Trx).
Abbreviation: GST, glutathione S-transferase.

Figure 4 Ligand-binding properties of JNK and TRAF2.

Notes: Under physiological conditions, cells possess low JNK activity. JNK is sequestered in the form of the GSTπ–JNK protein complex. GSTπ dissociates from the GSTπ–JNK complex upon oxidative stress induced by drug administration, resulting in the accumulation of GSTπ oligomers. This results in c-Jun phosphorylation and/or ATF2 activation, and this progress further impacts downstream events as well. Meanwhile, TRAF2 recruitment to the plasma membrane stimulates the production of ROS. Subsequent oxidation of the previously inactive ASK1–Trx complex causes dissociation of the ASK1 molecule. TRAF2 then binds to ASK1 to activate the ASK1–JNK signaling cascade. Nevertheless, on account of high expression in tumor cells, GSTπ acts as an endogenous negative regulatory switch by forming complexes with JNK, preventing TRAF2–ASK1 interactions and ultimately inhibiting tumor-cell apoptosis and proliferation.
Abbreviation: GST, glutathione S-transferase.

Table 1 Genetic polymorphisms of cytosolic GSTs

Class	Chromosome	Gene	Exon count	Alleles	Nucleotide variability	Reference(s)
α	6p12.2	GSTA1	7	GSTA1*A	Wild-type	^Citation116
				GSTA1*B	Promoter point mutation
		GSTA2	8	GSTA2*A	Pro110;Ser112;Lys196;Glu210	^Citation117, ^Citation118
				GSTA2*B	Pro110, Ser112, Lys196, Ala210
				GSTA2*C	Pro110;Thr112;Lys196;Glu210
				GSTA2*D	Pro110;Ser112;Asn196;Glu210
				GSTA2*E	Ser110;Ser112;Lys196;Glu210
μ	1p13.3	GSTM1	8	GSTM1*A	Lys173	^Citation119, ^Citation120
				GSTM1*B	Asn173
				GSTM1 null	Gene deletion
				GSTM1*1⋅2	Duplication
		GSTM3	9	GSTM3*A	Wild-type	^Citation121
				GSTM3*B	Protein unchanged
		GSTM4	10	GSTM4*A	Tyr2517	^Citation122, ^Citation123
				GSTM4*B	T2517C frameshift
π	11q13.2	GSTP1	7	GSTP1*A	Ile105;Ala114	^Citation124^–^Citation128
				GSTP1*B	Val105;Ala114
				GSTP1*C	Val105;Val114
				GSTP1*D	Ile105;Val114
θ	22q11.23	GSTT1	6	GSTT1*A	Thr104	^Citation124
				GSTT1*B	Pro104	^Citation129
				GSTT1*null	Gene deletion
		GSTT2	5	GSTT2*A	Met139	^Citation130, ^Citation131
				GSTT2*B	Ile139
ω	10q25.1	GSTO1	7	GSTO1*A	Ala140;Glu155	^Citation132, ^Citation133
				GSTO1*B	Ala140
				GSTO1*C	Asp140;Glu155
				GSTO1*D	Asp140
		GSTO2	10	GSTO2*A	Asn142	^Citation134, ^Citation135
				GSTO2*B	Asp142
δ	14q24.3	GSTZ1	12	GSTZ1*A	Lys32;Arg42;Thr82	^Citation136^–^Citation138
				GSTZ1*B	Lys32;Gly42;Thr82
				GSTZ1*C	Glu32;Gly42;Thr82
				GSTZ1*D	Glu32;Gly42;Met82

Abbreviation: GST: Glutathione S-transferase.

Table 2 Antitumor agents targeting GSTπ in context

Drugs	Selected examples	Functional significance	References
GSTπ inhibitors	EA and its analogs	Inhibiting detoxification activity, mainly by binding to substrate-binding sites of GSTπ	^Citation139, ^Citation140
	TLK117/TLK199 NBDHEX and its analogs	Promoting tumor-cell apoptosis by preventing combination of GSTπ and JNK and then activating MAPK pathway	^Citation62, ^Citation141 ^Citation142^–^Citation145
GSTπ prodrugs	GSH or GSH derivatives (TLK286)	Catalyzed by GSTπ to release nitrogen-mustard segment to induce tumor-cell apoptosis	^Citation146^–^Citation148
	NO prodrugs (JS-K)	Catalyzed by GSTπ to release high-concentration NO to kill tumor cells directly	^Citation149

Abbreviations: GST, glutathione S-transferase; EA, ethacrynic acid; NO, nitric oxide.

IorioASpinelliMPolimantiRGSTA1 gene variation associated with gestational hypertension and its involvement in pregnancy-related pathogenic conditionsEur J Obstet Gynecol Reprod Biol2015194343726321410

 PubMed Web of Science ®Google Scholar

BonifaziFStorciGBandiniGGlutathione transferase-A2 S112T polymorphism predicts survival, transplant-related mortality, busulfan and bilirubin blood levels after allogeneic stem cell transplantationHaematologica201499117217924056816

 PubMed Web of Science ®Google Scholar

ZhangWModenOMannervikBDifferences among allelic variants of human glutathione transferase A2-2 in the activation of azathioprineChem Biol Interact2010186211011720434437

 PubMed Web of Science ®Google Scholar

RodriguesDAMartinsJVSilvaKSEGSTM1 polymorphism in patients with clinical manifestations of atherosclerosisGenetics and Molecular Research: GMR2017161

 Web of Science ®Google Scholar

Abdur RehmanMYKamalATaqiMMMalikRNTracing biomarker of PAH-exposure and susceptibility factor (GSTM-polymorphism) among cancer patients in PakistanChemosphere201717838439028340461

