Mechanism of inhibition of ribonucleotide reductase with motexafin gadolinium (MGd).
Motexafin gadolinium (MGd) is an expanded porphyrin anticancer agent which selectively targets tumor cells and works as a radiation enhancer, with promising results in clinical trials. Its mechanism of action is oxidation of intracellular reducing molecules and acting as a direct inhibitor of mammalian ribonucleotide reductase (RNR). This paper focuses on the mechanism of inhibition of RNR by MGd. Our experimental data present at least two pathways for inhibition of RNR; one precluding subunits oligomerization and the other direct inhibition of the large catalytic subunit of the enzyme. Co-localization of MGd and RNR in the cytoplasm particularly in the S-phase may account for its inhibitory properties. These data can elucidate an important effect of MGd on the cancer cells with overproduction of RNR and its efficacy as an anticancer agent and not only as a general radiosensitizer.
Zahedi Avval
Farnaz
F
Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
Berndt
Carsten
C
Pramanik
Aladdin
A
Holmgren
Arne
A
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008665:Metalloporphyrins / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D018384:Oxidative Stress; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D008665:Metalloporphyrins; D021122:Protein Subunits; C437683:motexafin gadolinium; D012264:Ribonucleotide Reductases