Tyrosyl-DNA Phosphodiesterase 1 and Topoisomerase I Activities as Predictive Indicators for Glioblastoma Susceptibility to Genotoxic Agents

Abstract

Glioblastoma (GBM) patients have an estimated survival of ~15 months with treatment, and the standard of care only modestly enhances patient survival. Identifying biomarkers representing vulnerabilities may allow for the selection of efficacious chemotherapy options to address personalized variations in GBM tumors. Irinotecan targets topoisomerase I (TOP1) by forming a ternary DNA–TOP1 cleavage complex (TOP1cc), inducing apoptosis. Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a crucial repair enzyme that may reduce the effectiveness of irinotecan. We treated GBM cell lines with increasing concentrations of irinotecan and compared the IC50 values. We found that the TDP1/TOP1 activity ratio had the strongest correlation (Pearson correlation coefficient R = 0.972, based on the average from three sets of experiments) with IC50 values following irinotecan treatment. Increasing the TDP1/TOP1 activity ratio by the ectopic expression of wild-type TDP1 increased in irinotecan IC50, while the expression of the TDP1 catalytic-null mutant did not alter the susceptibility to irinotecan. The TDP1/TOP1 activity ratio may be a new predictive indicator for GBM vulnerability to irinotecan, allowing for the selection of individual patients for irinotecan treatment based on risk–benefit. Moreover, TDP1 inhibitors may be a novel combination treatment with irinotecan to improve GBM patient responsiveness to genotoxic chemotherapies.

Proteins from the DNA Damage Response: Regulation, Dysfunction, and Anticancer Strategies

“…Tyrosyl-DNA phosphodiesterase 1/2 (TDP1/2) resolve Top-DNA complexes by liberating Top1 or Top2 (respectively TDP1 and TDP2) from the DNA after the degradation of the cleavage complexes. A combination of inhibitors such as the Top1 inhibitor irinotecan with a TDP1 inhibitor also improves the treatment of glioblastoma [293]. A higher response to irinotecan (Top1 inhibitor) is obtained in BRCA2-mutated cancer with acquired resistance to olaparib (PARP inhibitor) showing the downregulation of TDP1 [294].…”

Novel Tdp1 Inhibitors Based on Adamantane Connected with Monoterpene Moieties via Heterocyclic Fragments

“…One of the DNA repair enzymes is tyrosyl-DNA-phosphodiesterase 1 (Tdp1), which is capable of cleaving different adducts from the DNA 3 -end restoring its integrity [9]. On the one hand, Tdp1 is overexpressed in some types of cancer, such as non-small lung cancer [10] and glioblastoma [11]. On the other hand, it has been shown that Tdp1 knockout mice and Tdp1-deficient cells are hypersensitive to Top1 inhibitors [12][13][14].…”

Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy

“…Furthermore, increased Tdp1 expression counteracts the cytotoxicity of CPTs [30,31], and is frequently observed in cancers resistant to CPT therapy [31][32][33]. Convincing evidence exists from preclinical studies that the ratio of Tdp1/Top1 activity influences cellular sensitivity to Top1 inhibitors [34,35], and that the suppression of Tdp1 activity leads to an increase in the sensitivity of tumor cells to CPTs [32,[36][37][38][39]. It is believed that targeted short-term treatment with a potent Tdp1 inhibitor will not lead to serious poisoning in normal cells.…”