Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.21 (thymidine kinase)
 7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two 5-fluorouracil (5-FU)-resistant cell lines from a Korean gastric cancer cell line were established by incubation of the cells with increasing concentration of 5-FU, and the resultant cell lines showed an over 800-fold increased resistance to 5-FU. To identify the mechanism of 5-FU resistance, the expressions of genes involved in 5-FU metabolism were examined by reverse transcriptase-polymerase chain reaction (RT-PCR). Expressions of orotate phosphoribosyltransferase (OPRT), thymidine phosphorylase (TP), and uridine phosphorylase (UP) were significantly downregulated in these cell lines, resulting in low incorporation of 5-FU into nucleic acids. In contrast, an increased expression of thymidine kinase (TK) was observed in 5-FU-resistant cells. These results strongly indicate that blocking of 5-FU incorporation into nucleic acids and TK overexpression may play a major role in 5-FU resistance in these cells. Interestingly, these cell lines showed cross-resistance to paclitaxel, cisplatin, and doxorubicin, suggesting that other factors such as HSP27 and Mn-SOD could be also involved in the mechanism of multidrug resistance in these cell lines.
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PMID:Establishment and characterization of 5-fluorouracil-resistant gastric cancer cells. 1097 11

Drug resistance is an important open problem in cancer treatment. In recent years, the heat shock protein HSP27 (HSPB1) was identified as a key player driving resistance development. HSP27 is overexpressed in many cancer types and influences cellular processes such as apoptosis, DNA repair, recombination, and formation of metastases. As a result cancer cells are able to suppress apoptosis and develop resistance to cytostatic drugs. To identify HSP27 inhibitors we follow a novel computational drug repositioning approach. We exploit a similarity between a predicted HSP27 binding site to a viral thymidine kinase to generate lead inhibitors for HSP27. Six of these leads were verified experimentally. They bind HSP27 and down-regulate its chaperone activity. Most importantly, all six compounds inhibit development of drug resistance in cellular assays. One of the leads - chlorpromazine - is an antipsychotic, which has a positive effect on survival time in human breast cancer. In summary, we make two important contributions: First, we put forward six novel leads, which inhibit HSP27 and tackle drug resistance. Second, we demonstrate the power of computational drug repositioning.
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PMID:New HSP27 inhibitors efficiently suppress drug resistance development in cancer cells. 2762 87