Dehydroepiandrosterone-α-2-Deoxyglucoside Exhibits Enhanced Anticancer Effects in MCF-7 Breast Cancer Cells and Inhibits Glucose-6-Phosphate Dehydrogenase Activity.
Chem Biol Drug Des
; 104(3): e14624, 2024 Sep.
Article
in En
| MEDLINE
| ID: mdl-39317696
ABSTRACT
In the pentose phosphate pathway, dehydroepiandrosterone (DHEA) uncompetitively inhibits glucose-6-phosphate dehydrogenase (G6PD), reducing NADPH production and increasing oxidative stress, which can influence the onset and/or progression of several diseases, including cancer. 2-Deoxy-D-glucose (2-DG), a glucose mimetic, competes with glucose for cellular uptake, inhibiting glycolysis and competing with glucose-6-phosphate (G-6-P) for G6PD activity. In this study, we report that DHEA-α-2-DG (5), an α-covalent conjugate of DHEA and 2-DG, exhibits better anticancer activity than DHEA, 2-DG, DHEA +2-DG, and polydatin in MCF-7 cells, and reduces NADPH/NADP+ ratio in cellular assays. In vitro enzyme kinetics and molecular docking studies showed that 5 uncompetitively inhibits human G6PD activity and binds to the structural NADP+ site but not to the catalytic NADP+ site. Further combining 5 with the FDA-approved drug tamoxifen enhanced its cytotoxicity against MCF-7 cells, suggesting that it could serve as a candidate for combination of drug strategies.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Dehydroepiandrosterone
/
Deoxyglucose
/
Molecular Docking Simulation
/
Glucosephosphate Dehydrogenase
/
Antineoplastic Agents
Limits:
Female
/
Humans
Language:
En
Journal:
Chem Biol Drug Des
/
Chem. biol. drug des. (Print)
/
Chemical biology & drug design (Print)
Journal subject:
BIOQUIMICA
/
FARMACIA
/
FARMACOLOGIA
Year:
2024
Document type:
Article
Affiliation country:
Taiwan
Country of publication:
United kingdom