Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report that all- trans retinoic acid (ATRA) enhanced the toxicity of docetaxel against DU145 and LNCaP prostate cancer cells, and that the nature of the interaction between ATRA and docetaxel was highly synergistic. Docetaxel-induced apoptotic cell death was associated with phosphorylation and hence inactivation of Bcl-2. ATRA enhanced docetaxel-induced apoptosis and combined treatment with ATRA and docetaxel resulted in down-regulation of Bcl-2. Docetaxel caused phosphorylation and hence inactivation of cdc2 kinase result ing in G2/M arrest. ATRA inhibited docetaxel-induced phosphorylation of cdc2 resulting in activation of cdc2 kinase and partial reversal of the G2/M arrest. ATRA also inhibited docetaxel-induced activation of MAPK indicating that the effects of docetaxel and ATRA on cdc2 phosphorylation are dependent on MAPK. We conclude that ATRA synergistically enhances docetaxel toxicity by down-regulating Bcl-2 expression and partially reverses the docetaxel-induced G2/M arrest by inhibiting docetaxel-induced cdc2 phosphorylation in a pathway that is dependent on MAPK.
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PMID:Modulation of docetaxel-induced apoptosis and cell cycle arrest by all- trans retinoic acid in prostate cancer cells. 1138 10

Gastric cancer is one of the leading causes of cancer death throughout the world. It is a disease in desperate need of new therapeutic approaches. Docetaxel, a semisynthetic taxane, has shown potent activity against a broad range of solid tumors. However, in gastric cancer, response rates to docetaxel remain only approximately 20%. In these studies we show that flavopiridol, a cyclin-dependent kinase inhibitor, potentiates docetaxel-induced apoptosis 3-fold in MKN-74 human gastric cells. This effect is sequence dependent, such that flavopiridol must follow docetaxel to induce this effect. Docetaxel induces transient arrest in the M phase of the cell cycle. Cells exit mitosis in a specific time window without cytokinesis with a decrease in cyclin B1/cdc-2 kinase activity and MPM-2 labeling. Flavopiridol treatment of docetaxel-treated cells enhances the exit from mitosis with a more rapid decrease in mitotic markers including MPM-2 labeling and cyclin B1/cdc2 kinase activity. In contrast, pretreatment with flavopiridol prevents cells from entering mitosis by inhibiting cyclin B1/cdc-2 kinase activity, thus antagonizing the docetaxel effect. The testing of this combination against MKN-74 xenografts confirms the sequence dependency. Treatment of MKN-74 tumor-bearing xenografts with docetaxel at a dose of 10 mg/kg followed 3-7 h later by flavopiridol at a dose of 2.5 mg/kg resulted in a 1-18% decrease in tumor volume. In contrast, treatment with docetaxel alone at this same dose resulted in a 394% increase in tumor volume. When flavopiridol was given immediately after docetaxel, the effect was not statistically different from that of docetaxel alone. The reverse combination of flavopiridol followed 7 h later by docetaxel was similar to treatment with docetaxel alone. Flavopiridol alone had no effect in this tumor model. Thus, flavopiridol, when combined with docetaxel in a sequence-specific manner, may provide a completely new therapeutic approach in the treatment of gastric cancer.
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PMID:Flavopiridol enhances the effect of docetaxel in vitro and in vivo in human gastric cancer cells. 1281 34

The Bmal1 gene plays a key role in controlling circadian rhythms. To better understand how the Bmal1 gene affects tumour growth and the response to anti-cancer drugs, we examined the effect of knockdown of Bmal1 by RNAi both in vitro and in vivo. Down-regulation of Bmal1 gene expression accelerated cell proliferation in vitro and promoted tumour growth in mice. Suppressing Bmal1 expression in murine colon cancer cells (C26) and fibroblast cells (L929) decreased apoptosis induced by Etoposid, reduced the distribution of cells in the G2/M phases treated by Docetaxel and decreased DNA damage induced by Cisplatin. Loss of Bmal1 reduced the expression of per1, per2, per3, wee1 and p53. The expression of p21 and c-myc was also altered in certain cell lines. However, Bmal1 deficiency increased the protein levels of cdc2, cyclin B1, cyclin D1 and cyclin E. Wee1 and cyclin A expression was minimally altered. Thus, the circadian clock gene Bmal1 plays a role in regulating tumour cell apoptosis, cell-cycle progression and DNA damage response and in homoeostasis regulation. Down-regulation of Bmal1 accelerates the development of tumours and may influence the response to anti-cancer drugs.
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PMID:Effects of the biological clock gene Bmal1 on tumour growth and anti-cancer drug activity. 2057 19