| Inhibition of the CaM-kinases augments cell death in response to oxygen radicals and oxygen radical inducing cancer therapies in MCF-7 human breast cancer cells. | |
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MedLine Citation:
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PMID: 16855386 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Many cancer treatments induce cell death through lethal oxidative stress. Oxidative stress also induces the activation of the calcium/calmodulin-dependent kinases (CaM-Ks), CaM-KII and CaM-KIV. In turn, the CaM-Ks are known to induce the activation of antiapoptotic signaling pathways, such as Akt, ERK, and NF-kappaB in many different cell types. The aim of this study was to determine the role of CaM-Kinases in resistance to hydrogen peroxide and three oxidative stress-inducing cancer therapies in MCF-7 breast cancer cells. We found that oxidative stress induced CaM-Kinase activity in MCF-7 breast cancer cells and that CaM-K inhibition increased hydrogen peroxide-induced cell death in MCF-7 human breast cancer cells. When MCF-7 cells were treated with doxorubicin, ionizing radiation, or photodynamic therapy in the presence of a CaM-K inhibitor a greater level of cell killing was observed than when cells were treated with doxorubicin, ionizing radiation, or photodynamic therapy alone. In support of this finding, CaM-K inhibition increased hydrogen peroxide-induced apoptosis in MCF-7 cells, as determined by increased number of apoptotic cells, DNA fragmentation, and PARP cleavage. Pharmacological and molecular inhibition indicated that CaM-KII was participating in hydrogen peroxide-induced ERK phosphorylation in breast cancer cells indicating a potential mechanism by which this sensitization occurs. This is the first time that CaM-K inhibition is reported to sensitize cancer cells to reactive oxygen intermediate inducing cancer treatments. |
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Authors:
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Oswaldo G Rodriguez-Mora; Michelle M Lahair; Mark J Evans; Charles J Kovacs; Ron R Allison; Claudio H Sibata; Kawana S White; James A McCubrey; Richard A Franklin |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2006-08-18 |
Journal Detail:
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Title: Cancer biology & therapy Volume: 5 ISSN: 1538-4047 ISO Abbreviation: Cancer Biol. Ther. Publication Date: 2006 Aug |
Date Detail:
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Created Date: 2006-10-13 Completed Date: 2007-01-08 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 101137842 Medline TA: Cancer Biol Ther Country: United States |
Other Details:
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Languages: eng Pagination: 1022-30 Citation Subset: IM |
Affiliation:
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Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, North Carolina 27834, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antibiotics, Antineoplastic
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pharmacology Apoptosis* Breast Neoplasms / enzymology*, pathology, therapy Calcium-Calmodulin-Dependent Protein Kinase Type 1 Calcium-Calmodulin-Dependent Protein Kinase Type 2 Calcium-Calmodulin-Dependent Protein Kinase Type 4 Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors*, genetics, metabolism Doxorubicin / pharmacology Flow Cytometry Humans Hydrogen Peroxide / pharmacology Immunoblotting Mitogen-Activated Protein Kinase 3 / metabolism Oxidants / pharmacology Oxidative Stress Phosphorylation / drug effects Photochemotherapy RNA, Small Interfering / pharmacology Radiation, Ionizing Reactive Oxygen Species / metabolism, pharmacology* Tumor Cells, Cultured |
| Grant Support | |
ID/Acronym/Agency:
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R01 CA51025/CA/NCI NIH HHS; R01 CA98195/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antibiotics, Antineoplastic; 0/Oxidants; 0/RNA, Small Interfering; 0/Reactive Oxygen Species; 23214-92-8/Doxorubicin; 7722-84-1/Hydrogen Peroxide; EC 2.7.11.17/CAMK1 protein, human; EC 2.7.11.17/CAMK4 protein, human; EC 2.7.11.17/Calcium-Calmodulin-Dependent Protein Kinase Type 1; EC 2.7.11.17/Calcium-Calmodulin-Dependent Protein Kinase Type 2; EC 2.7.11.17/Calcium-Calmodulin-Dependent Protein Kinase Type 4; EC 2.7.11.17/Calcium-Calmodulin-Dependent Protein Kinases; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3 |
| Comments/Corrections | |
Comment In:
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Cancer Biol Ther. 2006 Aug;5(8):1031-2
[PMID:
16998304
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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