Premium
γ‐GLUTAMYLTRANSFERASE OF CANCER CELLS AT THE CROSSROADS AMONG TUMOR PROGRESSION, DRUG RESISTANCE AND DRUG TARGETING.
Author(s) -
Pompella Alfonso,
Corti Alessandro,
Zunino Franco,
Paolicchi Aldo
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.438.6
Subject(s) - glutathione , chemistry , cisplatin , drug , drug resistance , metabolite , pharmacology , enzyme , cancer research , biochemistry , biology , medicine , chemotherapy , microbiology and biotechnology
γ‐Glutamyltransferase (GGT) is increased human malignancies, with roles in cell redox regulation and tumor progression (Paolicchi et al., Bioch. Pharm. 2002; Pompella et al., Curr. Op. Pharm. 2007). We have observed increased levels of DNA damage in GGT‐overexpressing cells, suppressed by specific GGT inhibitors, iron chelator DFO and lipid antioxidants. GGT is also implicated in drug resistance, as it favours the reconstitution of cellular glutathione. But the enzyme can actually play as a factor in drug sensitivity as well: i) protection offered by GGT against cisplatin depend on extra‐cellular reactions of cisplatin with GGT‐derived thiol metabolites (Franzini et al., EJC 2006, 42: 2623); ii) with 4‐[N‐(S‐glutathionyl‐acetyl)amino] phenylarsinous acid (GSAO) ‐ a promising anti‐angiogenic drug ‐ GGT activity acts as a sensitizing factor: GSAO is cleaved by GGT expressing cells, thus producing the active metabolite GCAO (Dilda et al., JBC 2008); iii) NO‐donor agents (e.g. S‐nitroso‐glutathione, GSNO) have been highlighted as "chemosensitizing agents". GGT selectively metabolizes GSNO (Angeli et al., ABB 2008), thus releasing its NO load: its expression may thus be exploited to target NO to GGT‐expressing tumor cells. Supported by Istituto Toscano Tumori (ITT, Firenze) and Fondazione Fibrosi Cistica (FFC, Verona) ‐ Italy.