Selective sensitization of retinoblastoma protein-deficient sarcoma cells to doxorubicin by flavopiridol-mediated inhibition of cyclin-dependent kinase 2 kinase activity Journal Article
| Authors: | Li, W.; Fan, J.; Bertino, J. R. |
| Article Title: | Selective sensitization of retinoblastoma protein-deficient sarcoma cells to doxorubicin by flavopiridol-mediated inhibition of cyclin-dependent kinase 2 kinase activity |
| Abstract: | We examined the effects of flavopiridol (FP), a cyclin-dependent kinase inhibitor, on doxorubicin (DOX)-induced cell killing in an osteosarcoma cell line (SaOs-2) that lacks functional retinoblastoma protein (pRb). The IC50 value for DOX was 7-fold lower when combined with a low dose (100 nM) FP in pRb-deficient SaOs-2 cells than in the absence of FP. In contrast, the IC50 value for DOX was not decreased in the presence of 100 nM FP in pRb-restored SaOs-2 cells. Consistent with this, FP enhanced DOX-induced activation of caspase-3, which correlates with apoptosis, in pRb-deficient cells but not in pRb-restored cells. Additional studies showed that FP decreased DOX-induced cell accumulation in S phase in retinoblastoma-restored cells but not in pRb-deficient cells. An increased expression of p21 and inhibition of cyclin-dependent kinase 2 kinase activity by FP was also observed in pRb-deficient cells but not in retinoblastoma-restored SaOs-2 cells. We conclude that pRb plays a key role in determining whether FP selectively sensitizes DOX-induced cell killing in human sarcoma cells. Because lack of functional pRb is a common abnormality in human cancers, the combination of FP with DOX in tumors lacking pRb would be worthy of further investigation. |
| Keywords: | osteosarcoma; controlled study; human cell; doxorubicin; antineoplastic agents; apoptosis; enzyme inhibition; gene expression; antineoplastic combined chemotherapy protocols; caspase 3; enzyme activation; tumor cells, cultured; enzyme activity; caspases; drug synergism; enzyme inhibitors; protein-serine-threonine kinases; flavonoids; flavopiridol; piperidines; protein deficiency; cyclin-dependent kinase inhibitor p21; antibiotics, antineoplastic; ic 50; cyclin-dependent kinases; cyclins; cyclin a; cyclin dependent kinase inhibitor; retinoblastoma protein; protein p21; s phase; cell killing; sensitization; g2 phase; enzyme induction; osteosarcoma cell; cyclin dependent kinase 2; cyclin-dependent kinase 2; sarcoma cell; correlation function; cdc2-cdc28 kinases; humans; human; priority journal; article |
| Journal Title: | Cancer Research |
| Volume: | 61 |
| Issue: | 6 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2001-03-15 |
| Start Page: | 2579 |
| End Page: | 2582 |
| Language: | English |
| PUBMED: | 11289134 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 21 May 2015 -- Source: Scopus |
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