 PubMed Web of Science ®Google Scholar

TanwarRIyengarARNageshKSPatilSSubhashBVGSTM1 null polymorphism prevalence in tobacco users, oral leukoplakia and oral squamous cell carcinoma patients in South Indian population: A polymerase chain reaction studyIndian J Dent Res201627435335827723629

 PubMedGoogle Scholar

XuYWangJDongWGSTM3 A/B polymorphism and risk for head and neck cancer: a meta-analysisPLoS One201491e8385124416175

 PubMed Web of Science ®Google Scholar

FengXDongCQShiJJZhouHFHeWZhengBSLack of association of glutathione S-transferase M3 gene polymorphism with the susceptibility of lung cancerAsian Pac J Cancer Prev20121394465446823167362

 PubMedGoogle Scholar

BhatAMasoodAWaniKAPromoter methylation and gene polymorphism are two independent events in regulation of GSTP1 gene expressionTumour Biol2017394101042831769756328443466

 PubMedGoogle Scholar

ChoiBKimMGHanNPopulation pharmacokinetics and pharmacodynamics of busulfan with GSTA1 polymorphisms in patients undergoing allogeneic hematopoietic stem cell transplantationPharmacogenomics201516141585159426419450

 PubMed Web of Science ®Google Scholar

SongYShanZLuoCGlutathione S-Transferase T1 (GSTT1) Null Polymorphism, Smoking, and Their Interaction in Coronary Heart Disease: A Comprehensive Meta-AnalysisHeart Lung Circ201726436237027686690

 PubMed Web of Science ®Google Scholar

JangSGKimIJKangHCGSTT2 promoter polymorphisms and colorectal cancer riskBMC Cancer200771617250773

 PubMed Web of Science ®Google Scholar

ChelvanayagamGWilceMCParkerMWTanKLBoardPGHomology model for the human GSTT2 Theta class glutathione transferaseProteins19972711181309037717

 PubMed Web of Science ®Google Scholar

XuYTWangJYinRGenetic polymorphisms in Glutathione S-transferase Omega (GSTO) and cancer risk: a meta-analysis of 20 studiesSci Rep20144657825300926

 PubMed Web of Science ®Google Scholar

PolimantiRGrazianoMELazzarinNVaqueroEManfellottoDFuciarelliMGSTO1 uncommon genetic variants are associated with recurrent miscarriage riskFertil Steril2014101373573924417908

 PubMed Web of Science ®Google Scholar

WangZQuKHuangZGlutathione S-transferase O2 gene rs157077 polymorphism predicts response to transarterial chemoembolization in hepatocellular carcinomaTumour Biol20153686463646925835968

 PubMedGoogle Scholar

StamenkovicMRadicTStefanovicIGlutathione S-transferase omega-2 polymorphism Asn142Asp modifies the risk of age-related cataract in smokers and subjects exposed to ultraviolet irradiationClin Exp Ophthalmol201442327728323927022

 PubMed Web of Science ®Google Scholar

LangaeeTYZhongGLiWThe influence of human GSTZ1 gene haplotype variations on GSTZ1 expressionPharmacogenet Genomics201525523924525738370

 PubMed Web of Science ®Google Scholar

Karakas-CelikSArasNAtesCGlutathione S-transferase Z1 (GSTZ1) gene polymorphism in gastric cancer: a preliminary study in a Turkish populationLab Med2014451374224719983

 PubMed Web of Science ®Google Scholar

BurgDFilippovDVHermannsRvan der MarelGAvan BoomJHMulderGJPeptidomimetic glutathione analogs as novel gammaGT stable GST inhibitorsBioorg Med Chem200210119520511738622

 PubMed Web of Science ®Google Scholar

LiTLiuGLiHYangXJingYZhaoGThe synthesis of ethacrynic acid thiazole derivatives as glutathione S-transferase pi inhibitorsBioorg Med Chem20122072316232222370342

 PubMed Web of Science ®Google Scholar

RazaAGaliliNSmithSPhase 1 multicenter dose-escalation study of ezatiostat hydrochloride (TLK199 tablets), a novel glutathione analog prodrug, in patients with myelodysplastic syndromeBlood2009113266533654019398716

 PubMed Web of Science ®Google Scholar

MahadevanDSuttonGREzatiostat hydrochloride for the treatment of myelodysplastic syndromesExpert Opin Investig Drugs2015245725733

 PubMed Web of Science ®Google Scholar

FulciCRotiliDDe LucaAA new nitrobenzoxadiazole-based GSTP1-1 inhibitor with a previously unheard of mechanism of action and high stabilityJ Enzyme Inhib Med Chem201732124024728097896

 PubMed Web of Science ®Google Scholar

GrazianiGArtusoSDe LucaAA new water soluble MAPK activator exerts antitumor activity in melanoma cells resistant to the BRAF inhibitor vemurafenibBiochem Pharmacol2015951162725795251

 PubMed Web of Science ®Google Scholar

RamsayEEDildaPJGlutathione S-conjugates as prodrugs to target drug-resistant tumorsFront Pharmacol2014518125157234

 PubMed Web of Science ®Google Scholar

VergoteIFinklerNdel CampoJPhase 3 randomised study of canfosfamide (Telcyta, TLK286) versus pegylated liposomal doxorubicin or topotecan as third-line therapy in patients with platinum-refractory or -resistant ovarian cancerEur J Cancer200945132324233219515553

 PubMed Web of Science ®Google Scholar

QiuMKeLZhangSZengXFangZLiuJJS-K, a GST-activated nitric oxide donor prodrug, enhances chemo-sensitivity in renal carcinoma cells and prevents cardiac myocytes toxicity induced by DoxorubicinCancer Chemother Pharmacol201780227528628608259

 PubMed Web of Science ®Google Scholar