Document Detail


HIV-1 Tat peptide immunoconjugates differentially sensitize breast cancer cells to selected antiproliferative agents that induce the cyclin-dependent kinase inhibitor p21WAF-1/CIP-1.
MedLine Citation:
PMID:  16984139     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In this study, we evaluated the ability of anti-p21 antibodies conjugated to 17-mer peptides [GRKKRRQRRRPPQGYGC] harboring the membrane-translocating and nuclear import sequences [underlined] of HIV-1 tat protein to inhibit the cyclin-dependent kinase inhibitor, p21(WAF-1/Cip-1) (p21) and differentially sensitize MDA-MB-468 and MCF-7 human breast cancer (BC) cells to the antiproliferative effects of treatments that induce or do not induce p21. BC cells were treated with increasing concentrations of epidermal growth factor (EGF; 0.5-10 nM), the topoisomerase I inhibitor, camptothecin (CPT; 0.1-4 muM), or increasing doses of gamma-radiation (2-20 Gy). Western blot was used to evaluate p21 expression. The effect of treatment on cell cycle distribution was studied. Growth inhibition was measured by the WST-1 assay. Expression of p21 was increased in MDA-MB-468 cells treated with EGF or CPT but not by gamma-irradiation. MCF-7 cells exhibited p21 upregulation following exposure to CPT and gamma-radiation but not EGF. EGF caused cell cycle arrest in G(1) phase for MDA-MB-468 cells. CPT caused G(1)-phase arrest in MDA-MB-468 cells and prolonged S phase in MCF-7 cells. gamma-Radiation caused an increase in cells in G(2)/M phase for MDA-MB-468 and MCF-7. MDA-MB-468 cells were growth-inhibited by EGF, CPT, and gamma-radiation. MCF-7 cells were growth-stimulated by EGF and inhibited by CPT and gamma-radiation. Combining EGF with tat-anti-p21 immunoconjugates (ICs) amplified the growth-inhibitory effect on MDA-MB-468 cells 1.2-fold to 2.3-fold, but had no effect on the growth stimulation of MCF-7 cells by EGF. Tat-anti-p21 ICs sensitized MCF-7 cells 1.4-fold to gamma-radiation but had no effect on the growth of gamma-irradiated MDA-MB-468 cells. Tat-anti-p21 ICs sensitized both MDA-MB-468 and MCF-7 cells 1.7-fold to CPT. We conclude that tat-anti-p21 ICs are promising sensitizers for cytotoxic cancer therapies and that their sensitization is dependent on treatment-related p21 expression. This general approach could potentially be extended to other growth-regulatory molecules that are associated with tumor growth and progression.
Authors:
Meiduo Hu; Judy Wang; Paul Chen; Raymond M Reilly
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Bioconjugate chemistry     Volume:  17     ISSN:  1043-1802     ISO Abbreviation:  Bioconjug. Chem.     Publication Date:    2006 Sep-Oct
Date Detail:
Created Date:  2006-09-20     Completed Date:  2007-05-15     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  9010319     Medline TA:  Bioconjug Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1280-7     Citation Subset:  IM    
Affiliation:
Division of Nuclear Medicine, University Health Network, Toronto, Canada.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Antibodies / genetics,  metabolism*
Antineoplastic Agents / metabolism*,  therapeutic use
Breast Neoplasms / drug therapy,  metabolism*
Cell Cycle / physiology
Cell Line, Tumor
Cell Proliferation
Cyclin-Dependent Kinase Inhibitor p21 / genetics,  metabolism*
Dose-Response Relationship, Drug
Female
Gene Expression Regulation
Gene Products, tat / genetics,  metabolism*
HIV-1
Humans
Immunoconjugates / genetics,  metabolism*,  therapeutic use
Molecular Sequence Data
Peptide Fragments / genetics,  metabolism*
tat Gene Products, Human Immunodeficiency Virus
Chemical
Reg. No./Substance:
0/Antibodies; 0/Antineoplastic Agents; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Gene Products, tat; 0/Immunoconjugates; 0/Peptide Fragments; 0/tat Gene Products, Human Immunodeficiency Virus

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