Abstract
One mechanism by which chemotherapeutic agents kill tumor cells is by induction of apoptosis. Basic fibroblast growth factor (bFGF/FGF-2) has been reported to inhibit apoptosis in NIH 3T3 cells treated with chemotherapy drugs. We have investigated how bFGF modulates apoptosis induced by cisplatin in NIH 3T3 cells. Treatment with 10 μg/ml cisplatin for 12 h induced apoptosis in 2 to 13% of the cells at 24 h post-treatment. Preincubation with 10 ng/ml bFGF for 24 h led to cisplatin-induced apoptosis in 20% to 50% of the cells. Preincubation with lower concentrations of bFGF (0.1–1 ng/ml) or simultaneous addition of bFGF and cisplatin had no effect on the amount of apoptosis. Pretreatment with bFGF also significantly decreased the dose-dependent survival of NIH 3T3 cells exposed to cisplatin, as determined by colony formation. Cells treated with 10 ng/ml bFGF showed a distinct morphology, appearing smaller and more refractile, before cisplatin exposure. The enhancement of cisplatin-induced apoptosis and the morphology shift demonstrated the same dose response to bFGF, and both effects were reversible if bFGF was removed from the medium for 24 h before cisplatin treatment. Mitogenic response to bFGF by NIH 3T3 cells saturated at 0.5 ng/ml, as measured by3H-thymidine uptake, and this response was blocked by coaddition of suramin, an inhibitor of FGF ligand-receptor interactions. Suramin did not reverse the enhancement of cisplatin-induced apoptosis by bFGF. Therefore, bFGF sensitized NIH 3T3 cells to cisplatin, and this effect might be mediated through a pathway separate from that used for mitogenic signaling.
Footnotes
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Send reprint requests to: Susan E. Kane, Department of Cell and Tumor Biology, City of Hope National Medical Center, 1500 E. Duarte Rd., Duarte, CA 91010. E-mail: skane{at}coh.org
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↵1 Current address: Department of Chemistry and Biochemistry, California State University, Los Angeles.
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This work was supported by grants to S.E.K. from the National Cancer Institute (CA64645 and CA71866). This work was presented previously as an abstract at the American Association of Cancer Research 90th annual meeting (April, 1999) and the AACR special conference, Molecular Determinants of Sensitivity to Antitumor Agents (March, 1999).
- Abbreviations:
- bFGF
- basic fibroblast growth factor
- TUNEL
- terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling
- PI
- propidium iodide
- HSPG
- heparan sulfate proteoglycan
- Received July 16, 1999.
- Accepted October 18, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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