Purvalanol A enhances cell killing by inhibiting up-regulation of CDC2 kinase activity in tumor cells irradiated with high doses of X rays.

Abstract

To clarify the relationship between CDC2 kinase activity and radiation-induced apoptosis, we examined whether the cyclin-dependent kinase (CDK) inhibitor purvalanol A enhanced radiation-induced apoptosis in gastric tumor cells. MKN45 cells exposed to 20 Gy of X rays increased the CDC2 kinase activity and the expression of regulatory proteins (phospho-CDC2 and cyclin B1) of the G2/M phase, followed by activation of the G2/M checkpoint, whereas the treatment of X-irradiated MKN45 cells with 20 microM purvalanol A suppressed the increase in the CDC2 kinase activity and expression of the G2/M-phase regulatory proteins and reduced the fraction of the cells in the G2/M phase in the cell cycle. Furthermore, this treatment resulted in not only a significant increase in radiation-induced apoptosis but also the loss of clonogenicity in both MKN45 (p53-wild) and MKN28 (p53-mutated) cells. The expression of anti-apoptosis proteins, inhibitor of apoptosis protein (IAP) family members (survivin and XIAP) and BCL2 family members (Bcl-X(L) and Bcl-2), in purvalanol A-treated cells with and without X rays was significantly lower than for cells exposed to X rays alone. These results suggest that the inhibition of radiation-induced CDC2 kinase activity by purvalanol A induces apoptosis through the enhancement of active fragments of caspase 3.

• Authors: Daisuke Iizuka, Osamu Inanami, Ikuo Kashiwakura, Mikinori Kuwabara
• Journal: Radiation research (Radiat Res) Vol. 167 Issue 5 Pg. 563-71 (May 2007) ISSN: 0033-7587 [Print] United States
• PMID: 17474786 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 6-((3-chloro)anilino)-2-(isopropyl-2-hydroxyethylamino)-9-isopropylpurine
• Cell Cycle Proteins
• Purines
• CDC2 Protein Kinase

Topics

• Apoptosis (drug effects, radiation effects)
• CDC2 Protein Kinase (metabolism)
• Cell Cycle Proteins (metabolism)
• Cell Division (drug effects, radiation effects)
• Cell Line
• G2 Phase (drug effects, radiation effects)
• Humans
• Neoplasms (enzymology, pathology)
• Purines (pharmacology)
• Up-Regulation (drug effects, radiation effects)
• X-Rays