Document Detail

Low-dose BBR3610 toxicity in colon cancer cells is p53-independent and enhanced by inhibition of epidermal growth factor receptor (ERBB1)-phosphatidyl inositol 3 kinase signaling.
MedLine Citation:
PMID:  17578896     Owner:  NLM     Status:  MEDLINE    
We have examined the mechanisms by which the multinuclear platinum chemotherapeutic BBR3610 kills human colon cancer cells. BBR3610 more efficiently killed HCT116, DLD1, SW480, and HT29 cells than BBR3464, cisplatin, or oxaliplatin. The amount of platinum uptake per cell and its incorporation into DNA were identical for BBR3464 and BBR3610. BBR3610 lethality (IC(75)) was unaltered comparing HCT116 wild-type and p53-/- cells, was reduced in p21-/- cells, and was enhanced in K-RAS D13 null cells. Small molecule or molecular inhibition of epidermal growth factor receptor (ERBB1) or phosphatidyl inositol 3 kinase (PI3K) enhanced BBR3610 toxicity in HCT116, DLD1, and SW480 cells. Small molecule or molecular inhibition of caspase 8 function abolished the toxicity of BBR3610 and of BBR3610 + ERBB1 inhibitor treatments, whereas inhibition of caspase 9 suppressed the ability of ERBB1 inhibitors to enhance BBR3610 lethality. Treatment with BBR3610 reduced AKT activity; the expression of dominant-negative AKT enhanced and expression of constitutively active AKT suppressed, respectively, the toxicity of BBR3610 and of BBR3610 + ERBB1 inhibitor treatments. Treatment with BBR3610 reduced expression of c-FLIP-s and MCL-1, levels that were maintained in cells expressing constitutively active AKT. Overexpression of c-FLIP-s or loss of BID function suppressed BBR3610 toxicity, whereas overexpression of XIAP or Bcl-xL suppressed the potentiation of cell killing by ERBB1 inhibitors. Collectively, our data argue that BBR3610 promotes cell killing via a caspase 8-dependent mechanism, which can be enhanced by ERBB1/PI3K inhibitors that promote additional BBR3610-dependent cell killing via activation of BAX and caspase 9.
Clint Mitchell; Peyman Kabolizadeh; John Ryan; John D Roberts; Adly Yacoub; David T Curiel; Paul B Fisher; Michael P Hagan; Nicholas P Farrell; Steven Grant; Paul Dent
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2007-06-19
Journal Detail:
Title:  Molecular pharmacology     Volume:  72     ISSN:  0026-895X     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2007 Sep 
Date Detail:
Created Date:  2007-08-24     Completed Date:  2007-10-19     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  704-14     Citation Subset:  IM    
Department of Biochemistry, Virginia Commonwealth University, Richmond, VA 23298-0035, USA.
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MeSH Terms
1-Phosphatidylinositol 3-Kinase / metabolism*
Antineoplastic Agents / chemistry,  toxicity*
Cell Survival / drug effects
Dose-Response Relationship, Drug
HCT116 Cells
Molecular Structure
Organoplatinum Compounds / chemistry,  toxicity*
Receptor, Epidermal Growth Factor / antagonists & inhibitors*
Signal Transduction*
Tumor Suppressor Protein p53 / metabolism*
Grant Support
Reg. No./Substance:
0/Antineoplastic Agents; 0/BBR3610; 0/Organoplatinum Compounds; 0/Tumor Suppressor Protein p53; EC 3-Kinase; EC, Epidermal Growth Factor

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