Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.4.4 (kinesin)
 5,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Castrate-resistant prostate cancer remains a major clinical challenge. Due to the toxicity profile of taxane-based chemotherapy and treatment failure in some patients, novel agents with improved efficacy to side effect profiles are urgently needed. Eg5, a member of the kinesin-5 family, controls the formation of the bipolar spindle during cell division, and suppressed Eg5 function leads to mitotic arrest. S-Trityl-L-cysteine (STLC) is a novel Eg5-specific small-molecule inhibitor. Here, we report the first study to evaluate its use in prostate cancer. In a panel of prostate cancer cells, LNCaP and PC3 cells were the most and least sensitive to STLC treatment, with a 7.2-fold difference in their respective GI(50) values: 250 nmol/L and 1.8 micromol/L. In LNCaP cells, treatment with either STLC or docetaxel resulted in transient G(2)-M arrest and subsequent caspase-mediated cell death. However, STLC- and docetaxel-treated PC3M cells have distinct fates: STLC induced a transient G(2)-M arrest, followed by polyploidy; in contrast, docetaxel-treated PC3M cells progressed to apoptosis after a transient G(2)-M arrest. Docetaxel-resistant LNCaP-derived (LDocR) cells respond to STLC in a similar manner to the parental cells. Although the docetaxel-resistant PC3M-derived (PDocR) cell line and its parental PC3M cells have similar GI(50) to STLC treatment, PDocR cells showed significantly more G(2)-M arrest and less apoptosis. Hence, although docetaxel-resistant prostate cancer cells remain responsive to Eg5 inhibition with STLC, there are key differences at the cell cycle level, which may have implication in future development.
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PMID:Docetaxel-resistant prostate cancer cells remain sensitive to S-trityl-L-cysteine-mediated Eg5 inhibition. 2051 52

Docetaxel-based combination chemotherapy remains the predominant treatment for castration-resistant prostate cancer. However, taxane-related drug resistance and neurotoxicity have prompted us to develop substitute treatment strategies. Eg5 (kinesin spindle protein), which is crucial for bipolar spindle formation and duplicated chromosome separation during the early phase of mitosis, has emerged as an attractive target for cancer chemotherapy. The aim of this study was to investigate the anticancer efficacy of S-(methoxytrityl)-L-cysteine (S(MeO)TLC), a novel Eg5 inhibitor in prostate cancer. Eg5 expression was examined in human prostate cancer cell lines and tissue microarrays were constructed from clinical specimens. Antiproliferative activity of S(MeO)TLC in prostate cancer cells was assessed by a cell viability assay. The anticancer effect and inhibitory mechanism of S(MeO)TLC in prostate cancer cells was further explored by Hoechst staining, flow cytometry and immunofluorescence. In addition, the antitumor effect of S(MeO)TLC on subcutaneous xenograft models was assessed. Eg5 expression was identified in PC3, DU145 and LNCaP cells. More than half of prostate cancer clinical specimens displayed Eg5 expression. S(MeO)TLC exhibited more powerful anticancer activity in prostate cancer cells compared with the other four Eg5 inhibitors tested. S(MeO)TLC induced cell death after arresting dividing cells at mitosis with distinct monopolar spindle formation. S(MeO)TLC exhibited its significant inhibitory activity (P<0.05) on subcutaneous xenograft models also through induction of mitotic arrest. We conclude that Eg5 is a good target for prostate cancer chemotherapy, and S(MeO)TLC is a potent promising anticancer agent in prostate cancer.
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PMID:A potent chemotherapeutic strategy in prostate cancer: S-(methoxytrityl)-L-cysteine, a novel Eg5 inhibitor. 2131 14

Antimitotic agents are widely used in cancer chemotherapy but the numerous side effects and the onset of resistance limit their clinical efficacy. Therefore, with the purpose of discovering more selective and efficient anticancer agents to be administered alone or in combination with traditional drugs, we synthesized a large library of 1,3,4-thiadiazoline analogues, maintaining the pharmacophoric structure of an antiproliferative compound known as K858: this is a new inhibitor of kinesin Eg5, able to induce the mitotic arrest in colorectal cancer cells and in xenograft ovarian cancer cells. We screened 103 compounds to assess their antiproliferative activity on PC3 prostate cancer cell line. Two derivatives, compounds 32 (corresponding to K858) and 33, have shown to be the most effective against prostate tumor cells and also towards two melanoma cell lines (SK-MEL-5 and SK-MEL-28) at low micromolar concentrations, confirming the pharmacological activity of this scaffold and revealing the potential role of 1,3,4-thiadiazolines in the management of cancer.
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PMID:Synthesis and pharmacological screening of a large library of 1,3,4-thiadiazolines as innovative therapeutic tools for the treatment of prostate cancer and melanoma. 2649 71