Metabolism of the Tumor Angiogenesis Inhibitor 4-(N-(S-Glutathionylacetyl)amino) phenylarsonous Acid

被引:31
作者
Dilda, Pierre J. [1 ]
Ramsay, Emma E. [1 ]
Corti, Alessandro [2 ]
Pompella, Alfonso [1 ]
Hogg, Philip J. [1 ,3 ]
机构
[1] Univ New S Wales, Ctr Canc Res, Sydney, NSW 2052, Australia
[2] Univ Pisa, Sch Med, I-56126 Pisa, Italy
[3] Childrens Canc Inst Australia Med Res, Randwick, NSW 2031, Australia
基金
英国医学研究理事会;
关键词
D O I
10.1074/jbc.M804470200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid (GSAO) is a small, synthetic mitochondrial poison that targets angiogenic endothelial cells and is currently being tested in a Phase I/IIa clinical trial. The trivalent arsenical of GSAO reacts with and perturbs adenine nucleotide translocase of the inner mitochondrial membrane of endothelial cells, which leads to proliferation arrest. Three observations indicated that the gamma-glutamyl residue of GSAO is cleaved at the endothelial cell surface by gamma-glutamyl transpeptidase (gamma GT). GSAO was found to be an efficient substrate for gamma GT, endothelial cell accumulation and antiproliferative activity of GSAO was blunted by a competitive substrate and an active site inhibitor of gamma GT, and the level of cell surface gamma GT correlated strongly with the sensitivity of cells to GSAO. Using transport inhibitors, it was revealed that the resulting metabolite of GSAO cleavage by gamma GT, 4-(N-(S-cysteinylglycylacetyl) amino) phenylarsonous acid (GCAO), was transported across the plasma membrane by an organic anion transporter. Furthermore, GCAO is likely processed by dipeptidases in the cytosol to 4-(N-(S-cysteinylacetyl) amino) phenylarsonous acid (CAO), and it is this metabolite that reacts with mitochondrial adenine nucleotide translocase. Taken together, our findings indicate that gamma GT processing of GSAO at the cell surface is the rate-limiting step in its antiangiogenic activity. This information can explain the kidney toxicity at high doses of GSAO noted in preclinical studies and will aid in the anticipation of potential side effects in humans and in the design of better antimitochondrial cancer drugs.
引用
收藏
页码:35428 / 35434
页数:7
相关论文
共 23 条
[11]   The superfamily of organic anion transporting polypeptides [J].
Hagenbuch, B ;
Meier, PJ .
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 2003, 1609 (01) :1-18
[12]   The permeability transition pore complex: another view [J].
Halestrap, AP ;
McStay, GP ;
Clarke, SJ .
BIOCHIMIE, 2002, 84 (2-3) :153-166
[13]   Immunohistochemical detection of gamma-glutamyl transpeptidase in normal human tissue [J].
Hanigan, MH ;
Frierson, HF .
JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY, 1996, 44 (10) :1101-1108
[14]   GAMMA-GLUTAMYL TRANSPEPTIDASE - SIDEDNESS OF ITS ACTIVE-SITE ON RENAL BRUSH-BORDER MEMBRANE [J].
HORIUCHI, S ;
INOUE, M ;
MORINO, Y .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1978, 87 (03) :429-437
[15]   PRACTICAL POINTS REGARDING ROUTINE DETERMINATION OF GAMMA-GLUTAMYL TRANSFERASE (GAMMA-GT) IN SERUM WITH A KINETIC METHOD AT 37 DEGREES C [J].
HUSEBY, NE ;
STROMME, JH .
SCANDINAVIAN JOURNAL OF CLINICAL & LABORATORY INVESTIGATION, 1974, 34 (04) :357-363
[16]   Hepatic mercapturic acid formation:: Involvement of cytosolic cysteinylglycine S-conjugate dipeptidase activity [J].
Jösch, C ;
Sies, H ;
Akerboom, TPM .
BIOCHEMICAL PHARMACOLOGY, 1998, 56 (06) :763-771
[17]   Involvement of human organic anion transporting polypeptide OATP-B (SLC21A9) in pH-dependent transport across intestinal apical membrane [J].
Kobayashi, D ;
Nozawa, T ;
Imai, K ;
Nezu, JI ;
Tsuji, A ;
Tamai, I .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2003, 306 (02) :703-708
[18]   The MRP family of drug efflux pumps [J].
Kruh, GD ;
Belinsky, MG .
ONCOGENE, 2003, 22 (47) :7537-7552
[19]   Arsenite induces apoptosis via a direct effect on the mitochondrial permeability transition pore [J].
Larochette, N ;
Decaudin, D ;
Jacotot, E ;
Brenner, C ;
Marzo, I ;
Susin, SA ;
Zamzami, N ;
Xie, ZH ;
Reed, J ;
Kroemer, G .
EXPERIMENTAL CELL RESEARCH, 1999, 249 (02) :413-421
[20]   Polymorphisms in human organic anion-transporting polypeptide 1A2 (OATP1A2) - Implications for altered drug disposition and central nervous system drug entry [J].
Lee, W ;
Glaeser, H ;
Smith, LH ;
Roberts, RL ;
Moeckel, GW ;
Gervasini, G ;
Leake, BF ;
Kim, RB .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (10) :9610-9617