Mouse leukemia L1210 cells selected for resistance to the ribonucleotide reductase inhibitor, 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone show altered response to DNA damaging agents

An L1210 cell line (MQ-580) selected for resistance to the ribonucleotide reductase inhibitor, 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone (MAIQ), had been previously shown to have altered properties related to the non-heme iron subunit of ribonucleotide reductase (RR). In addition, the MQ-580 cells had other metabolic alterations that were consistent with multidrug resistance. Neither the wild-type (WT) nor the MQ-580 cells showed a G(0)G(1) block in response to X-irradiation. Since the MQ-580 cells also showed resistance to adriamycin (ADR), the WT cells were more sensitive to the effects of ADR than the MQ-580 cells. However, when the MQ-580 cells were treated with the combination of ADR plus verapamil, the MQ-580 cells showed cellular responses that included cell cycle block in G(2)/M and increased apoptosis. The WT cells, in response to the combination of ADR plus verapamil, blocked in the S-phase of the cell cycle with an increased necrotic cell population in comparison to treatment with ADR alone. While MAIQ could be shown to cause an apoptotic I response in the WT and MQ-580 cells, the concentrations of MAIQ required to induce apoptosis were 20- to 40-times the IC50, value. However, even though the MQ-580 cells were 8-fold more resistant to MAIQ than the WT cells, the MQ-580 cells were more sensitive to MAIQ-induced apoptosis. These data show that alterations at the RR site lead to phenotypic expressions not overtly related to RR. However, because of the critical role that RR plays in cell division and DNA repair, the changes observed with respect to cell cycle and apoptosis, may in fact, be a direct consequence of the alteration at RR.