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bFGF rescues imatinib/STI571-induced apoptosis of sis-NIH3T3 fibroblasts
Mitsuhiro Ohshima1, Yoko Yamaguchi, Kai Kappert
1Department of Biochemistry, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan. oshima-m@dent.nihon-u.ac.jp
Abstract:
PDGF-B-transfected, sis-NIH3T3 fibroblasts serve as a model system for examining the role of PDGF signaling in tumors. We have found that imatinib/STI571, a tyrosine kinase inhibitor targeting PDGF receptors, induces apoptosis of sis-NIH3T3 fibroblasts cultured under serum free conditions, which was rescued by the addition of 10% newborn calf serum (NCS). Therefore, growth factors included in serum were tested with regard to their ability to rescue imatinib-induced apoptosis. While PDGF-AB, EGF, and IGF-I failed to protect imatinib-induced sis-NIH3T3 cell apoptosis, bFGF rescued it. The effects of bFGF were confirmed by both cell viability assays and Bax/Bcl-2 gene expression ratio. An FGF receptor inhibitor, PD166866, invalidated the protective effect of bFGF. However, combination of imatinib and PD166866 failed to induce cell death of sis-NIH3T3 cells when cultured in 10% NCS. These results indicate that synergistic administration of some types of tyrosine kinase inhibitors need to be tested under in vivo-like conditions to establish novel strategies in anti-cancer therapy.
Insights
Imatinib-induced apoptosis in cancer cells was rescued by basic fibroblast growth factor (bFGF). Combination therapies targeting tyrosine kinases require in vivo-like conditions for effective anti-cancer strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- PDGF-B-transfected sis-NIH3T3 fibroblasts model PDGF signaling in tumors.
- Imatinib (STI571), a PDGF receptor tyrosine kinase inhibitor, induces apoptosis in these cells under serum-free conditions.
Purpose of the Study:
- To investigate growth factors that rescue imatinib-induced apoptosis.
- To explore the role of bFGF and its receptor in this rescue mechanism.
- To evaluate combination therapy strategies for anti-cancer treatment.
Main Methods:
- Utilized sis-NIH3T3 fibroblasts as a model system.
- Administered imatinib and various growth factors (PDGF-AB, EGF, IGF-I, bFGF).
- Assessed cell viability and Bax/Bcl-2 gene expression ratio.
- Employed an FGF receptor inhibitor (PD166866) to block bFGF signaling.
Main Results:
- Basic fibroblast growth factor (bFGF) rescued imatinib-induced apoptosis, unlike PDGF-AB, EGF, or IGF-I.
- bFGF's protective effect was confirmed by cell viability and Bax/Bcl-2 ratio.
- FGF receptor inhibition negated bFGF's protective effect.
- Combined imatinib and PD166866 did not induce cell death in serum-containing conditions.
Conclusions:
- bFGF plays a significant role in protecting cells from imatinib-induced apoptosis.
- Synergistic tyrosine kinase inhibitor therapies may require testing under conditions mimicking the in vivo environment.
- Novel anti-cancer therapeutic strategies necessitate careful consideration of cellular context and combination treatments.
