Flavopiridol, a cyclin-dependent kinase inhibitor, prevents spindle inhibitor-induced endoreduplication in human cancer cells Journal Article
| Authors: | Motwani, M.; Li, X. K.; Schwartz, G. K. |
| Article Title: | Flavopiridol, a cyclin-dependent kinase inhibitor, prevents spindle inhibitor-induced endoreduplication in human cancer cells |
| Abstract: | Defects in cell cycle checkpoints can lead to chromosome abnormality, aneuploidy, and genomic instability, all of which can contribute to tumorigenesis. Recent studies and data presented in this study indicate that cells with compromised G1 checkpoint endoreduplicate and become polyploid in response to microtubule inhibitors. Previous studies have shown that polyploid cells are unstable and lose chromosomes randomly to give aneuploidy. In this study, we show that endoreduplication and polyploidation can be prevented by inhibiting the cyclin-dependent kinases (Cdks) by flavopiridol, a synthetic flavone presently undergoing phase II clinical trials. In our initial studies, we treated MCF-7 cells with paclitaxel, which results in the arrest of cells in G1 with 4n DNA content (pseudo G1). This was coincident with increased p53 and p21 protein expression and decreased cyclin E/Cdk2 kinase activity. In contrast, G1 checkpoint-compromised MDA- MB-468 (p53-/- and pRb-/-) and p21-/- HCT116 do not arrest in the pseudo G1 state after exposure to microtubule inhibitors and enter in the S phase with 4n DNA content. More than 60% of MDA-MB-468 cells accumulate with >4n DNA content after 72 h of nocodazole treatment. The MPM-2 labeling showed that 8n cells also undergo mitosis. These cells display deregulated and persistent activation of cyclin E/Cdk2 and cyclin B1/cdc2 kinase activity. Administration of flavopiridol after mitotic block results in the arrest of cells in the pseudo G1 state and the dramatic decrease in cells containing >4n DNA content in MDA-MB-468 cells. The cyclin E/Cdk2 and cyclin B1/cdc2 kinase activities remained low after exit from mitosis. Furthermore, pRb was hypophosphorylated after the addition of flavopiridol in p21-deficient HCT116 cells, indicating the arrest of cells at the pseudo G1 state. Based on these studies, we propose that flavopiridol preserves the genomic stability by preventing endoreduplication and polyploidy and thus has the potential to be used as a chemopreventive agent to prevent the occurrence of neoplasia. |
| Keywords: | human cell; antineoplastic agents; paclitaxel; dna replication; cell cycle s phase; cell division; chemoprophylaxis; gene expression; tumor cells, cultured; phosphorylation; protein p53; carcinogenesis; gene activation; enzyme inhibitors; protein-serine-threonine kinases; cancer cell; mitosis spindle; flavonoids; flavopiridol; piperidines; cyclin b1; cyclin-dependent kinases; cyclin b; cyclin dependent kinase inhibitor; retinoblastoma protein; microtubules; protein p21; cell cycle g1 phase; g1 phase; polyploidy; cyclin e; nocodazole; gene activity; cyclin dependent kinase 2; cyclin-dependent kinase 2; mitosis inhibition; cdc2 protein kinase; cdc2-cdc28 kinases; humans; human; priority journal; article |
| Journal Title: | Clinical Cancer Research |
| Volume: | 6 |
| Issue: | 3 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2000-03-01 |
| Start Page: | 924 |
| End Page: | 932 |
| Language: | English |
| PUBMED: | 10741717 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 18 November 2015 -- Source: Scopus |
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