A study of cytotoxic synergy of UCN-01 and flavopiridol in syngeneic pair of cell lines

Kongming Wu, Mark D'Amico, Chenguang Wang, Chris Albanese, Richard G. Pestell, Sridhar Mani

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Flavopiridol and UCN-01 are two novel protein kinase inhibitors with diverse cellular effects that may complement each other with regards to induction of apoptosis. HeLa cells engineered to overexpress human survivin (HeLa-S) were at least ∼4.8-fold resistant to UCN-01 relative to proliferation observed in control HeLa cells (HeLa-V). Flavopiridol cytotoxicity as measured using the MTT assay was unaffected in HeLa-S cells when compared with HeLa-V cells. Similarly, simultaneous treatment of HeLa-V cells with flavopiridol and UCN-01 for 72 hours did not result in synergistic inhibition of proliferation; however, in HeLa-S cells, this combination resulted in synergistic inhibition of cell proliferation. Flavopiridol and UCN-01 augmented apoptosis in HeLa-S cells (as compared with HeLa-V cells) as measured by caspase-3 cellular activity assay, DNA fragmentation and PARP cleavage by western blot. In HeLa-V and -S cells, combination treatment resulted in caspase-8 cleavage. Caspase-9 was expressed in HeLa-V cells; however, there was a marked reduction of caspase-9 content in HeLa-S cells only. Combination treatment resulted in a significant reduction in survivin abundance in HeLa-S and SKBR3-UR cells, but not in their respective parental lines. The synergy of Flavopiridol and UCN-01 are selectively toxic to survivin-overexpressing cell lines and the mechanism of toxicity involves caspase-dependent cell death.

Original languageEnglish (US)
Pages (from-to)299-309
Number of pages11
JournalInvestigational New Drugs
Volume23
Issue number4
DOIs
Publication statusPublished - Aug 1 2005

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Keywords

  • Caspases
  • Flavopiridol
  • HeLa cells
  • IAP
  • Survivin
  • UCN-01

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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