Abstract | PURPOSE: EXPERIMENTAL DESIGN: Cell growth in the presence of various combinations of NVP-ADW742, imatinib ( STI571; Gleevec/ Glivec), and chemotherapeutic agents was monitored using a 3-(4,5 dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay and analyzed using the Chou-Talalay multiple- drug-effect equation. Induction of apoptosis was assessed using terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) and Western blot analysis of procaspase 3 and poly(ADP-ribose)polymerase cleavage. IGF-I-induced vascular endothelial cell growth factor expression was monitored by Northern blot and ELISA. RESULTS:
NVP-ADW742 synergistically enhanced sensitivity of multiple SCLC cell lines to etoposide and carboplatin. Maximal enhancement occurred at concentrations of NVP-ADW742 that eliminated basal PI3K-Akt activity in individual cell lines. In the WBA cell line, in which the c-Kit receptor tyrosine kinase is partly responsible for basal PI3K-Akt activity, the combination of NVP-ADW742 and imatinib was superior to NVP-ADW742 alone in sensitizing the cells to etoposide. Enhancement of the sensitivity of SCLC cell lines to etoposide, as determined by MTT assay, correlated closely with sensitization to the induction of apoptosis as measured by TUNEL and caspase activation assays. Treatment with NVP-ADW742 also eliminated IGF-I-mediated expression of vascular endothelial cell growth factor, suggesting that in addition to enhancing sensitivity of SCLC to chemotherapy, this kinase inhibitor could potentially inhibit angiogenesis in vivo. CONCLUSIONS: Inhibition of IGF-IR signaling synergistically enhances the sensitivity of SCLC to etoposide and carboplatin. This enhancement in sensitivity to chemotherapy tightly correlates with inhibition of PI3K-Akt activation. Future SCLC clinical trials incorporating IGF-IR inhibitors alone or in combination with other kinase inhibitors should include assessment of PI3K-Akt activity as a pharmacodynamic end-point.
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Authors | G Sakuntala Warshamana-Greene, Julie Litz, Elisabeth Buchdunger, Carlos García-Echeverría, Francesco Hofmann, Geoffrey W Krystal |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 11
Issue 4
Pg. 1563-71
(Feb 15 2005)
ISSN: 1078-0432 [Print] United States |
PMID | 15746061
(Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- Antineoplastic Agents
- Protein Kinase Inhibitors
- Proto-Oncogene Proteins
- Pyrimidines
- Pyrroles
- RNA, Messenger
- Vascular Endothelial Growth Factor A
- Insulin-Like Growth Factor I
- Etoposide
- Carboplatin
- Receptor, IGF Type 1
- AKT1 protein, human
- Protein Serine-Threonine Kinases
- Proto-Oncogene Proteins c-akt
- NVP ADW742
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Topics |
- Antineoplastic Agents
(pharmacology)
- Apoptosis
(drug effects)
- Carboplatin
(pharmacology)
- Carcinoma, Small Cell
(drug therapy, pathology)
- Cell Division
(drug effects)
- Cell Line, Tumor
- Cell Survival
(drug effects)
- Dose-Response Relationship, Drug
- Drug Synergism
- Enzyme-Linked Immunosorbent Assay
- Etoposide
(pharmacology)
- Gene Expression Regulation, Neoplastic
(drug effects)
- Humans
- In Situ Nick-End Labeling
- Insulin-Like Growth Factor I
(pharmacology)
- Lung Neoplasms
(drug therapy, metabolism, pathology)
- Protein Kinase Inhibitors
(pharmacology)
- Protein Serine-Threonine Kinases
(metabolism)
- Proto-Oncogene Proteins
(metabolism)
- Proto-Oncogene Proteins c-akt
- Pyrimidines
(pharmacology)
- Pyrroles
(pharmacology)
- RNA, Messenger
(genetics, metabolism)
- Receptor, IGF Type 1
(antagonists & inhibitors, metabolism)
- Vascular Endothelial Growth Factor A
(genetics, metabolism)
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