Pharmacological targeting of glucose-6-phosphate dehydrogenase in human erythrocytes by Bay 11-7082, parthenolide and dimethyl fumarate

被引：35

作者：

Ghashghaeinia, Mehrdad ^{[1
]}

Giustarini, Daniela ^{[2
]}

Koralkova, Pavla ^{[3
]}

Koeberle, Martin ^{[4
]}

Alzoubi, Kousi ^{[5
]}

Bissinger, Rosi ^{[5
]}

Hosseinzadeh, Zohreh ^{[6
]}

Dreischer, Peter ^{[7
]}

Bernhardt, Ingolf ^{[8
]}

Lang, Florian ^{[5
]}

Toulany, Mahmoud ^{[9
]}

Wieder, Thomas ^{[10
]}

Mojzikova, Renata ^{[3
]}

Rossi, Ranieri ^{[2
]}

Mrowietz, Ulrich ^{[1
]}

机构：

[1] Univ Med Ctr Schleswig Holstein, Psoriasis Ctr, Dept Dermatol, Campus Kiel,Schittenhelmstr 7, D-24105 Kiel, Germany

[2] Univ Siena, Dept Life Sci, Lab Pharmacol & Toxicol, Via A Moro 2, I-53100 Siena, Italy

[3] Palacky Univ, Fac Med & Dent, Dept Biol, Hnevotinska 3, Olomouc 77515, Czech Republic

[4] Tech Univ Munich, Dept Dermatol & Allergy, Biedersteinerstr 29, D-80802 Munich, Germany

[5] Univ Tubingen, Dept Cardiol Vasc Med & Physiol, Gmelinstr 5, D-72076 Tubingen, Germany

[6] Univ Tubingen, Ctr Ophthalmol, Inst Ophthalm Res, Frondsbergstr 23, D-72076 Tubingen, Germany

[7] Univ Tubingen, Inst Phys 2, Keplerstr 15, D-72074 Tubingen, Germany

[8] Univ Saarland, Biophys Lab, Campus A2-4, D-66123 Saarbrucken, Germany

[9] Univ Tubingen, Dept Radiat Oncol, Div Radiobiol & Mol Environm Res, Rontgenweg 11, D-72076 Tubingen, Germany

[10] Univ Tubingen, Dept Dermatol, Rontgenweg 11, D-72076 Tubingen, Germany

来源：

SCIENTIFIC REPORTS | 2016年 / 6卷

关键词：

FACTOR-KAPPA-B; SESQUITERPENE LACTONE PARTHENOLIDE; PENTOSE-PHOSPHATE PATHWAY; PROGRAMMED CELL-DEATH; NITRIC-OXIDE; PLASMODIUM-FALCIPARUM; GLUTATHIONE-REDUCTASE; NAD(P)H OXIDASE; INHIBITION; DEHYDROEPIANDROSTERONE;

D O I：

10.1038/srep28754

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

In mature erythrocytes, glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH) yield NADPH, a crucial cofactor of the enzyme glutathione reductase (GR) converting glutathione disulfide (GSSG) into its reduced state (GSH). GSH is essential for detoxification processes in and survival of erythrocytes. We explored whether the anti-inflammatory compounds Bay 11-7082, parthenolide and dimethyl fumarate (DMF) were able to completely deplete a common target (GSH), and to impair the function of upstream enzymes of GSH recycling and replenishment. Treatment of erythrocytes with Bay 11-7082, parthenolide or DMF led to concentration-dependent eryptosis resulting from complete depletion of GSH. GSH depletion was due to strong inhibition of G6PDH activity. Bay 11-7082 and DMF, but not parthenolide, were able to inhibit the GR activity. This approach "Inhibitors, Detection of their common target that is completely depleted or inactivated when pharmacologically relevant concentrations of each single inhibitor are applied, Subsequent functional analysis of upstream enzymes for this target" (IDS), can be applied to a broad range of inhibitors and cell types according to the selected target. The specific G6PDH inhibitory effect of these compounds may be exploited for the treatment of human diseases with high NADPH and GSH consumption rates, including malaria, trypanosomiasis, cancer or obesity.

引用

页数：12

共 63 条

[1] The role of glutathione in brain tumor drug resistance [J].