Antitumour effect of cyclin-dependent kinase inhibitors (p16(INK4A), p18(INK4C), p19(INK4D), p21(WAF1/CIP1) and p27(KIP1)) on malignant glioma cells - PubMed (original) (raw)
Antitumour effect of cyclin-dependent kinase inhibitors (p16(INK4A), p18(INK4C), p19(INK4D), p21(WAF1/CIP1) and p27(KIP1)) on malignant glioma cells
T Komata et al. Br J Cancer. 2003.
Abstract
Cyclin-dependent kinase inhibitors (CDKIs) are considered as novel anticancer agents because of their ability to induce growth arrest or apoptosis in tumour cells. It has not yet been fully determined, however, which CDKI is the best candidate for the treatment of malignant gliomas and whether normal brain tissues are affected by CDKI expression. Using recombinant adenoviral vectors that express CDKIs (p16(INK4A), p18(INK4C), p19(INK4D), p21(WAF1/CIP1) and p27(KIP1)), we compared the antitumour effect of CDKIs on malignant glioma cell lines (A172, GB-1, T98G, U87-MG, U251-MG and U373-MG). p27(KIP1) showed higher ability to suppress the growth of all tumour cells tested than other CDKIs. Interestingly, overexpression of p27(KIP1) induced autophagic cell death, but not apoptosis in tumour cells. On the other hand, p27(KIP1) overexpression did not inhibit the viability of cultured astrocytes (RNB) nor induced autophagy. Overall, our findings suggest that gene transfer of p27(KIP1) may be a promising approach for the therapy of malignant gliomas.
Figures
Figure 1
Effect of adenovirus expressing CDKIs on cell viability of malignant glioma cell lines. Tumour cells were seeded at 5 × 103 cells well−1 (0.1 ml) in 96-well flat-bottomed plates and incubated overnight at 37°C. On the following day, U373-MG, U251-MG, U87-MG cells, A172 cells, GB-1 and T98G cells were infected with AdBHGΔl,3, AdMH4pl6, AdMH4pl8, AdMH4pl9, AdMH4p21 or AdMH4p27 as indicated (day 0). On day 3, the cell viability was determined using a trypan blue dye exclusion assay. Values are given as the percentage of viable cells of AdBHGΔl ,3-infected cultures. Results shown are the means±s.d. of three independent experiments. U373-MG, U251-MG, U87-MG, A172 and GB-1 cells were infected at 60 MOI, while 180 MOI was used for T98G cells.
Figure 2
Effect of AdMH4p27 on RNB cells. U373-MG or RNB cells were seeded at 5 × 103 cells well−1 (0.1 ml) in 96-well flat-bottomed plates and incubated overnight at 37°C. On the following day, cells were infected with AdBHGΔl,3 or AdMH4p27 at 60 MOI. On day 3, the cell viability was determined using a trypan blue dye exclusion assay. Values are given as the percentage of viable cells of AdBHGΔl,3-infected cultures. Results shown are the means±s.d. of three independent experiments.
Figure 3
Effect of AdMH4p27 on induction of autophagy. At 72 h after the adenoviral infection with AdBHGΔl,3 or AdMH4p27, U373-MG or RNB cells were treated with 1 _μ_g ml−1 of acridine orange, and incubated at 37°C for 15 min. Viable cells were observed under the fluorescence microscope. Results shown are representative of three independent experiments.
References
- Alleyne Jr CH, He J, Yang J, Hunter SB, Cotsonis G, James CD, Olson JJ (1999) Analysis of cyclin dependent kinase inhibitors in malignant astrocytomas. Int J Oncol 14: 1111–1116 - PubMed
- Bursch W, Ellinger A, Gemer C, Frohwein U, Schulte-Hermann R (2000) Programmed cell death (PCD). Apoptosis, autophagic PCD, or others? Ann NY Acad Sci 926: 1–12 - PubMed
- Craig C, Wersto R, Kim M, Ohri E, Li Z, Katayose D, Lee SJ, Trepel J, Cowan K, Seth P (1997) A recombinant adenovirus expressing p27Kip1 induces cell cycle arrest and loss of cyclin-Cdk activity in human breast cancer cells. Oncogene 14: 2283–2289 - PubMed
- Esposito V, Baldi A, De Luca A, Groger AM, Loda M, Giordano GG, Caputi M, Baldi F, Pagano M, Giordano A (1997) Prognostic role of the cyclin-dependent kinase inhibitor p27 in non-small cell lung cancer. Cancer Res 57: 3381–3385 - PubMed
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