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Moreover, MGd can also affect the CGS 21680 HCl donor systems of RNR, particularly the Trx system as shown in our previous paper [19]. However, also the Grx system the electron donor for RNR operating via glutathionylated R1 (Zahedi Avval and Holmgren, in preparation) may be affected by MGd via depletion of GSH in the cell [15] and [32].
Our results showed that the molecular mechanism of RNR inhibition by MGd involves direct targeting of the R1. The activity assay showed when the two subunits are in a similar range the inhibition does not change by increasing the R2 amount, but adding more R1 can overcome the inhibition with MGd showing its effect on the R1 subunit (Fig. 2). The specific binding of MGd to R1 (not R2) was detected with FCS experiments which was confirmed by the other method as well (Fig. 3).
It has been shown that MGd accumulates mainly within cytoplasmic compartments and partially in some cell lines in the nucleus after longer incubation [33]. Thus, considering the cytoplasmic localization of RNR [34] and [35] the prerequisite of co-localization of the protein and the drug is fulfilled. S-phase DNA synthesis requires a high dNTP supply and, RNR inhibition is central for reduction of intracellular pools and treatment of cancer. The clinical use of RNR inhibitors in chemotherapy is not new and side effects due to toxic effects on normal proliferating cells are problematic. The selective tumor enrichment of MGd in human malignancies [32] is an advantage. Other effects of MGd like depletion of various intracellular reducing agents such as glutathione, ascorbate, flavins and NADPH necessary for repair of oxidative damage [14] and [15] or prevention of DNA strand breaks [32] are making this agent more efficient.