| Centchroman mediated apoptosis involves cross-talk between extrinsic/intrinsic pathways and oxidative regulation. | |
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MedLine Citation:
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PMID: 21034746 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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AIMS: Centchroman (CC) has been established as a potent antineoplastic agent in MCF-7 (ER+ve) and MDA MB-231 (ER-ve) Human Breast Cancer Cells (HBCCs) previously by us. To elucidate its antineoplastic action, we investigated the factors involved in cell-cycle progression and apoptosis. MAIN METHODS: Tamoxifen (TAM), a widely used antiestrogen was employed as a positive control. Role of Cycloheximide (CHX), Actinomycin-D (Act-D) and caspases were explored using specific inhibitors. Involvement of cell-cycle and apoptosis related factors were explored using western blotting and immunoprecipitation. KEY FINDINGS: Metabolic inhibitors viz. CHX, Act-D and pan-Caspase inhibitor, Z-VAD-FMK attenuated CC-induced apoptosis. The upregulation of both p21(Waf1/Cip1) and p27(Kip1) along with p21-CDK6 (Cyclin Dependent Kinase 6) and p21-PCNA (Proliferating Cell Nuclear Antigen) interaction suggests their role in CC-induced cell-cycle arrest. The downregulation of Cyclin-D(1) and -E levels further confirms the antiestrogenic profile of CC. Unlike MDA MB-231, in MCF-7 cells, CC upregulates the level of phospho-p53 (Ser-15) and FasL, suggesting the involvement of extrinsic pathway. CC altered the intracytosolic balance of members of Bcl-2 family along with the cleavage of Poly (ADP-ribose) polymerase (PARP), Bcl-X(L), Bid and AIF (Apoptosis Inducing Factor). The evaluation of Mitogen Activated Protein Kinases (MAPKs) using specific inhibitors and Western blotting confirms CC-induced the upregulation of phospho-c-Jun and phospho-p38. Additionally elevated SOD (Superoxide Dismutase) and unaltered CAT (Catalase) expression further suggest the involvement of oxidative stress. SIGNIFICANCE: These results confirm that the antineoplasticity of CC in MCF-7 and MDA MB-231 cells involves the extrinsic and intrinsic pathways of apoptosis along with oxidative stress. |
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Authors:
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Manisha Nigam; Neetu Singh; Vishal Ranjan; Deeba Zaidi; Ramesh Sharma; Deepti Nigam; Dwijendra Kumar Gupta; Shanthy Sundaram; Anil Kumar Balapure |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't Date: 2010-10-27 |
Journal Detail:
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Title: Life sciences Volume: 87 ISSN: 1879-0631 ISO Abbreviation: Life Sci. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-11-29 Completed Date: 2010-12-22 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0375521 Medline TA: Life Sci Country: Netherlands |
Other Details:
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Languages: eng Pagination: 750-8 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Tissue and Cell Culture Unit (TCCU), Central Drug Research Institute, Council of Scientific & Industrial Research, Lucknow, India-226001. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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pharmacology* Apoptosis / drug effects* Breast Neoplasms / drug therapy*, pathology Caspases / metabolism Cell Cycle / drug effects Cell Line, Tumor Centchroman / pharmacology* Cycloheximide / pharmacology Dactinomycin / pharmacology Down-Regulation / drug effects Estrogen Antagonists / pharmacology* Female Humans Immunoprecipitation Oxidative Stress / drug effects Tamoxifen / pharmacology Up-Regulation / drug effects |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Estrogen Antagonists; 10540-29-1/Tamoxifen; 31477-60-8/Centchroman; 50-76-0/Dactinomycin; 66-81-9/Cycloheximide; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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