Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aurora kinases play an essential role in the regulation of mitosis. The kinases are overexpressed in a variety of cancer cells and are involved in tumorgenesis. Although aurora kinase inhibitors are potential agents for treatment of leukemia, the establishment of efficacious combination therapies is an attractive approach for making good use of these agents. In this study, we examined the effects of a specific aurora kinase inhibitor, VE-465, in combination with various conventional anti-leukemia agents, including doxorubicin, daunorubicin, idarubicin, mitoxantron, cytosine arabinoside, vincristine and etoposide, on acute myeloid leukemia cell lines (HL60, U937, THP-1 and KY821), chronic myeloid leukemia cell lines (KCL22, K562 and KU812) and primary leukemia cells. We found that a combination of VE-465 and vincristine had a synergistic/additive inhibitory effect on the growth of leukemia cells. VE-465 initially increased G2/M-phase cells, followed by induction of sub-G1 cells. Vincristine enhanced this effect of VE-465. The combination of VE-465 and vincristine increased the levels of cleaved caspase 3, cleaved caspase 7, cleaved caspase 9, cleaved PARP and Phospho-Chk2, suggesting that the combination caused Chk2-mediated activation of the G2/M checkpoint, resulting in sequential induction of apoptosis. Interestingly, the combination markedly decreased the level of Phospho-ERK1/2, suggesting that the combination alters a network of cellular signaling pathways. In contrast, combinations of VE-465 and other agents showed no synergistic inhibitory effect but rather had an antagonistic effect. In conclusion, our results indicate the utility of the combination of VE-465 and vincristine as a potential therapy for myeloid leukemia.
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PMID:Vincristine potentiates the anti-proliferative effect of an aurora kinase inhibitor, VE-465, in myeloid leukemia cells. 2197 83

Emergence of resistance to Tyrosine-Kinase Inhibitors (TKIs), such as imatinib, dasatinib and nilotinib, in Chronic Myelogenous Leukemia (CML) demands new therapeutic strategies. We and others have previously established bortezomib, a selective proteasome inhibitor, as an important potential treatment in CML. Here we show that the combined regimens of bortezomib with mitotic inhibitors, such as the microtubule-stabilizing agent Paclitaxel and the PLK1 inhibitor BI2536, efficiently kill TKIs-resistant and -sensitive Bcr-Abl-positive leukemic cells. Combined treatment activates caspases 8, 9 and 3, which correlate with caspase-induced PARP cleavage. These effects are associated with a marked increase in activation of the stress-related MAP kinases p38MAPK and JNK. Interestingly, combined treatment induces a marked decrease in the total and phosphorylated Bcr-Abl protein levels, and inhibits signaling pathways downstream of Bcr-Abl: downregulation of STAT3 and STAT5 phosphorylation and/or total levels and a decrease in phosphorylation of the Bcr-Abl-associated proteins CrkL and Lyn. Moreover, we found that other mitotic inhibitors (Vincristine and Docetaxel), in combination with bortezomib, also suppress the Bcr-Abl-induced pro-survival signals and result in caspase 3 activation. These results open novel possibilities for the treatment of Bcr-Abl-positive leukemias, especially in the imatinib, dasatinib and nilotinib-resistant CML cases.
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PMID:Combination of bortezomib and mitotic inhibitors down-modulate Bcr-Abl and efficiently eliminates tyrosine-kinase inhibitor sensitive and resistant Bcr-Abl-positive leukemic cells. 2415 50

During the latest decades, the interest on the effectiveness of natural compounds and their impact on human health constantly increased, especially on those demonstrating to be effective on cancer. Molecules coming from nature are currently used in chemotherapy like Taxol, Vincristine or Vinblastine, and several other natural substances have been showed to be active in reducing cancer cell progression and migration. Among them, astaxanthin, a xanthophyll red colored carotenoid, displayed different biological activities including, antinflammatory, antioxidant, proapoptotic, and anticancer effects. It can induce apoptosis through downregulation of antiapoptotic protein (Bcl-2, p-Bad, and survivin) expression and upregulation of proapoptotic ones (Bax/Bad and PARP). Thanks to these mechanisms, it can exert anticancer effects towards colorectal cancer, melanoma, or gastric carcinoma cell lines. Moreover, it possesses antiproliferative activity in many experimental models and enhances the effectiveness of conventional chemotherapic drugs on tumor cells underling its potential future use. This review provides an overview of the current knowledge on the anticancer potential of astaxanthin by modulating several molecular targets. While it has been clearly demonstrated its multitarget activity in the prevention and regression of malignant cells in in vitro or in preclinical investigations, further clinical studies are needed to assess its real potential as anticancer in humans.
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PMID:Astaxanthin anticancer effects are mediated through multiple molecular mechanisms: A systematic review. 3205 95