Document Detail


8-Amino-adenosine activates p53-independent cell death of metastatic breast cancers.
MedLine Citation:
PMID:  22973058     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
8-Amino-adenosine (8-NH(2)-Ado) is a ribose sugar nucleoside analogue that reduces cellular ATP levels and inhibits mRNA synthesis. Estrogen receptor-negative (ER-) metastatic breast cancers often contain mutant p53; therefore, we asked if 8-NH(2)-Ado could kill breast cancer cells without activating the p53-pathway. Regardless of the breast cancer subtype tested or the p53 status of the cells, 8-NH(2)-Ado was more cytotoxic than either gemcitabine or etoposide. 8-NH(2)-Ado treatment inhibited cell proliferation, activated cell death, and did not activate transcription of the p53 target gene p21 or increase protein levels of either p53 or p21. This occurred in the estrogen receptor-positive (ER+) MCF-7 cells that express wild-type p53, the ER+ T47-D cells that express mutant p53, and the ER- MDA-MB-468 cells or MDA-MB-231 cells that both express mutant p53. 8-NH(2)-Ado induced apoptotic death of MCF-7 cells and apoptosis was not inhibited by knockdown of functional p53. Moreover, the pan-caspase inhibitor Z-VAD blocked the 8-NH(2)-Ado-induced MCF-7 cell death. Interestingly, 8-NH(2)-Ado caused the MDA-MB-231 cells to detach from the plate with only limited evidence of apoptotic cell death markers and the cell death was not inhibited by Z-VAD. Inhibition of MDA-MB-231 cell autophagy, by reduction of ATG7 or 3-methyladenine treatment, did not block this 8-NH(2)-Ado-mediated cytotoxicity. Importantly 8-NH(2)-Ado was highly cytotoxic to triple-negative breast cancer cells and worked through a pathway that did not require wild-type p53 for cytoxicity. Therefore, 8-NH(2)-Ado should be considered for the treatment of triple-negative breast cancers that are chemotherapy resistant.
Authors:
Alla Polotskaia; Sandy Hoffman; Nancy L Krett; Mala Shanmugam; Steven T Rosen; Jill Bargonetti
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-09-12
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  11     ISSN:  1538-8514     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-12     Completed Date:  2013-04-23     Revised Date:  2013-11-06    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2495-504     Citation Subset:  IM    
Copyright Information:
©2012 AACR.
Affiliation:
Department of Biological Sciences, Hunter College, CUNY, 695 Park Ave., New York, NY 10065, USA.
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MeSH Terms
Descriptor/Qualifier:
Adenosine / analogs & derivatives*,  pharmacology
Antineoplastic Agents / pharmacology
Autophagy / drug effects
Breast Neoplasms / metabolism*,  pathology*
Caspase Inhibitors / pharmacology
Cell Death / drug effects
Cell Line, Tumor
Cyclin-Dependent Kinase Inhibitor p21 / genetics
Doxycycline / chemistry,  pharmacology
Female
Humans
Mutant Proteins / metabolism
Neoplasm Metastasis
Oligopeptides / pharmacology
Receptors, Estrogen / metabolism
Signal Transduction / drug effects
Transcription, Genetic / drug effects
Tumor Suppressor Protein p53 / metabolism*
Grant Support
ID/Acronym/Agency:
1SC1CA137843/CA/NCI NIH HHS; G12 MD007599/MD/NIMHD NIH HHS; G12 RR003037/RR/NCRR NIH HHS; RR003037/RR/NCRR NIH HHS; SC1 CA137843/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Caspase Inhibitors; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Mutant Proteins; 0/Oligopeptides; 0/Receptors, Estrogen; 0/Tumor Suppressor Protein p53; 0/benzyloxycarbonyl-valyl-alanyl-aspartic acid; 3868-33-5/8-aminoadenosine; 564-25-0/Doxycycline; 58-61-7/Adenosine
Comments/Corrections

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