Document Detail


STI571 sensitizes breast cancer cells to 5-fluorouracil, cisplatin and camptothecin in a cell type-specific manner.
MedLine Citation:
PMID:  19427998     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Previously, we demonstrated that Abl kinases are highly active in invasive breast cancer cell lines, and contribute to survival in response to nutrient deprivation, invasion and proliferation. To determine whether an Abl kinase inhibitor, STI571 (Gleevec; imatinib mesylate) sensitizes breast cancer cells to chemotherapeutic agents, we treated three breast cancer cell lines (BT-549, MDA-MB-231, and MDA-MB-468) that have active Abl kinases, with STI571 in combination with several conventional chemotherapeutic drugs frequently used to treat breast cancer, and assessed the effect on cell viability, proliferation, and apoptosis. We found that STI571 had synergistic effects with cisplatin in BT-549 and to some extent in MDA-MB-468 cells; synergized with camptothecin using an alternate dosing regimen in MDA-MB-231 cells; and STI571 synergistically sensitized MDA-MB-468 cells to paclitaxel and to high doses of 5-fluorouracil. Significantly, STI571 increased the ability of cisplatin to inhibit constitutive activation of PI3K/Akt in BT-549 cells, synergized with camptothecin to increase the stability of IkappaB in MDA-MB-231 cells, and in MDA-MB-468 cells, camptothecin and 5-fluorouracil inhibited STI571-dependent activation of STAT3. In other cell line/drug combinations, STI571 had additive or antagonistic effects, indicating that the ability of STI571 to sensitize breast cancer cells to chemotherapeutic agents is cell type-dependent. Significantly, unlike cisplatin, paclitaxel, and camptothecin, mechloroethamine was strongly antagonistic to STI571, and the effect was not cell line-dependent. Taken together, these data indicate that the cellular milieu governs the response of breast cancer cells to STI571/chemotherapeutic combination regimens, which suggests that treatment with these combinations requires individualization.
Authors:
Jonathan T Sims; Sourik Ganguly; Leann S Fiore; Chris J Holler; Eun-Sil Park; Rina Plattner
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-04-14
Journal Detail:
Title:  Biochemical pharmacology     Volume:  78     ISSN:  1873-2968     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-06-01     Completed Date:  2009-06-22     Revised Date:  2011-05-05    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  249-60     Citation Subset:  IM    
Affiliation:
Department of Molecular and Biomedical Pharmacology, 209 Combs Research Building, University of Kentucky School of Medicine, Lexington, KY 40536, USA.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology*
Camptothecin / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Cisplatin / pharmacology*
Drug Synergism
Fluorouracil / pharmacology*
Humans
Piperazines / pharmacology*
Pyrimidines / pharmacology*
Grant Support
ID/Acronym/Agency:
1R01CA116784/CA/NCI NIH HHS; P20 RR020171-047711/RR/NCRR NIH HHS; P20 RR20171/RR/NCRR NIH HHS; R01 CA116784-02/CA/NCI NIH HHS; R01 CA116784-05/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Piperazines; 0/Pyrimidines; 152459-95-5/imatinib; 15663-27-1/Cisplatin; 51-21-8/Fluorouracil; 7689-03-4/Camptothecin
Comments/Corrections

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