TYMS (Thymidylate Synthetase)

5-Fluorouracil (5-FU) and its prodrugs are widely used drugs for chemotherapy in various cancers. In conclusion, our study reveals that everolimus sensitizes breast cancer to fluoropyrimidines by destabilizing TYMS through modulation of its O-GlcNAcylation. These findings support a promising combination strategy to improve the therapeutic efficacy of 5-FU and capecitabine in breast cancer.

Against breast cancer cells, 6m displayed ~3-fold superior activity than 5-fluorouracil while against pancreatic cancer cells, it exhibited comparable to superior activity...ADME analysis proposes favorable features for good oral bioavailability. This study ascertains 6m as a promising lead for further biological evaluation and structural optimization toward the development of potential anticancer agents against pancreatic and breast cancers.

Molecular docking, molecular dynamics simulations, and MM-GBSA analyses supported stable binding of the active compounds within the catalytic sites of the investigated enzymes. Overall, these findings identify compounds 1, 9, 12, and 13 as promising multi-target anticancer leads warranting further optimization and development.

Mechanistically, NFATC2 transcriptionally activates CST1, which subsequently abrogates senescence through SOX4 stabilization; ectopic SOX4 expression rescues senescence induced by CST1 depletion. These findings establish CST1 as a promising therapeutic target and provide mechanistic insights for CCA intervention strategies.

Parabens may promote HNSCC progression by disrupting cell cycle regulation and immune responses via direct interactions with key hub genes. These findings provide a novel mechanistic basis for the carcinogenic potential of parabens in HNSCC and underscore the need for further experimental and epidemiological validation.

Our study identifies SMC4 as a regulator that promotes radioresistance and potentially modulates the tumor immune microenvironment in cervical cancer, likely by coordinating DNA damage repair and activating the SMAD3-NF-κB pathway. These findings suggest that SMC4 could be a potential therapeutic target for radiosensitization and a candidate biomarker for patient stratification.

Background: Colorectal and pancreatic cancers remain therapeutically challenging, with limitations in efficacy and limitations due to toxicity from conventional antimetabolites such as 5-fluorouracil (5-FU), methotrexate (MTX), and gemcitabine (GEM). Lactam steroidal antimetabolite hybrids, particularly CS23, act as dual TS/DHFR inhibitors, inducing apoptosis and cell cycle arrest with improved selectivity. Their strong in silico-in vitro concordance provides a compelling preclinical rationale for further evaluation of steroidal antimetabolites as next-generation therapeutics for resistant gastrointestinal malignancies.

In vitro, BPA and DEP (but not DMP/DOP) increased colony formation (p < 0.01), accelerated wound closure, upregulated oncogenic genes (e.g., CDK2/MET/CCNA2; p < 0.05), and elevated p-MEK without changing total MEK in 5-8 F and TPC-1 cells. Collectively, BPA and DEP promote head and neck tumor progression through MEK pathway activation and cell-cycle dysregulation.

ADA, NT5E and TYMS can serve as potential diagnostic markers and therapeutic targets for OSCC. The study has reference value for early diagnosis and the development of individualised treatment strategies.

Capecitabine is an oral prodrug that is converted to 5-FU via three enzyme-catalysed steps: carboxylesterase (CES), cytidine deaminase (CDA), and thymidine phosphorylase (TYMS). After recovery and follow-up, she continued to receive 5-FU, leucovorin, and oxaliplatin therapy which she tolerated well and completed six months of therapy. This case shows that the severe adverse effects of capecitabine therapy in a patient with a CDA ultrametabolizer profile can be successfully switched to 5-FU-based therapy at a normal dose and tolerate this alternative fluoropyrimidine.

Our findings suggest that MBZ modulates nucleotide synthesis pathways, contributing to its selective antiproliferative effects in GC cells. This study highlights potential new pharmacological targets for drug repurposing and further investigation into the broader therapeutic applications of MBZ.