Targeting of topoisomerases for prognosis and drug resistance in ovarian cancer

Abstract

BackgroudAs magicians of the DNA world, topoisomerases resolve all of the topological problems in relation to DNA during a variety of genetic processes. While the prognostic value of topoisomerase isoenzymes in epithelial ovarian carcinoma (EOC) is still elusive. In current study, we investigated the prognostic value of topoisomerase isoenzymes in the EOC patients. Kaplan Meier plotter (KM plotter) database were used to assess the relevance of individual topoisomerase isoenzyme mRNA expression to EOC patients overall survival (OS), in which updated survival information and gene expression data were from a total of 1,648 EOC patients.ResultsHigh expression of TOP1 and TOP2A were found to be correlated to worse OS in all patients and serous patients, but not in endometrioid patients. Contrary to TOP1 and TOP2A, TOP3A and TOP3B expression were associated with better OS in all patients and serous patients, but not in endometrioid patients. While TOP2B were not found any significant prognostic value for EOC patients. From the Oncomine database, we also found widespread upregulation in the expression of TOP1 and TOP2A genes in primary tumor tissues. Albeit limited in number, all datasets exhibiting differential expression showed TOP3A and TOP3B under-regulated.ConclusionThese results strongly supported that TOP1 and TOP2A were potential biomarkers for predicting poor survival of EOC patients, while TOP3A and TOP3B were expected to be further exploited as tumor suppressors. Comprehensive understanding of the topoisomerase isoforms may have guiding significance for the diagnosis treatment and prognosis in EOC patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13048-016-0244-9) contains supplementary material, which is available to authorized users.

Topoisomerase 1B poisons: Over a half‐century of drug leads, clinical candidates, and serendipitous discoveries

“…46 It was also suggested recently that Top1 may be a biomarker for poor prognosis in grade III endothelial ovarian cancer patients. 47 Taken together, these results suggest that Top1 may be a promising target for therapeutic intervention in cancer.…”

“…Zhao et al found by reverse transcription polymerase chain reaction (RT‐PCR) that high levels of Top1 correlated with reduced disease‐free survival in breast cancer patients (not treated with Top1 poisons), while other studies have correlated high Top1 with reduced survival in postoperative nonsmall‐cell lung cancer patients and poor prognosis in ovarian cancer . It was also suggested recently that Top1 may be a biomarker for poor prognosis in grade III endothelial ovarian cancer patients . Taken together, these results suggest that Top1 may be a promising target for therapeutic intervention in cancer.…”

“…A virtual screen using the Top1‐DNA crystal structure independently identified 43 as a potential Top1 poison, and N ‐benzoyl derivatives prepared by Dong et al have improved cytotoxicity . The cytotoxic and apoptosis‐inducing activity of 43 was confirmed in 2015, and 100 mg/kg 43 prevents tumor growth in ovarian tumor xenografts in mice . Interestingly, Cai et al discovered that the SAR of the closely‐related tetrahydroangustines overlaps with that of 43 , with N ‐benzoylation conferring the best activity, although the proposed binding mode (with the benzoyl group facing the major groove) differs from that proposed for the analogs prepared by Dong et al Recently, the Zhang and Sheng groups (Second Military Medical University/Fujian University, China) discovered that amino and hydroxyl derivatives of 43 are very cytotoxic dual Top1/Top2 poisons .…”

“…239 The cytotoxic and apoptosis-inducing activity of 43 was confirmed in 2015, and 100 mg/kg 43 prevents tumor growth in ovarian tumor xenografts in mice. 47 Interestingly, Cai et al 244 Fujian University, China) discovered that amino and hydroxyl derivatives of 43 are very cytotoxic dual Top1/Top2 poisons. 245 These compounds were also optimized to inhibit tubulin polymerization 246 or histone deacetylase 247 in addition to poisoning topoisomerases, providing cytotoxic agents with multiple mechanisms of action.…”

Distinct prognostic roles of HSPB1 expression in non-small cell lung cancer

“…By using the genome sequencing and bioinformatics approaches, TCGA catalogues genetic mutations responsible for various cancers, and this provides a rich source for investigators to analyze the potential mechanism of cancer pathogenesis. The "Kaplan-Meier plotter" (KM plotter), established using the gene expression data and relapse free and overall survival information downloaded from TCGA, as well as The European Genome-phenome Archive (EGA) and Gene Expression Omnibus (GEO) [9]. KM plotter has been reported to analyze the prognostic value of a particular gene and potential drug targets in NSCLC and other cancers [10][11][12][13][14].…”