Human Thymidylate Synthase Inhibitors Halting Ovarian Cancer Growth

Ferrari, Stefania; Severi, Leda; Pozzi, Cecilia; Quotadamo, Antonio; Ponterini, Glauco; Losi, Lorena; Marverti, Gaetano; Costi, Maria Paola

doi:10.1016/bs.vh.2017.12.002

Cited by 12 publications

(9 citation statements)

References 120 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…8 The X-ray crystal structures of the complexes with hTS of the LR peptide showed binding at the monomer–monomer interface of the inactive form of the enzyme ( Figure 1 C). 9 − 11 Kinetic results were consistent with this unusual binding mode and with an inhibition mechanism based on stabilization of the inactive conformation of the enzyme. These peptides represent the only TS inhibitors that bind at the protein–protein interface, cause inhibition of cancer cell growth, and, at the same time, do not induce overexpression of hTS and lead to a reduced expression of the DHFR enzyme.…”

Section: Introductionsupporting

confidence: 70%

Folic Acid–Peptide Conjugates Combine Selective Cancer Cell Internalization with Thymidylate Synthase Dimer Interface Targeting

et al. 2021

Self Cite

View full text Add to dashboard Cite

Drug–target interaction, cellular internalization, and target engagement should be addressed to design a lead with high chances of success in further optimization stages. Accordingly, we have designed conjugates of folic acid with anticancer peptides able to bind human thymidylate synthase (hTS) and enter cancer cells through folate receptor α (FRα) highly expressed by several cancer cells. Mechanistic analyses and molecular modeling simulations have shown that these conjugates bind the hTS monomer–monomer interface with affinities over 20 times larger than the enzyme active site. When tested on several cancer cell models, these conjugates exhibited FRα selectivity at nanomolar concentrations. A similar selectivity was observed when the conjugates were delivered in synergistic or additive combinations with anticancer agents. At variance with 5-fluorouracil and other anticancer drugs that target the hTS catalytic pocket, these conjugates do not induce overexpression of this protein and can thus help combating drug resistance associated with high hTS levels.

show abstract

Section: Introductionsupporting

confidence: 70%

Folic Acid–Peptide Conjugates Combine Selective Cancer Cell Internalization with Thymidylate Synthase Dimer Interface Targeting

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…TOP2A expression is detected in various types of tumors (22), it is typically expressed at high levels in rapidly proliferating cells (23). TYMS is a highly conserved enzyme and essential for cell survival due to its important role in DNA biosynthesis (24)(25)(26). TYMS is also an mRNA-binding protein by binding mRNA to coordinately regulate the cellular gene expression (8).…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of TYMS as a Potential Biomarker for Risk of Metastasis Development in Hepatocellular Carcinoma

Zhao

et al. 2021

Front. Oncol.

View full text Add to dashboard Cite

Metastasis is the major cause of hepatocellular carcinoma (HCC) mortality. Unfortunately, there are few reports on effective biomarkers for HCC metastasis. This study aimed to discover potential key genes of HCC, which could provide new insights for HCC metastasis. GEO (Gene Expression Omnibus) microarray and TCGA (The Cancer Genome Atlas) datasets were integrated to screen for candidate genes involved in HCC metastasis. Differentially expressed genes (DEGs) were screened, and then we performed enrichment analysis of Gene Ontology (GO), together with Kyoto Encyclopedia of Genes and Genomes (KEGG). A protein-protein interaction network was then built and analyzed utilizing STRING and Cytoscape, followed by the identification of 10 hub genes by cytoHubba. Four genes were associated with survival, their prognostic value was verified by prognostic signature analysis. Thymidylate synthase (TYMS) gene was identified as significant HCC metastasis-associated genes after mRNA expression validation and IHC analysis. TYMS silencing in HCC cells remarkedly inhibited growth and invasion. Finally, we found TYMS silencing dramatically decrease DNA synthesis and extracellular matrix (ECM) degradation, resulting in the inhibition of HCC metastasis, indicating TYMS had close associations with HCC development. These findings provided new insights into HCC metastasis and identified candidate gene prognosis signatures for HCC metastasis.

show abstract

“…Studies have shown that overexpression of TS is believed to confer resistance to 5FU-based adjuvant chemotherapy, and has been considerably associated with the poor prognosis of the subset of aggressive solid tumors, including breast, lung, stomach, and colorectal cancer (25,26). Moreover, in many clinical studies, a significant positive correlation was observed between overexpression of TS and resistance to 5-FU in various malignant tumor using 5-FU-based chemotherapy (27,28). Thus, TS overexpression is used as an important independent prognostic factor and a biomarker for evaluating the response or resistance to fluoropyrimidine-based chemotherapy (22,29,30).…”

Section: Discussionmentioning

confidence: 99%

Thymidylate synthase (TS) immunostaining in the diagnosis of the myoepithelial cells, basal cells, stratified epithelium cells, and associated tumors

Guo¹,

Tian²,

Zhang³

et al. 2020

Transl Cancer Res TCR

View full text Add to dashboard Cite

Background: Thymidylate synthase (TS) is an important prognostic biomarker for resistance to 5FUbased adjuvant chemotherapy. Recently, we found that TS was specifically expressed in the nucleus of the myoepithelial cell (MEC), basal cell (BC), transitional epithelial cell (TEC), squamous epithelial cell (SEC), and associated tumor using immunostaining. This prompted us to examine whether TS could be used as a diagnostic biomarker for MEC, BC, TEC, SEC, and associated tumors. Methods: Formalin-fixed, paraffin-embedded specimens from 186 cases of tumors were immunostaining for expression of TS and p63. The diagnostic capability of TS as a reliable diagnostic marker was evaluated and compared with the expression of p63.Results: TS exhibited a strong specific and stable nuclear immunoreactivity in all specimens including MEC, BC, TEC, and SEC when compared with p63. Notably, a variable degree of TS cytoplasmic positive immunoreactivity was observed in 58.3% of squamous-cell carcinoma (SQCC), 37.5% of basal cell carcinoma (BCC), 44.4% transitional-cell carcinomas (TCC), 41.7% mixed tumor (MT) and 56.5% of adenocarcinoma (ADC) specimens. Conclusions:In addition to being used as a strong prognostic factor for 5-FU resistance, TS also serves as a promising putative diagnostic marker for identifying MEC, BC, SEC, and TEC from GEC, and for distinguishing SQCC, BCC, TCC, and MT from ADC.

show abstract

Human Thymidylate Synthase Inhibitors Halting Ovarian Cancer Growth

Cited by 12 publications

References 120 publications

Folic Acid–Peptide Conjugates Combine Selective Cancer Cell Internalization with Thymidylate Synthase Dimer Interface Targeting

Folic Acid–Peptide Conjugates Combine Selective Cancer Cell Internalization with Thymidylate Synthase Dimer Interface Targeting

Identification and Validation of TYMS as a Potential Biomarker for Risk of Metastasis Development in Hepatocellular Carcinoma

Thymidylate synthase (TS) immunostaining in the diagnosis of the myoepithelial cells, basal cells, stratified epithelium cells, and associated tumors

Contact Info

Product

Resources

About