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Figure 1 | Journal of Translational Medicine

Figure 1

From: Ribonucleotide reductase inhibition restores platinum-sensitivity in platinum-resistant ovarian cancer: a Gynecologic Oncology Group Study

Figure 1

3-aminopyridine-2-carboxyaldehyde-thiosemicarbazone (3-AP) lowered 6-hour deoxycytidine triphosphates (dCTP) pools and was associated with elevated 24-hour posttherapy M2 and M2b protein. Panel A: SKOV3 and OVCAR3 cells were treated with cisplatin (5 μM) and/or 3-AP (5 μM) for 6 hours and assayed for dCTP pool by a DNA polymerase extension assay. Cisplatin treatment elevated 6-hour post therapy dCTP levels, indirectly suggesting a rise in RNR activity. dCTP levels 6 hours after cisplatin treatment (and 18 hours after start of 3-AP treatment) were indistinguishable from dCTP levels in cisplatin alone treated cells (P = 1.0). When 3-AP was administered alone or co-administered with cisplatin, substantial reduction in dCTP levels were detected 6 hours post therapy (P < 0.001, star). Means (± standard error) are reported. Panel B: Immunoblots for M2 and M2b protein and corresponding dCTP level are depicted for control and treated cells (t = 0 h [before] and 24 h [after start of cisplatin]). M2 and M2b showed moderate increase after cisplatin treatment or after ribonucleotide reductase blockade by 3-AP. Corresponding 24-hour dCTP level after cisplatin, an indicator of rise in ribonucleotide reductase activity in response to cisplatin-mediated DNA damage, was higher than baseline (P < 0.01, star). Increased ribonucleotide reductase activity occurred in the 3-AP then cisplatin treatment (P < 0.01, star). In the three 3-AP treatment groups, 24-hour recovery of ribonucleotide reductase activity after 3-AP inactivation was found. Whether return to baseline or elevated recovery of activity happens because of transcriptional replacement of the M2 and/or M2b subunits or other mechanism is not discerned. Means (± standard error) are reported for RNR activity.

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